Summary: Cannabidiol, or CBD, blocks the ability of lysophosphatidylinositol (LPI) to amplify neural signals in the hippocampus. LPI weakens the signals that counter seizures, further explaining the value of CBD to treat epilepsy.
Source: NYU
A study reveals a previously unknown way in which cannabidiol (CBD), a substance found in cannabis, reduces seizures in many treatment-resistant forms of pediatric epilepsy.
Led by researchers at NYU Grossman School of Medicine, the new study found that CBD blocked signals carried by a molecule called lysophosphatidylinositol (LPI). Found in brain cells called neurons, LPI is thought to amplify nerve signals as part of normal function, but can be hijacked by disease to promote seizures.
Published online February 13 in Neuron, the work confirmed a previous finding that CBD blocks the ability of LPI to amplify nerve signals in a brain region called the hippocampus. The current findings argue for the first time that LPI also weakens signals that counter seizures, further explaining the value of CBD treatment.
“Our results deepen the field’s understanding of a central seizure-inducing mechanism, with many implications for the pursuit of new treatment approaches,” said corresponding author Richard W. Tsien, chair of the Department of Physiology and Neuroscience at NYU Langone Health.
“The study also clarified, not just how CBD counters seizures, but more broadly how circuits are balanced in the brain,” added Tsien. “Related imbalances are present in autism and schizophrenia, so the paper may have a broader impact.”
Disease-causing loop
The study results build on how each neuron “fires” to send an electrical pulse down an extension of itself until it reaches a synapse, the gap that connects it to the next cell in a neuronal pathway. When it reaches the cell’s end before the synapse, the pulse triggers the release of compounds called neurotransmitters that float across the gap to affect the next cell in line.
Upon crossing, such signals either encourage the cell to fire (excitation), or apply the brakes on firing (inhibition). Balance between the two are essential to brain function; too much excitation promotes seizures.
The new study looked at several rodent models to explore mechanisms behind seizures, often by measuring information-carrying electrical current flows with fine-tipped electrodes. Other experiments looked at the effect of LPI by genetically removing its main signaling partner, or by measuring the release of LPI following seizures.
The tests confirmed past findings that LPI influences nerve signals by binding to a protein called G-coupled receptor 55 (GPR55), on neuron cell surfaces. This LPI-GPR55 presynaptic interaction was found to cause the release of calcium ions within the cell, which encouraged cells to release glutamate, the main excitatory neurotransmitter.
Further, when LPI activated GPR55 on the other side of the synapse, it weakened inhibition, by decreasing the supply and proper arrangement of proteins necessary for inhibition. Collectively, this creates a “dangerous” two-pronged mechanism to increase excitability, say the authors.
The research team found that either genetically engineering mice to lack GPR55, or treating mice with plant-derived CBD prior to seizure-inducing stimuli, blocked LPI-mediated effects on both excitatory and inhibitory synaptic transmission. While prior studies had implicated GPR55 as a seizure-reducing target of CBD, the current work provided a more detailed, proposed mechanism of action.
The authors propose that CBD blocks a “positive feedback loop” in which seizures increase LPI-GPR55 signaling, which likely encourages more seizures, which in turn increases levels of both LPI and GPR55. The proposed vicious cycle provides one process that could explain repeated epileptic seizures, although future studies are needed to confirm this.
Further, the current study examined the plant-based cannabinoid CBD, but the authors note that LPI is part of signaling network that includes “endocannabinoids” like 2-Arachidonoylglycerol (2-AG) that occur naturally in human tissues. LPI and 2-AG target receptors also regulated by CBD, but have different actions at the synapse.
While LPI amplifies incoming electrical signals, endocannabinoids like 2-AG respond to increases in brain activity by dialing down the release of neurotransmitters from nerve cells. Interestingly, LPI and 2-AG can be converted into each other through actions of enzymes.
“Theoretically, the brain could control activity by toggling between pro-excitatory LPI and the restorative actions of 2-AG,” said first study author Evan Rosenberg, Ph.D., a post-doctoral scholar in the Tsein’s lab.
“Drug designers could inhibit the enzymes that underpin LPI production or promote its conversion to 2-AG, as an additional approach to control seizures. LPI could also serve as a biomarker of seizures or predictor of clinical responsiveness to CBD, providing an area of future research.”
About this neuropharmacology and epilepsy research news
Author: Press Office
Source: NYU
Contact: Press Office – NYU
Image: The image is credited to Tsien et al, Cell Press
Original Research: Open access.
“Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity” by Richard Tsien et al. Neuron
Abstract
Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity
Highlights
- LPI, a GPR55 ligand, regulates the hippocampal E:I ratio
- LPI weakens postsynaptic inhibition through dispersal of γ2 and gephyrin clusters
- Acute seizures upregulate GPR55 and LPI, producing a pernicious positive feedback loop
- CBD dampens elevation of E-I ratio and excitability, thus opposing recurrent seizures
Summary
Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsies, but the mechanism(s) of anti-seizure action remain unclear.
In one leading model, CBD acts at glutamatergic axon terminals, blocking the pro-excitatory actions of an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), at the G-protein-coupled receptor GPR55. However, the impact of LPI-GPR55 signaling at inhibitory synapses and in epileptogenesis remains underexplored.
We found that LPI transiently increased hippocampal CA3-CA1 excitatory presynaptic release probability and evoked synaptic strength in WT mice, while attenuating inhibitory postsynaptic strength by decreasing GABAARγ2 and gephyrin puncta. LPI effects at excitatory and inhibitory synapses were eliminated by CBD pre-treatment and absent after GPR55 deletion.
Acute pentylenetrazole-induced seizures elevated GPR55 and LPI levels, and chronic lithium-pilocarpine-induced epileptogenesis potentiated LPI’s pro-excitatory effects.
We propose that CBD exerts potential anti-seizure effects by blocking LPI’s synaptic effects and dampening hyperexcitability.
A study reveals a previously unknown way in which cannabidiol (CBD), a substance found in cannabis, reduces seizures in many treatment-resistant forms of pediatric epilepsy.
Led by researchers at NYU Grossman School of Medicine, the new study found that CBD blocked signals carried by a molecule called lysophosphatidylinositol (LPI). Found in brain cells called neurons, LPI is thought to amplify nerve signals as part of normal function, but can be hijacked by disease to promote seizures.
Published online February 13 in Neuron, the work confirmed a previous finding that CBD blocks the ability of LPI to amplify nerve signals in a brain region called the hippocampus. The current findings argue for the first time that LPI also weakens signals that counter seizures, further explaining the value of CBD treatment.
Our results deepen the field's understanding of a central seizure-inducing mechanism, with many implications for the pursuit of new treatment approaches."
Richard W. Tsien, PhD, corresponding author, chair of the Department of Physiology and Neuroscience at NYU Langone Health
"The study also clarified, not just how CBD counters seizures, but more broadly how circuits are balanced in the brain," adds Dr. Tsien, also director of NYU Langone's Neuroscience Institute. "Related imbalances are present in autism and schizophrenia, so the paper may have a broader impact."
The study results build on how each neuron "fires" to send an electrical pulse down an extension of itself until it reaches a synapse, the gap that connects it to the next cell in a neuronal pathway. When it reaches the cell's end before the synapse, the pulse triggers the release of compounds called neurotransmitters that float across the gap to affect the next cell in line. Upon crossing, such signals either encourage the cell to fire (excitation), or apply the brakes on firing (inhibition). Balance between the two is essential to brain function; too much excitation promotes seizures.
The new study looked at several rodent models to explore mechanisms behind seizures, often by measuring information-carrying electrical current flows with fine-tipped electrodes. Other experiments looked at the effect of LPI by genetically removing its main signaling partner, or by measuring the release of LPI following seizures.
