A review article I created for a class in 2012. The paper attempts to overview the roles of GABA(A) receptors [Including pharmacology, mutations, and developmental disorders] in causing or alleviating Temporal Lobe Epilepsy (TLE).
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. Disturbances in glutamate transmission and NMDA receptor hypofunction are associated with schizophrenia. The NMDA receptor hypofunction hypothesis proposes that reduced NMDA receptor activity leads to increased mesolimbic dopamine activity causing positive symptoms and reduced mesocortical dopamine causing negative and cognitive symptoms. Several clinical studies have explored using NMDA agonists and drugs targeting downstream glutamate release as adjunctive treatments for schizophrenia with some success in improving symptoms. Ongoing research continues to develop new glutamatergic drugs for treating schizophrenia.
Glutamate receptors play an important role in many neurological conditions. They are involved in processes like synaptic plasticity and excitotoxicity. Dysfunctions in glutamate receptors have been linked to conditions like ADHD, autism, ischemia, multiple sclerosis, Parkinson's, schizophrenia, and seizures. Glutamate receptors, especially NMDA and AMPA receptors, are implicated in several neurodegenerative and neuroimmune diseases as well. Targeting glutamate receptors may provide treatment strategies for some of these conditions.
Glutamatergic neurotransmission involves glutamate, the major excitatory neurotransmitter in the brain. There are two pathways for glutamate synthesis from precursors and multiple receptor types including NMDA, AMPA, KA, and metabotropic receptors. The different receptor subunits provide diversity in function. Glutamate signaling is involved in many brain pathways and clinical implications include roles in schizophrenia, Parkinson's disease, and drug mechanisms of action.
Glutamate is the major excitatory neurotransmitter in the central nervous system. It acts through ionotropic and metabotropic receptors. Ionotropic receptors are ligand-gated ion channels composed of NMDA, AMPA, and kainate receptor subtypes that allow cation influx. Metabotropic receptors are G protein-coupled receptors divided into three groups based on sequence homology and signaling pathways. Glutamate receptors play important roles in normal neurotransmission but excessive activation can lead to excitotoxicity involved in various neurological disorders.
1) The document presents information on glutamate and glycine, two important neurotransmitters in the central nervous system.
2) Glutamate is the major excitatory neurotransmitter in the brain and is synthesized from glucose or glutamine. It acts through ionotropic and metabotropic receptors.
3) Glycine is another neurotransmitter that acts as an obligatory co-agonist along with glutamate at NMDA receptors, allowing calcium influx and excitation of postsynaptic neurons. Excess glutamate activation can lead to excitotoxicity and neuronal damage in various neurological conditions.
Beta Amyloid Dysfunction Hypothesis in Alzheimer`s DiseaseHeinz Hillen
- The document presents the Beta Amyloid Dysfunction (BAD) hypothesis as a revision to the classical amyloid cascade hypothesis.
- The BAD hypothesis proposes that physiological amyloid beta (Aβ) monomer is essential for synaptic processes, while disease occurs when Aβ metabolism is disturbed, leading to early misfolded species and reduced synaptic Aβ levels.
- It suggests immunotherapy could work by removing early misfolded Aβ species with highly specific antibodies, thereby restoring normal Aβ processing and rescuing neurons, without affecting physiological Aβ or causing side effects from lowering overall Aβ levels.
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. Disturbances in glutamate transmission and NMDA receptor hypofunction are associated with schizophrenia. The NMDA receptor hypofunction hypothesis proposes that reduced NMDA receptor activity leads to increased mesolimbic dopamine activity causing positive symptoms and reduced mesocortical dopamine causing negative and cognitive symptoms. Several clinical studies have explored using NMDA agonists and drugs targeting downstream glutamate release as adjunctive treatments for schizophrenia with some success in improving symptoms. Ongoing research continues to develop new glutamatergic drugs for treating schizophrenia.
Glutamate receptors play an important role in many neurological conditions. They are involved in processes like synaptic plasticity and excitotoxicity. Dysfunctions in glutamate receptors have been linked to conditions like ADHD, autism, ischemia, multiple sclerosis, Parkinson's, schizophrenia, and seizures. Glutamate receptors, especially NMDA and AMPA receptors, are implicated in several neurodegenerative and neuroimmune diseases as well. Targeting glutamate receptors may provide treatment strategies for some of these conditions.
Glutamatergic neurotransmission involves glutamate, the major excitatory neurotransmitter in the brain. There are two pathways for glutamate synthesis from precursors and multiple receptor types including NMDA, AMPA, KA, and metabotropic receptors. The different receptor subunits provide diversity in function. Glutamate signaling is involved in many brain pathways and clinical implications include roles in schizophrenia, Parkinson's disease, and drug mechanisms of action.
Glutamate is the major excitatory neurotransmitter in the central nervous system. It acts through ionotropic and metabotropic receptors. Ionotropic receptors are ligand-gated ion channels composed of NMDA, AMPA, and kainate receptor subtypes that allow cation influx. Metabotropic receptors are G protein-coupled receptors divided into three groups based on sequence homology and signaling pathways. Glutamate receptors play important roles in normal neurotransmission but excessive activation can lead to excitotoxicity involved in various neurological disorders.
1) The document presents information on glutamate and glycine, two important neurotransmitters in the central nervous system.