The tests confirmed past findings that LPI influences nerve signals by binding to a protein called G-coupled receptor 55 (GPR55) on neuron cell surfaces. This LPI-GPR55 presynaptic interaction was found to cause the release of calcium ions within the cell, which encouraged cells to release glutamate, the main excitatory neurotransmitter.
Further, when LPI activated GPR55 on the other side of the synapse, it weakened inhibition, by decreasing the supply and proper arrangement of proteins necessary for inhibition. Collectively, this creates a "dangerous" two-pronged mechanism to increase excitability, say the authors.
The research team found that either genetically engineering mice to lack GPR55, or treating mice with plant-derived CBD before seizure-inducing stimuli, blocked LPI-mediated effects on both excitatory and inhibitory synaptic transmission. While prior studies had implicated GPR55 as a seizure-reducing target of CBD, the current work provided a more detailed, proposed mechanism of action.
The authors propose that CBD blocks a "positive feedback loop" in which seizures increase LPI-GPR55 signaling, which likely encourages more seizures, which in turn increases levels of both LPI and GPR55. The proposed vicious cycle provides one process that could explain repeated epileptic seizures, although future studies are needed to confirm this.
Further, the current study examined the plant-based cannabinoid CBD, but the authors note that LPI is part of signaling network that includes "endocannabinoids" like 2-Arachidonoylglycerol (2-AG) that occur naturally in human tissues. LPI and 2-AG target receptors also regulated by CBD, but have different actions at the synapse. While LPI amplifies incoming electrical signals, endocannabinoids like 2-AG respond to increases in brain activity by dialing down the release of neurotransmitters from nerve cells. Interestingly, LPI and 2-AG can be converted into each other through actions of enzymes.
"Theoretically, the brain could control activity by toggling between pro-excitatory LPI and the restorative actions of 2-AG," says first study author Evan Rosenberg, PhD, a postdoctoral scholar in the Tsien lab. "Drug designers could inhibit the enzymes that underpin LPI production or promote its conversion to 2-AG, as an additional approach to control seizures. LPI could also serve as a biomarker of seizures or predictor of clinical responsiveness to CBD, providing an area of future research."
Along with Dr. Tsien and Dr. Rosenberg, study authors in the Department of Neuroscience and Physiology and Neuroscience Institute at NYU Langone were Simon Chamberland, Erica Nebet, Xiaohan Wang, Sam McKenzie, Alejandro Salah, Nicolas Chenouard, Simon Sun, and György Buzsáki, MD, PhD. NYU Langone authors also were Orrin Devinsky, MD, in the Department of Neurology, Rebecca Rose in the Division of Advanced Research Technologies, and Drew R. Jones, PhD, in the Department of Biochemistry and Molecular Pharmacology.
Source:
Journal reference:
Rosenberg, E.C., et al. (2023) Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity. Neuron. doi.org/10.1016/j.neuron.2023.01.018.
A study by researchers in the U.S. and U.K. has revealed a previously unknown mechanism by which cannabidiol (CBD)—a non-psychoactive component of cannabis—reduces seizures in many treatment-resistant forms of pediatric epilepsy. Led by researchers at NYU Grossman School of Medicine, the new study, in rodent models, found that CBD blocked signals carried by a molecule called lysophosphatidylinositol (LPI) in neurons. LPI is thought to amplify nerve signals as part of normal function, but can be hijacked by disease to promote seizures.
The new research confirmed a previous finding that CBD blocks the ability of LPI to amplify nerve signals in the brain’s hippocampus, and argues for the first time that LPI also weakens signals that counter seizures, further explaining the value of CBD treatment.
“Our results deepen the field’s understanding of a central seizure-inducing mechanism, with many implications for the pursuit of new treatment approaches,” said corresponding author Richard W. Tsien, PhD, chair of the Department of Physiology and Neuroscience at NYU Langone Health. “The study also clarified, not just how CBD counters seizures, but more broadly how circuits are balanced in the brain. Related imbalances are present in autism and schizophrenia, so the paper may have a broader impact.”
Tsein, together with colleagues at NYU Langone, and collaborators in the U.S. and U.K., reported on their work in Neuron, in a paper titled “Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity.”
When a neuron “fires” it sends an electrical pulse down an extension of itself until it reaches a synapse, the gap that connects one neuron to the next cell in a neuronal pathway. When the electrical impulse reaches the cell’s end before the synapse, it triggers the release of neurotransmitters that are travel across the gap to reach the next cell. Upon crossing this synapse, such signals either encourage the next cell to fire (excitation), or apply the brakes on firing (inhibition). Balance between the two are essential to brain function; too much excitation promotes seizures, and an imbalance between inhibition and excitation is also implicated in other disorders. “Neuronal circuits require coordination between synaptic excitation (E) and inhibition (I) for proper function,” the authors wrote, ”and disruptions in the excitatory-to-inhibitory (E:I) ratio contribute to epilepsy, autism spectrum disorders, and schizophrenia.”
But while cannabidiol has been shown to reduce seizures in multiple forms of pediatric epilepsies, the mechanism(s) of anti-seizure action remain unclear. “In preclinical models, CBD reduces spontaneous recurrent seizures and regulates the E:I ratio in acute seizures; however, the molecular signaling underlying CBD’s anti-seizure actions remains poorly defined.”
Possible therapeutic targets of CBD encompass ion channels, transporters, and transmembrane signaling proteins, the team noted. Among the proposed candidates are two GPCRs: the cannabinoid receptor CB1R and the receptor GPR55. “In one model, CBD acts at glutamatergic axon terminals, blocking the pro-excitatory actions of the endogenous membrane phospholipid lysophosphatidylinositol, at the G-protein-coupled receptor GPR55 … However, the impact of LPI-GPR55 signaling at inhibitory synapses and in epileptogenesis remains underexplored.”
For their new study, the team looked at several rodent models to explore mechanisms behind seizures. “… we focused on the LPI-GPR55 signaling pathway as a potential modulator of E:I ratio and anti-seizure target of CBD.
To do this they used a variety of techniques that included measuring information-carrying electrical current flows with fine-tipped electrodes, or by investigating the effect of LPI by genetically removing its main signaling partner, or by measuring the release of LPI following seizures. Their collective results confirmed past findings that LPI influences nerve signals by binding to GPR55, on neuron cell surfaces. This LPI-GPR55 presynaptic interaction was found to cause the release of calcium ions within the cell, which encouraged cells to release glutamate, the main excitatory neurotransmitter.
Further, when LPI activated GPR55 on the other side of the synapse, it weakened inhibition, by decreasing the supply and proper arrangement of proteins necessary for inhibition. Collectively, this creates a “dangerous” two-pronged mechanism to increase excitability, say the authors. “We found that LPI triggers aGPR55-dependent dual mechanism to elevate network excitability: a transient elevation in presynaptic excitatory release probability, complemented by a slower sustained reduction of inhibitory synaptic strength,” the investigators stated.
The research team found that LPI-mediated effects on both excitatory and inhibitory synaptic transmission could be blocked either by genetically engineering mice to lack GPR55, or by treating mice with plant-derived CBD prior to seizure-inducing stimuli. While prior studies had implicated GPR55 as a seizure-reducing target of CBD, the current work provided a more detailed, proposed mechanism of action.
The authors propose that CBD blocks a positive feedback loop in which seizures increase LPI-GPR55 signaling, which likely encourages more seizures, which in turn increases levels of both LPI and GPR55. “Our observations suggest a positive feedback loop whereby LPI promotes hyperexcitability, which in turn increases the expression of LPI and GPR55,” they further explained. “We tentatively propose that CBD can extinguish a potentially regenerative loop in which hyperactivity enhances LPI-GPR55 signaling, further shifting the E:I ratio … Our experiments provide new insights on synaptic mechanisms of CBD’s anti-seizure effects.”
The team concluded that CBD could represent a potential therapeutic agent in treatment-resistant epilepsy patients who don’t respond to current drugs, such as benzodiazepines, possibly due to LPI-GPR55 effects.
The proposed vicious cycle also represents one process that could explain repeated epileptic seizures, although future studies are needed to confirm this. Further, the current study examined the plant-based cannabinoid CBD, but the authors note that LPI is part of signaling network that includes endocannabinoids such as 2-Arachidonoylglycerol (2-AG) that occur naturally in human tissues. LPI and 2-AG target receptors also regulated by CBD, but have different actions at the synapse. While LPI amplifies incoming electrical signals, endocannabinoids such as 2-AG respond to increases in brain activity by dialing down the release of neurotransmitters from nerve cells. Interestingly, LPI and 2-AG can be converted into each other through actions of enzymes.
“Theoretically, the brain could control activity by toggling between pro-excitatory LPI and the restorative actions of 2-AG,” said first study author Evan Rosenberg, PhD, a postdoctoral scholar in the Tsein’s lab. “Drug designers could inhibit the enzymes that underpin LPI production or promote its conversion to 2-AG, as an additional approach to control seizures. LPI could also serve as a biomarker of seizures or predictor of clinical responsiveness to CBD, providing an area of future research.”
This microscope image of the brain region called the hippocampus shows the protein targeted by cannabis-derived CBD, GPR55 (red), and brain cells (blue) that send their extensions out to form the layers seen in the image. The interconnected nature of the hippocampus makes it a major site of for the initiation and spread of seizures. Credit: Tsien et al, Courtesy of Cell Press
Study findings suggest specific targets for future drugs.
A previously unknown way in which cannabidiol (CBD), a substance found in cannabis, reduces seizures in many treatment-resistant forms of pediatric epilepsy has been revealed by a new scientific study.
Led by researchers at NYU Grossman School of Medicine, the study found that CBD blocked signals carried by a molecule called lysophosphatidylinositol (LPI). Found in brain cells called neurons, LPI is thought to amplify nerve signals as part of normal function, but can be hijacked by disease to promote seizures.
Published online on February 13 in the journal Neuron, the work confirmed a previous finding that CBD blocks the ability of LPI to amplify nerve signals in a brain region called the hippocampus. The current findings argue for the first time that LPI also weakens signals that counter seizures, further explaining the value of CBD treatment.
“Our results deepen the field’s understanding of a central seizure-inducing mechanism, with many implications for the pursuit of new treatment approaches,” said corresponding author Richard W. Tsien, chair of the Department of Physiology and Neuroscience at NYU Langone Health.
“The study also clarified, not just how CBD counters seizures, but more broadly how circuits are balanced in the brain,” added Tsien. “Related imbalances are present in autism and schizophrenia, so the paper may have a broader impact.”
Disease-Causing Loop
The study results build on how each neuron “fires” to send an electrical pulse down an extension of itself until it reaches a synapse, the gap that connects it to the next cell in a neuronal pathway. When it reaches the cell’s end before the synapse, the pulse triggers the release of compounds called neurotransmitters that float across the gap to affect the next cell in line. Upon crossing, such signals either encourage the cell to fire (excitation), or apply the brakes on firing (inhibition). Balance between the two are essential to brain function; too much excitation promotes seizures.
The new study looked at several rodent models to explore mechanisms behind seizures, often by measuring information-carrying electrical current flows with fine-tipped electrodes. Other experiments looked at the effect of LPI by genetically removing its main signaling partner, or by measuring the release of LPI following seizures.
The tests confirmed past findings that LPI influences nerve signals by binding to a protein called G-coupled receptor 55 (GPR55), on neuron cell surfaces. This LPI-GPR55 presynaptic interaction was found to cause the release of calcium ions within the cell, which encouraged cells to release glutamate, the main excitatory neurotransmitter. Further, when LPI activated GPR55 on the other side of the synapse, it weakened inhibition, by decreasing the supply and proper arrangement of proteins necessary for inhibition. Collectively, this creates a “dangerous” two-pronged mechanism to increase excitability, say the authors.
The research team found that either genetically engineering mice to lack GPR55, or treating mice with plant-derived CBD prior to seizure-inducing stimuli, blocked LPI-mediated effects on both excitatory and inhibitory synaptic transmission. While prior studies had implicated GPR55 as a seizure-reducing target of CBD, the current work provided a more detailed, proposed mechanism of action.
The authors propose that CBD blocks a “positive feedback loop” in which seizures increase LPI-GPR55 signaling, which likely encourages more seizures, which in turn increases levels of both LPI and GPR55. The proposed vicious cycle provides one process that could explain repeated epileptic seizures, although future studies are needed to confirm this.
Further, the current study examined the plant-based cannabinoid CBD, but the authors note that LPI is part of a signaling network that includes “endocannabinoids” like 2-Arachidonoylglycerol (2-AG) that occur naturally in human tissues. LPI and 2-AG target receptors are also regulated by CBD, but have different actions at the synapse. While LPI amplifies incoming electrical signals, endocannabinoids like 2-AG respond to increases in brain activity by dialing down the release of neurotransmitters from nerve cells. Interestingly, LPI and 2-AG can be converted into each other through actions of enzymes.
“Theoretically, the brain could control activity by toggling between pro-excitatory LPI and the restorative actions of 2-AG,” said first study author Evan Rosenberg, PhD, a post-doctoral scholar in the Tsein’s lab. “Drug designers could inhibit the enzymes that underpin LPI production or promote its conversion to 2-AG, as an additional approach to control seizures. LPI could also serve as a biomarker of seizures or predictor of clinical responsiveness to CBD, providing an area of future research.”
Reference: “Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity” by Evan C. Rosenberg, Simon Chamberland, Michael Bazelot, Erica R. Nebet, Xiaohan Wang, Sam McKenzie, Swati Jain, Stuart Greenhill, Max Wilson, Nicole Marley, Alejandro Salah, Shanice Bailey, Pabitra Hriday Patra, Rebecca Rose, Nicolas Chenouard, Simón(e) D. Sun, Drew Jones, György Buzsáki, Orrin Devinsky, Gavin Woodhall, Helen E. Scharfman, Benjamin J. Whalley and Richard W. Tsien, 13 February 2023, Neuron.
DOI: 10.1016/j.neuron.2023.01.018
Along with Tsien and Rosenberg, study authors in the Department of Neuroscience & Physiology and Neuroscience Institute at NYU Langone Health were Simon Chamberland, Erica Nebet, Xiaohan Wang, Sam McKenzie, Alejandro Salah, Nicolas Chenouard, Simon Sun, and György Buzsáki. Also NYU Langone authors were Orrin Devinsky in the Department of Neurology, Rebecca Rose in the Department of Advanced Research Technologies, and Drew Jones in the Department of Biochemistry and Molecular Pharmacology. Also study authors were Michael Bazelot, Shanice Bailey, Pabitra Hriday Patra, and Benjamin Whalley at the School of Chemistry, Food and Nutritional Sciences, and Pharmacy, University of Reading, Hopkins Life Science Building, Whiteknights, Reading, United Kingdom; Swati Jain and Helen Scharfman in the Departments of Child and Adolescent Psychiatry, Neuroscience & Physiology, and Psychiatry at NYU, and the Center for Dementia Research at the Nathan Kline Institute for Psychiatric Research; Stuart Greenhill, Max Wilson, Nicole Marley, and Gavin Woodhall of the Aston Neuroscience Institute, School of Life and Health Sciences at Aston University in Birmingham, United Kingdom.
This work was supported by funding from the Ruth L. Kirschstein National Research Service Awards (NRSA) for Individual Pre-doctoral MD/PhDs (F30 NS100293), the NYU MSTP Training Grant (T32GM007308), as well as by National Institutes of Health grant (NIMH) 5R37MH071739), NIDA grant DA040484-01, the Simons Foundation, the Vulnerable Brain Project, FACES (Finding a Cure for Epilepsy & Seizures), the Charles H. Revson Senior Fellowship in Biomedical Science, the Andrew Ellis and Emily Segal Investigator Grant from the Brain and Behavior Research Foundation, a postdoctoral fellowship from the Fonds de Recherche du Québec – Santé (FRQS), and a K99/R00 Pathway to Independence Award from NIMH (1K99MH126157-01). The services of the NYU Metabolomics Core and Experimental Pathology Research Laboratory Core were supported by Perlmutter Cancer Center Support Grant P30CA016087.
Over the last 20 years, the use of cannabidiol (CBD) to treat epileptic seizures has gained traction, particularly where anti-seizure medications have failed. CBD’s anticonvulsant properties are well-known; however, a new study has highlighted a previously unknown way CBD reduces seizures, especially in people with treatment-resistant epilepsy.
In very basic physiological terms, electrical impulses travel down a neuronal pathway until they reach a gap, or synapse. Here, neurotransmitters are released and traverse the gap, either exciting or inhibiting the next cell in line.
To function properly, neuronal circuits require coordination between synaptic excitation and inhibition. Dysfunction in the excitatory-inhibitory (E:I) ratio can result in seizures. While it is known that G-protein-coupled receptor 55 (GPR55), present on the surface of neuronal cells, regulates the E:I ratio, the exact mechanism by which it does so is not well understood.
Likewise, how CBD, the non-euphoric component of cannabis, suppresses seizure activity at a molecular level is poorly understood. It is thought that CBD acts as an antagonist, blocking the effects of the lipid lysophosphatidylinositol (LPI), a naturally occurring GPR55 agonist.
Previous double-blind, placebo-controlled phase III clinical trials undertaken in the US have demonstrated that CBD reduces spontaneous recurrent seizures and regulates the E:I ratio in acute seizures. The efficacy of these trials has led the FDA to approve a plant-derived, purified form of CBD to treat seizure disorders.
A study led by researchers at NYU Grossman School of Medicine used rodents to test the relationship between LPI and GPR55 as a potential modulator of E:I ratio and the impact that CBD has on both.
Researchers confirmed a previous finding that CBD blocks the ability of LPI to amplify nerve signals in the hippocampus, the area of the brain associated with epilepsy.
But they also discovered something previously unknown: when LPI interacts with GPR55, it weakens the signals that suppress seizures. This means that the LPI-GPR55 pathway can result in a positive feedback loop whereby seizures increase LPI-GPR55 signaling, producing more seizures and increasing levels of LPI-GPR55. The process continues in a vicious cycle, providing one explanation for prolonged seizure activity.
Findings suggest that CBD effectively short-circuits this feedback loop, restoring the E:I ratio, thereby further increasing CBD's value as an anticonvulsant treatment.
“Our results deepen the field’s understanding of a central seizure-inducing mechanism, with many implications for the pursuit of new treatment approaches,” said Richard Tsien, chair of the Department of Physiology and Neuroscience at NYU Langone Health and corresponding author of the study.
Given that E:I imbalances are found in other conditions, the findings of this study have the potential for wider application.
“The study also clarified, not just how CBD counters seizures, but more broadly how circuits are balanced in the brain,” Tsien said. “Related imbalances are present in autism and schizophrenia, so the paper may have a broader impact.”
The new study was published in Neuron.
Source: NYU Langone Health via EurekAlert!
Led by researchers at NYU Grossman School of Medicine, the new study found that CBD blocked signals carried by a molecule called lysophosphatidylinositol (LPI). Found in brain cells called neurons, LPI is thought to amplify nerve signals as part of normal function, but can be hijacked by disease to promote seizures.
The study reveals a previously unknown way in which cannabidiol (CBD), a substance found in cannabis, reduces seizures in many treatment-resistant forms of pediatric epilepsy.
Published online February 13 in Neuron, the work confirmed a previous finding that CBD blocks the ability of LPI to amplify nerve signals in a brain region called the hippocampus. The current findings argue for the first time that LPI also weakens signals that counter seizures, further explaining the value of CBD treatment.
“Our results deepen the field’s understanding of a central seizure-inducing mechanism, with many implications for the pursuit of new treatment approaches,” said corresponding author Richard W. Tsien, chair of the Department of Physiology and Neuroscience at NYU Langone Health.
“The study also clarified, not just how CBD counters seizures, but more broadly how circuits are balanced in the brain,” added Tsien. “Related imbalances are present in autism and schizophrenia, so the paper may have a broader impact.”
Disease-Causing Loop
The study results build on how each neuron “fires” to send an electrical pulse down an extension of itself until it reaches a synapse, the gap that connects it to the next cell in a neuronal pathway. When it reaches the cell’s end before the synapse, the pulse triggers the release of compounds called neurotransmitters that float across the gap to affect the next cell in line. Upon crossing, such signals either encourage the cell to fire (excitation), or apply the brakes on firing (inhibition). Balance between the two are essential to brain function; too much excitation promotes seizures.
The new study looked at several rodent models to explore mechanisms behind seizures, often by measuring information-carrying electrical current flows with fine-tipped electrodes. Other experiments looked at the effect of LPI by genetically removing its main signaling partner, or by measuring the release of LPI following seizures.
The tests confirmed past findings that LPI influences nerve signals by binding to a protein called G-coupled receptor 55 (GPR55), on neuron cell surfaces. This LPI-GPR55 presynaptic interaction was found to cause the release of calcium ions within the cell, which encouraged cells to release glutamate, the main excitatory neurotransmitter. Further, when LPI activated GPR55 on the other side of the synapse, it weakened inhibition, by decreasing the supply and proper arrangement of proteins necessary for inhibition. Collectively, this creates a “dangerous” two-pronged mechanism to increase excitability, say the authors.
The research team found that either genetically engineering mice to lack GPR55, or treating mice with plant-derived CBD prior to seizure-inducing stimuli, blocked LPI-mediated effects on both excitatory and inhibitory synaptic transmission. While prior studies had implicated GPR55 as a seizure-reducing target of CBD, the current work provided a more detailed, proposed mechanism of action.
The authors propose that CBD blocks a “positive feedback loop” in which seizures increase LPI-GPR55 signaling, which likely encourages more seizures, which in turn increases levels of both LPI and GPR55. The proposed vicious cycle provides one process that could explain repeated epileptic seizures, although future studies are needed to confirm this.
Further, the current study examined the plant-based cannabinoid CBD, but the authors note that LPI is part of signaling network that includes “endocannabinoids” like 2-Arachidonoylglycerol (2-AG) that occur naturally in human tissues. LPI and 2-AG target receptors also regulated by CBD, but have different actions at the synapse. While LPI amplifies incoming electrical signals, endocannabinoids like 2-AG respond to increases in brain activity by dialing down the release of neurotransmitters from nerve cells. Interestingly, LPI and 2-AG can be converted into each other through actions of enzymes.
“Theoretically, the brain could control activity by toggling between pro-excitatory LPI and the restorative actions of 2-AG,” said first study author Evan Rosenberg, PhD, a post-doctoral scholar in the Tsein’s lab. “Drug designers could inhibit the enzymes that underpin LPI production or promote its conversion to 2-AG, as an additional approach to control seizures. LPI could also serve as a biomarker of seizures or predictor of clinical responsiveness to CBD, providing an area of future research.”
Reference:
Richard W. Tsien et al,Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity,Neuron,doi 10.1016/j.neuron.2023.01.018
General Education - Mathematical Perspective A: Project-Based Calculus I
This is the first in a two-course sequence intended for students majoring in mathematics, science, or engineering. It emphasizes the understanding of concepts, and using them to solve physical problems. The course covers functions, limits, continuity, the derivative, rules of differentiation, applications of the derivative, Riemann sums, definite integrals, and indefinite integrals. (Prerequisite: A- or better in MATH-111 or A- or better in ((NMTH-260 or NMTH-272 or NMTH-275) and NMTH-220) or a math placement test score greater than or equal to 70 or department permission to enroll in this class.) Lecture 6 (Fall, Spring, Summer).
General Education - Mathematical Perspective B: Project-Based Calculus II
This is the second in a two-course sequence intended for students majoring in mathematics, science, or engineering. It emphasizes the understanding of concepts, and using them to solve physical problems. The course covers techniques of integration including integration by parts, partial fractions, improper integrals, applications of integration, representing functions by infinite series, convergence and divergence of series, parametric curves, and polar coordinates. (Prerequisites: C- or better in (MATH-181 or MATH-173 or 1016-282) or (MATH-171 and MATH-180) or equivalent course(s).) Lecture 6 (Fall, Spring, Summer).
Engineering Mechanics Laboratory
This course examines classical Newtonian mechanics from a calculus-based fundamental perspective with close coupling to integrated laboratory experiences. courses include kinematics; Newton's laws of motion; work-energy theorem, and power; systems of particles and linear momentum; circular motion and rotation; mechanical waves, and oscillations and gravitation within the context of mechanical engineering, using mechanical engineering conventions and nomenclature. Each syllabu is reviewed in lecture, and then thoroughly studied in an accompanying laboratory session. Students conduct experiments using modern data acquisition technology; and analyze, interpret, and present the results using modern computer software. (Prerequisite: This class is restricted to MECE-BS or ENGRX-UND or MECEDU-BS students. Co-requisites: MATH-171 or MATH-181 or MATH-181A or MATH-172 or equivalent course.) Lec/Lab 5 (Fall, Spring).
Statics
This basic course treats the equilibrium of particles and rigid bodies under the action of forces. It integrates the mathematical subjects of calculus, vector algebra and simultaneous algebraic equations with the physical concepts of equilibrium in two and three dimensions. courses include concepts of force and moment, friction, centroids and moments of inertia, and equilibrium of trusses, frames and machines. (Prerequisites: MECE-102 or PHYS-211 or PHYS-211A or PHYS-206 or equivalent course and restricted to MECE-BS or MECEDU-BS or MECE-MN or ENGRX-UND students. Co-requisites: MATH-182 or MATH-182A or MATH-173 or equivalent course.) Lecture 3 (Fall, Spring).
Engineering Design Tools
This course combines the elements of Design process, Computer Aided Design (CAD), and Machine Shop Fabrication in the context of a design/build/test project. You will learn how to work in a team and use a formalized design process to justify and support design choices, how to use a CAD package to create three-dimensional models and assemblies, and how to safely fabricate metal parts using vertical mills and lathes. (This course is restricted to MECE-BS or MECE-MN or ENGRX-UND or MECEDU-BS Major students.) Lab 1 (Fall, Spring).
Introduction to Programming for Engineers
This course provides the student with an overview of the use of computer programming for solving problems encountered in engineering. Students will learn how to develop an algorithm for solving a problem and to translate that algorithm into computer code using fundamental structured programming techniques. The programming language(s) employed are selected to support computational problem-solving in higher-level mechanical engineering courses. (This course is restricted to students in MECE-BS or ENGRX-UND or MECEDU-BS. Co-requisite: MATH-181 or MATH-181A or MATH-172 or equivalent course.) Lec/Lab 4 (Fall, Spring).
RIT 365: RIT Connections
RIT 365 students participate in experiential learning opportunities designed to launch them into their career at RIT, support them in making multiple and varied connections across the university, and immerse them in processes of competency development. Students will plan for and reflect on their first-year experiences, receive feedback, and develop a personal plan for future action in order to develop foundational self-awareness and recognize broad-based professional competencies. Lecture 1 (Fall, Spring).
General Education - First Year Writing (WI)
General Education - Ethical Perspective
General Education - Artistic Perspective
General Education - Elective
Engineering Co-op Preparation
This course will prepare students, who are entering their second year of study, for both the job search and employment in the field of engineering. Students will learn strategies for conducting a successful job search, including the preparation of resumes and cover letters; behavioral interviewing techniques and effective use of social media in the application process. Professional and ethical responsibilities during the job search and for co-op and subsequent professional experiences will be discussed. (This course is restricted to students in Kate Gleason College of Engineering with at least 2nd year standing.) Lecture 1 (Fall, Spring).
Multivariable Calculus
This course is principally a study of the calculus of functions of two or more variables, but also includes the study of vectors, vector-valued functions and their derivatives. The course covers limits, partial derivatives, multiple integrals, and includes applications in physics. Credit cannot be granted for both this course and MATH-221. (Prerequisite: C- or better MATH-173 or MATH-182 or MATH-182A or equivalent course.) Lecture 3 (Fall, Spring, Summer).
Differential Equations
This course is an introduction to the study of ordinary differential equations and their applications. courses include solutions to first order equations and linear second order equations, method of undetermined coefficients, variation of parameters, linear independence and the Wronskian, vibrating systems, and Laplace transforms. (Prerequisite: MATH-173 or MATH-182 or MATH-182A or equivalent course.) Lecture 3 (Fall, Spring, Summer).
Thermodynamics I
A basic course introducing the classical theory of thermodynamics. Applications of the first law of thermodynamics are used to introduce the student to thermodynamic processes for closed and open systems. The Clausius and Kelvin-Planck statements of the second law are then correlated with the concept of entropy and enthalpy to investigate both real and reversible processes and the thermodynamic properties of pure substances. These techniques are then used to evaluate thermodynamic cycles for a variety of applications in power generation and refrigeration. Students are then introduced to techniques to Boost thermal efficiency of these cycles such as reheat, regeneration, and co-generation. (Prerequisites: MECE-102 or PHYS-211 or PHYS-211A or PHYS-206 or equivalent course. Co-requisites: MATH-182 or or MATH-182A or MATH-173 or equivalent course. This course is restricted to MECE-BS or MECEDU-BS or MECE-MN or ENGRX-UND students.) Lecture 3 (Fall, Spring).
Strength of Materials I
A basic course in the fundamental principles of the mechanics of deformable media, including stress, strain, deflections and the relationships among them. The basic loadings of tension, compression, shear, torsion and bending are also included. (Prerequisites: MECE-103 or equivalent course. This course is restricted to MECE-BS or MECEDU-BS or MECE-MN students.) Lecture 3 (Fall, Spring).
Strength of Materials I Laboratory
A required laboratory course taken concurrently with MECE-203. Students investigate a metallic material’s response to axial, torsional, and bending loads. Students are introduced to reduction and analysis of data, basic experimental techniques, and effective report writing. (This course is restricted to students in MECE-BS or MECEDU-BS or MECE-MN or ENGRX-UND students. Co-requisites: MECE-203) Lab 2 (Fall, Spring).
Dynamics
A basic course in the kinematics and kinetics of particles and rigid bodies. Newton's Laws and the theorems of work-energy and impulse momentum are applied to a variety of particle problems. Systems of particles are employed to transition to the analysis of rigid body problems. Absolute and relative motion are used to investigate the kinematics and kinetics of systems of rigid bodies. Newton's Laws are applied to a variety of two-dimensional rigid body problems. (Prerequisites: MECE-103 or equivalent course. This course is restricted to MECE-BS or MECEDU-BS or MECE-MN students.) Lecture 3 (Fall, Spring).
Fluid Mechanics I
This course investigates the physical characteristics of a fluid: density, stress, pressure, viscosity, temperature, vapor pressure, compressibility. Descriptions of flows include Lagrangian and Eulerian; stream-lines, path-lines and streak-lines. Classification of flows include fluid statics, hydrostatic pressure at a point, pressure field in a static fluid, manometry, forces on submerged surfaces, buoyancy, standard and adiabatic atmospheres. Flow fields and fundamental laws are investigated including systems and control volumes, Reynolds Transport theorem, integral control volume analysis of basic equations for stationary and moving control volumes. Inviscid Bernoulli and the Engineering Bernoulli equation are utilized when analyzing fluid systems. Other concepts studied include incompressible flow in pipes; laminar and turbulent flows, separation phenomenon, dimensional analysis. (Prerequisites: MECE-110 or equivalent course. This course is restricted to MECE-BS or MECEDU-BS or MECE-MN students.) Lecture 3 (Fall, Spring).
Engineering Measurements Lab (WI-PR)
This course is focused on developing skills and knowledge in the areas of instrumentation, computer data acquisition (DAQ), measurement theory, uncertainty analysis, data analysis, and technical report writing. Specific courses that are covered include: • Physical dimension variability assessment • Centrifugal pump performance evaluation • Temperature, pressure, and flow instrumentation and measurements • LabVIEW programming and DAQ hardware application • Transient measurements including computer data acquisition • Digital signal input and output Each syllabu includes background theoretical content with some individual exercises and then a team-based lab with accompanying lab report. Reports are submitted first in draft form and are reviewed by peers in class before preparing them for final draft submission (Prerequisites: MECE-102 or PHYS-211 or PHYS-211A or PHYS-206 or equivalent course and restricted to MECE-BS or MECEDU-BS students.) Lec/Lab 3 (Fall, Spring).
General Education - Global Perspective
General Education - Social Perspective
General Education - Scientific Principles Perspective
General Education - Immersion 1
Circuits I
Covers basics of DC circuit analysis starting with the definition of voltage, current, resistance, power and energy. Linearity and superposition, together with Kirchhoff's laws, are applied to analysis of circuits having series, parallel and other combinations of circuit elements. Thevenin, Norton and maximum power transfer theorems are proved and applied. Circuits with ideal op-amps are introduced. Inductance and capacitance are introduced and the transient response of RL, RC and RLC circuits to step inputs is established. Practical aspects of the properties of passive devices and batteries are discussed, as are the characteristics of battery-powered circuitry. The laboratory component incorporates use of both computer and manually controlled instrumentation including power supplies, signal generators and oscilloscopes to reinforce concepts discussed in class as well as circuit design and simulation software. (Prerequisite: MATH-173 or MATH-182 or MATH-182A or equivalent course.) Lab 3 (Fall, Spring, Summer).
Materials Science with Applications
This course provides the student with an overview of structure, properties, and processing of metals, polymers, and ceramics. Relevant basic manufacturing processes and materials selection is also discussed. There is a particular emphasis on steels, but significant attention is given to non-ferrous metals, ceramics, and polymers (Prerequisite: MECE-203 or equivalent course. This course is restricted to students in MECE-BS, MECEDU-BS, MECE-MN or ENGRX-UND programs.) Lecture 3 (Fall, Spring).
Materials Science with Applications Laboratory
A required laboratory course taken concurrently with MECE-304 Fundamentals of Materials Science or MECE-305 Materials Science with Applications. Students investigate the effects of the structure, alloying, and processing of materials on their mechanical properties. Students are also introduced to standardized testing methods and effective, professional, report writing. (This course is restricted to students in MECE-BS or MECEDU-BS or MECE-MN or ISEE-BS or ISEEDU-BS or ENGRX-UND students.) Lab 2 (Fall, Spring).
System Dynamics
This required course introduces the student to lumped parameter system modeling, analysis and design. The determination and solution of differential equations that model system behavior is a vital aspect of the course. System response phenomena are characterized in both time and frequency domains and evaluated based on performance criteria. Laboratory exercises enhance student proficiency with model simulation, basic instrumentation, data acquisition, data analysis, and model validation. (Prerequisites: MECE-205 and MATH-231 or equivalent courses. Co-requisites: EEEE-281 This course is restricted to MECE-BS or MECEDU-BS or MECE-MN students.) Lec/Lab 4 (Fall, Spring).
Boundary Value Problems
This course provides an introduction to boundary value problems. courses include Fourier series, separation of variables, Laplace's equation, the heat equation, and the wave equation in Cartesian and polar coordinate systems. (Prerequisites: (MATH-231 or MATH-233) and (MATH-219 or MATH-221) or equivalent courses.) Lecture 3 (Fall, Spring).
Cooperative Education (fall, summer)
Nominally three months of full-time, paid employment in the mechanical engineering field. (Prerequisites: (MECE-110 and MECE-203 and MECE-211 and EGEN-099) or MECE-499. This course is restricted to MECE-BS or MECEDU-BS students.) CO OP (Fall, Spring, Summer).
General Education - Natural Science Inquiry Perspective: University Physics II
This course is a continuation of PHYS-211, University Physics I. courses include electrostatics, Gauss' law, electric field and potential, capacitance, resistance, DC circuits, magnetic field, Ampere's law, inductance, and geometrical and physical optics. The course is taught in a lecture/workshop format that integrates the material traditionally found in separate lecture and laboratory courses. (Prerequisites: (PHYS-211 or PHYS-211A or PHYS-206 or PHYS-216) or (MECE-102, MECE-103 and MECE-205) and (MATH-182 or MATH-172 or MATH-182A) or equivalent courses. Grades of C- or better are required in all prerequisite courses.) Lec/Lab 6 (Fall, Spring).
Linear Algebra
This course is an introduction to the basic concepts of linear algebra, and techniques of matrix manipulation. courses include linear transformations, Gaussian elimination, matrix arithmetic, determinants, vector spaces, linear independence, basis, null space, row space, and column space of a matrix, eigenvalues, eigenvectors, change of basis, similarity and diagonalization. Various applications are studied throughout the course. (Prerequisites: MATH-190 or MATH-200 or MATH-219 or MATH-220 or MATH-221 or MATH-221H or equivalent course.) Lecture 3 (Fall, Spring).
Engineering Applications Laboratory
As a modification of the more “traditional” lab approach, students work in teams to complete an open-ended project involving theoretical and empirical analyses of an assigned system, applying engineering concepts and skills learned throughout prior courses. After successfully completing this course, students will have achieved a higher level of understanding of, and proficiency in, the tasks of qualitative treatment of real systems, development and implementation of analytical models, design and implementation of experimental investigations, and validation of results. (Prerequisites: (MECE-102 or PHYS-211 or PHYS-211A or PHYS-206) and MECE-104 and MECE-211 or equivalent courses and is restricted to MECE-BS or MECEDU-BS students. Co-requisites: MECE-210 or equivalent course.) Lab 2 (Fall, Spring).
Heat Transfer I
A first course in the fundamentals of heat transfer by conduction, convection and radiation, together with applications to typical engineering systems. courses include one- and two-dimensional steady state and transient heat conduction, radiation exchange between black and gray surfaces, correlation equations for laminar/turbulent internal and external convection, and an introduction to heat exchangers analysis and design by LMTD and NTU methods. (Prerequisites: MECE-210 or equivalent course. This course is restricted to MECE-BS or MECEDU-BS or MECE-MN students.) Lecture 3 (Fall, Spring).
Contemporary Issues
This course introduces students to contemporary technologies in a specific field of mechanical engineering. In the process of exploring these technologies, the course teaches and applies skills related to communication, economic analysis, ethical analysis, and explores the positive and negative effects of technologies on our society and environment. Specific attention is focused on current events both domestically and internationally. (Prerequisite or Co-requisites: MECE-499 or equivalent course. This course is restricted to MECE-BS or MECEDU-BS students.) Lecture 3 (Fall, Spring).
Cooperative Education (summer)
Nominally three months of full-time, paid employment in the mechanical engineering field. (Prerequisites: (MECE-110 and MECE-203 and MECE-211 and EGEN-099) or MECE-499. This course is restricted to MECE-BS or MECEDU-BS students.) CO OP (Fall, Spring, Summer).
Graduate Policy Analysis
This course provides graduate students with necessary tools to help them become effective policy analysts. The course places particular emphasis on understanding the policy process, the different approaches to policy analysis, and the application of quantitative and qualitative methods for evaluating public policies. Students will apply these tools to contemporary public policy decision making at the local, state, federal, and international levels. Lecture 3 (Fall).
Graduate Decision Analysis
This course provides students with an introduction to decision science and analysis. The course focuses on several important tools for making good decisions, including decision trees, including forecasting, risk analysis, and multi-attribute decision making. Students will apply these tools to contemporary public policy decision making at the local, state, federal, and international levels. Lecture 3 (Spring).
Applied Statistics
This course covers basic statistical concepts and techniques including descriptive statistics, probability, inference, and quality control. The statistical package Minitab will be used to reinforce these techniques. The focus of this course is on statistical applications and quality improvement in engineering. This course is intended for engineering programs and has a calculus prerequisite. Note: This course may not be taken for credit if credit is to be earned in STAT-145 or STAT-155 or MATH 252.. (Prerequisite: MATH-173 or MATH-182 or MATH-182A or equivalent course.) Lecture 3 (Fall, Spring).
Graduate Science and Technology Policy Seminar
Examines how federal and international policies are developed to influence research and development, innovation, and the transfer of technology in the United States and other selected nations. Students in the course will apply basic policy skills, concepts, and methods to contemporary science and technology policy topics. (This class is restricted to degree-seeking graduate students or those with permission from instructor.) Seminar (Fall).
ME Extended Core Elective
General Education - ME Approved Science Elective
General Education - Immersion 2
Open Elective
Multidisciplinary Sr. Design I
This is the first in a two-course sequence oriented to the solution of real-world engineering design problems. This is a capstone learning experience that integrates engineering theory, principles, and processes within a collaborative environment. Multidisciplinary student teams follow a systems engineering design process, which includes assessing customer needs, developing engineering specifications, generating and evaluating concepts, choosing an approach, developing the details of the design, and implementing the design to the extent feasible, for example by building and testing a prototype or implementing a chosen set of improvements to a process. This first course focuses primarily on defining the problem and developing the design, but may include elements of build/ implementation. The second course may include elements of design, but focuses on build/implementation and communicating information about the final design. (Prerequisites: MECE-301 and MECE-499 or equivalent courses. This course is restricted to MECE-BS or MECEDU-BS students.) Lecture 6 (Fall, Spring).
Multidisciplinary Sr. Design II
This is the second in a two-course sequence oriented to the solution of real-world engineering design problems. This is a capstone learning experience that integrates engineering theory, principles, and processes within a collaborative environment. Multidisciplinary student teams follow a systems engineering design process, which includes assessing customer needs, developing engineering specifications, generating and evaluating concepts, choosing an approach, developing the details of the design, and implementing the design to the extent feasible, for example by building and testing a prototype or implementing a chosen set of improvements to a process. The first course focuses primarily on defining the problem and developing the design, but may include elements of build/ implementation. This second course may include elements of design, but focuses on build/implementation and communicating information about the final design. (Prerequisites: MECE-497 or equivalent course. This course is restricted to MECE-BS or MECEDU-BS students.) Lecture 6 (Fall, Spring).
Readings in Public Policy
An in-depth inquiry into key contemporary public policy issues. Students will be exposed to a wide range of important public policy texts, and will learn how to write a literature review in a policy area of their choosing. (This class is restricted to degree-seeking graduate students or those with permission from instructor.) Seminar (Fall).
Evaluation and Research Design
The focus of this course is on evaluation of program outcomes and research design. Students will explore the questions and methodologies associated with meeting programmatic outcomes, secondary or unanticipated effects, and an analysis of alternative means for achieving program outcomes. Critique of evaluation research methodologies will also be considered. Seminar (Spring).
Open Elective
Applied Elective/Public Policy Electives
Open Elective/Public Policy Elective
General Education - Immersion 3
6
Capstone Research Experience
The Public Policy Capstone Experience serves as a culminating experience for those MS in Science, Technology and Public Policy students who chose this option in the Public Policy Department. Over the course of the semester, students will have the opportunity to investigate and address contemporary courses in science and technology policy using analytic skills and theoretical knowledge learned over the course of their MS degree. Project 1 (Fall, Spring, Summer).
Public Policy Thesis
The master's thesis in science, technology, and public policy requires the student to select a thesis topic, advisor and committee; prepare a written thesis proposal for approval by the faculty; present and defend the thesis before a thesis committee; and submit a bound copy of the thesis to the library and to the program chair. (Enrollment in this course requires permission from the department offering the course.) Thesis 3 (Fall, Spring, Summer).
Comprehensive test plus 2 Graduate Electives
150
A study reveals a previously unknown way in which cannabidiol (CBD), a substance found in cannabis, reduces seizures in many treatment-resistant forms of pediatric epilepsy.
Led by researchers at NYU Grossman School of Medicine, the new study found that CBD blocked signals carried by a molecule called lysophosphatidylinositol (LPI). Found in brain cells called neurons, LPI is thought to amplify nerve signals as part of normal function, but can be hijacked by disease to promote seizures.
Published online February 13 in Neuron, the work confirmed a previous finding that CBD blocks the ability of LPI to amplify nerve signals in a brain region called the hippocampus. The current findings argue for the first time that LPI also weakens signals that counter seizures, further explaining the value of CBD treatment.
"Our results deepen the field's understanding of a central seizure-inducing mechanism, with many implications for the pursuit of new treatment approaches," said corresponding author Richard W. Tsien, chair of the Department of Physiology and Neuroscience at NYU Langone Health.
"The study also clarified, not just how CBD counters seizures, but more broadly how circuits are balanced in the brain," added Tsien. "Related imbalances are present in autism and schizophrenia, so the paper may have a broader impact."
The study results build on how each neuron "fires" to send an electrical pulse down an extension of itself until it reaches a synapse, the gap that connects it to the next cell in a neuronal pathway. When it reaches the cell's end before the synapse, the pulse triggers the release of compounds called neurotransmitters that float across the gap to affect the next cell in line. Upon crossing, such signals either encourage the cell to fire (excitation), or apply the brakes on firing (inhibition). Balance between the two are essential to brain function; too much excitation promotes seizures.
The new study looked at several rodent models to explore mechanisms behind seizures, often by measuring information-carrying electrical current flows with fine-tipped electrodes. Other experiments looked at the effect of LPI by genetically removing its main signaling partner, or by measuring the release of LPI following seizures.
The tests confirmed past findings that LPI influences nerve signals by binding to a protein called G-coupled receptor 55 (GPR55), on neuron cell surfaces. This LPI-GPR55 presynaptic interaction was found to cause the release of calcium ions within the cell, which encouraged cells to release glutamate, the main excitatory neurotransmitter. Further, when LPI activated GPR55 on the other side of the synapse, it weakened inhibition, by decreasing the supply and proper arrangement of proteins necessary for inhibition. Collectively, this creates a "dangerous" two-pronged mechanism to increase excitability, say the authors.
The research team found that either genetically engineering mice to lack GPR55, or treating mice with plant-derived CBD prior to seizure-inducing stimuli, blocked LPI-mediated effects on both excitatory and inhibitory synaptic transmission. While prior studies had implicated GPR55 as a seizure-reducing target of CBD, the current work provided a more detailed, proposed mechanism of action.
The authors propose that CBD blocks a "positive feedback loop" in which seizures increase LPI-GPR55 signaling, which likely encourages more seizures, which in turn increases levels of both LPI and GPR55. The proposed vicious cycle provides one process that could explain repeated epileptic seizures, although future studies are needed to confirm this.
Further, the current study examined the plant-based cannabinoid CBD, but the authors note that LPI is part of signaling network that includes "endocannabinoids" like 2-Arachidonoylglycerol (2-AG) that occur naturally in human tissues. LPI and 2-AG target receptors also regulated by CBD, but have different actions at the synapse. While LPI amplifies incoming electrical signals, endocannabinoids like 2-AG respond to increases in brain activity by dialing down the release of neurotransmitters from nerve cells. Interestingly, LPI and 2-AG can be converted into each other through actions of enzymes.
"Theoretically, the brain could control activity by toggling between pro-excitatory LPI and the restorative actions of 2-AG," said first study author Evan Rosenberg, Ph.D., a post-doctoral scholar in the Tsein's lab. "Drug designers could inhibit the enzymes that underpin LPI production or promote its conversion to 2-AG, as an additional approach to control seizures. LPI could also serve as a biomarker of seizures or predictor of clinical responsiveness to CBD, providing an area of future research."
More information: Richard Tsien & colleauges, Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity, Neuron (2023). DOI: 10.1016/j.neuron.2023.01.018. www.cell.com/neuron/fulltext/S0896-6273(23)00066-1
Citation: Study reveals how CBD counters epileptic seizures (2023, February 13) retrieved 19 February 2023 from https://medicalxpress.com/news/2023-02-reveals-cbd-counters-epileptic-seizures.html
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.
Findings Suggest Specific Targets for Future Drugs
NEW YORK, Feb. 13, 2023 /PRNewswire/ -- A study reveals a previously unknown way in which cannabidiol (CBD), a substance found in cannabis, reduces seizures in treatment-resistant forms of pediatric epilepsy.
Led by researchers at NYU Grossman School of Medicine, the new study found that CBD blocked signals carried by a molecule called lysophosphatidylinositol (LPI). Found in brain cells called neurons, LPI is thought to amplify nerve signals as part of normal function, but can be hijacked by disease to promote seizures.
Published online February 13 in Neuron, the work confirmed a previous finding that CBD blocks the ability of LPI to amplify nerve signals in a brain region called the hippocampus. The current findings argue for the first time that LPI also weakens signals that counter seizures, further explaining the value of CBD treatment.
"Our results deepen the field's understanding of a central seizure-inducing mechanism, with many implications for the pursuit of new treatment approaches," said corresponding author Richard W. Tsien, chair of the Department of Physiology and Neuroscience at NYU Langone Health.
"The study also clarified, not just how CBD counters seizures, but more broadly how circuits are balanced in the brain," added Tsien. "Related imbalances are present in autism and schizophrenia, so the paper may have a broader impact."
Disease-Causing Loop
The study results build on how each neuron "fires" to send an electrical pulse down an extension of itself until it reaches a synapse, the gap that connects it to the next cell in a neuronal pathway. When it reaches the cell's end before the synapse, the pulse triggers the release of compounds called neurotransmitters that float across the gap to affect the next cell in line. Upon crossing, such signals either encourage the cell to fire (excitation), or apply the brakes on firing (inhibition). Balance between the two are essential to brain function; too much excitation promotes seizures.
The new study looked at several rodent models to explore mechanisms behind seizures, often by measuring information-carrying electrical current flows with fine-tipped electrodes. Other experiments looked at the effect of LPI by genetically removing its main signaling partner, or by measuring the release of LPI following seizures.
The tests confirmed past findings that LPI influences nerve signals by binding to a protein called G-coupled receptor 55 (GPR55), on neuron cell surfaces. This LPI-GPR55 presynaptic interaction was found to cause the release of calcium ions within the cell, which encouraged cells to release glutamate, the main excitatory neurotransmitter. Further, when LPI activated GPR55 on the other side of the synapse, it weakened inhibition, by decreasing the supply and proper arrangement of the necessary proteins. Collectively, this creates a "dangerous" two-pronged mechanism to increase excitability, say the authors.
The research team found that either genetically engineering mice to lack GPR55, or treating mice with plant-derived CBD prior to seizure-inducing stimuli, blocked LPI-mediated effects on both excitatory and inhibitory synaptic transmission. While prior studies had implicated GPR55 as a seizure-reducing target of CBD, the current work provided a more detailed, proposed mechanism of action.
The authors propose that CBD blocks a "positive feedback loop" in which seizures increase LPI-GPR55 signaling, which likely encourages more seizures, which in turn increases levels of both LPI and GPR55. The proposed vicious cycle provides one process that could explain repeated epileptic seizures, although future studies are needed to confirm this.
Further, the current study examined the plant-based cannabinoid CBD, but the authors note that LPI is part of signaling network that includes "endocannabinoids" like 2-Arachidonoylglycerol (2-AG) that occur naturally in human tissues. LPI and 2-AG target receptors that are also regulated by CBD, but have different actions at the synapse. While LPI amplifies incoming electrical signals, endocannabinoids like 2-AG respond to increases in brain activity by dialing down the release of neurotransmitters from nerve cells. Interestingly, LPI and 2-AG can be converted into each other through actions of enzymes.
"Theoretically, the brain could control activity by toggling between pro-excitatory LPI and the restorative actions of 2-AG," said first study author Evan Rosenberg, PhD, a post-doctoral scholar in the Tsein's lab. "Drug designers could inhibit the enzymes that enable LPI production or promote its conversion to 2-AG, as an additional approach to control seizures. LPI could also serve as a biomarker of seizures or predictor of clinical responsiveness to CBD, providing an area of future research."
Along with Tsien and Rosenberg, study authors in the Department of Neuroscience & Physiology and Neuroscience Institute at NYU Langone Health were Simon Chamberland, Erica Nebet, Xiaohan Wang, Sam McKenzie, Alejandro Salah, Nicolas Chenouard, Simon Sun, and György Buzsáki. Also NYU Langone authors were Orrin Devinsky in the Department of Neurology, Rebecca Rose in the Department of Advanced Research Technologies, and Drew Jones in the Department of Biochemistry and Molecular Pharmacology. Also study authors were Michael Bazelot, Shanice Bailey, Pabitra Hriday Patra, and Benjamin Whalley at the School of Chemistry, Food and Nutritional Sciences, and Pharmacy, University of Reading, Hopkins Life Science Building, Whiteknights, Reading, United Kingdom; Swati Jain and Helen Scharfman in the Departments of Child and Adolescent Psychiatry, Neuroscience & Physiology, and Psychiatry at NYU, and the Center for Dementia Research at the Nathan Kline Institute for Psychiatric Research; Stuart Greenhill, Max Wilson, Nicole Marley, and Gavin Woodhall of the Aston Neuroscience Institute, School of Life and Health Sciences at Aston University in Birmingham, United Kingdom.
This work was supported by funding from the Ruth L. Kirschstein National Research Service Awards (NRSA) for Individual Pre-doctoral MD/PhDs (F30 NS100293), the NYU MSTP Training Grant (T32GM007308), as well as by National Institutes of Health grant (NIMH) 5R37MH071739), NIDA grant DA040484-01, the Simons Foundation, the Vulnerable Brain Project, FACES (Finding a Cure for Epilepsy & Seizures), the Charles H. Revson Senior Fellowship in Biomedical Science, the Andrew Ellis and Emily Segal Investigator Grant from the Brain and Behavior Research Foundation, a postdoctoral fellowship from the Fonds de Recherche du Québec - Santé (FRQS), and a K99/R00 Pathway to Independence Award from NIMH (1K99MH126157-01). The services of the NYU Metabolomics Core and Experimental Pathology Research Laboratory Core were supported by Perlmutter Cancer Center Support Grant P30CA016087.
Contact:
Gregory Williams
gregory.williams@nyulangone.org
View original content to obtain multimedia:https://www.prnewswire.com/news-releases/study-reveals-how-cbd-counters-epileptic-seizures-301745673.html
SOURCE NYU Grossman School of Medicine and NYU Langone Health