2) Glutamate is the major excitatory neurotransmitter in the brain and is synthesized from glucose or glutamine. It acts through ionotropic and metabotropic receptors.
3) Glycine is another neurotransmitter that acts as an obligatory co-agonist along with glutamate at NMDA receptors, allowing calcium influx and excitation of postsynaptic neurons. Excess glutamate activation can lead to excitotoxicity and neuronal damage in various neurological conditions.
Beta Amyloid Dysfunction Hypothesis in Alzheimer`s DiseaseHeinz Hillen
- The document presents the Beta Amyloid Dysfunction (BAD) hypothesis as a revision to the classical amyloid cascade hypothesis.
- The BAD hypothesis proposes that physiological amyloid beta (Aβ) monomer is essential for synaptic processes, while disease occurs when Aβ metabolism is disturbed, leading to early misfolded species and reduced synaptic Aβ levels.
- It suggests immunotherapy could work by removing early misfolded Aβ species with highly specific antibodies, thereby restoring normal Aβ processing and rescuing neurons, without affecting physiological Aβ or causing side effects from lowering overall Aβ levels.
This document discusses glutamate receptors, including their history, types, roles, and drugs that act on them. It notes that glutamate is the major excitatory neurotransmitter in the central nervous system. There are two main types of glutamate receptors: ionotropic receptors which are ligand-gated ion channels including NMDA, AMPA, and kainate receptors, and metabotropic G protein-coupled receptors divided into groups 1, 2, and 3. The roles of glutamate receptors include synaptic plasticity, learning and memory, and excitotoxicity. Many drugs have been developed that act as agonists or antagonists at glutamate receptors and are being investigated for conditions like Alzheimer's, Parkinson
This document discusses amyloid-beta (Aβ) and tau in Alzheimer's disease (AD) pathogenesis. It states that Aβ accumulation triggers AD, and that Aβ oligomers interact with tau signaling pathways, leading to tau hyperphosphorylation and neurofibrillary tangles. Hyperphosphorylated tau then disrupts axonal transport. The document outlines various therapeutic targets for AD, including reducing Aβ accumulation, inhibiting tau hyperphosphorylation, and supporting acetylcholine and glutamate signaling.
The document outlines a research proposal to study the cellular mechanisms underlying cognitive deficits caused by traumatic brain injury (TBI). The central hypothesis is that TBI causes pathological alterations in GABAergic function that lead to imbalances in excitatory and inhibitory synaptic transmission in the hippocampus, resulting in hippocampal dysfunction and cognitive impairment. Three specific aims are described to characterize alterations in GABAergic function in the dentate gyrus and areas CA1 and CA3 of the hippocampus at one week and over months following TBI using electrophysiological and other techniques.
Decreases Expression of PGC-1α in the Alzheimer Disease Brain Impaire Mitocho...rana alhakimi
Alzheimer is the most neurodegenerative disorder in the aged people. It is characterized by senile, accumulation of amyloid plaque, neurofibrillary tangle and progressive decline in brain memory cells.
Alzheimer disease is associated with inflammatory response, synaptic damage and mitochondrial dysfunctions which are a prominent and early feature of Alzheimer disease.
The Role of DNA Methylation as an Epigenetic Mechanism of the Neuroadaptation...RachaelWong11
- DNA methylation and demethylation through enzymes like Dnmt and Tet act as an epigenetic mechanism underlying the neuroadaptations caused by cocaine use disorder.
- In the nucleus accumbens, acute cocaine exposure reduces Dnmt and Tet1 mRNA levels initially but Dnmt levels rise with prolonged withdrawal while Tet levels remain low, indicating permanent methylation changes. Knockdown of Tet1 enhances cocaine seeking while overexpression reduces it.
- Specifically in the nucleus accumbens shell, Dnmt3a2 regulates plasticity genes to form cocaine-cue associations; reducing Dnmt3a2 decreases reinstatement of cocaine seeking but can cause compensatory elevation of Dnmt3b which
74th ICREA Colloquium "Autoimmunity meets neurodegeneration: different pathwa...ICREA
Studies during the last 10 years have revealed a new category of brain diseases in which crucial neuronal receptors are attacked by autoantibodies. As a result of this attack there is a reduction of the target synaptic proteins leading to alterations in synaptic transmission. The clinical manifestations vary according to the receptor involved, and may resemble many of the symptoms caused by neurodegenerative diseases in which specific receptors are involved, including among others Parkinson, epilepsy, chronically progressive sleep disease, or schizophrenia.
Adult rats were induced into status epilepticus (SE) using lithium chloride and pilocarpine. Ganaxolone (GNX) and diazepam (DZP), alone and in combination, were administered 15 minutes after SE onset. GNX (6 mg/kg) and sub-therapeutic DZP (5 mg/kg) together produced a complete block of SE, indicating a synergistic antiepileptic effect. Pharmacokinetic analysis found no interaction between the drugs. GNX effects on EEG were similar to propofol. The results suggest GNX enhances DZP's antiepileptic activity at GABA-A receptors and could improve treatment of refractory SE.
neurosteroid and neuropeptide biosynthetic pathway mechanism of action marketed formulation applications classifications recent findings refrences prepred by jonaid ali a student of m pharm 2nd sem jamia hamdard new delhi.
Epileptogenesis is the process by which normal brain tissue is transformed into tissue capable of generating spontaneous recurrent seizures. It involves multiple mechanisms including genetic and acquired factors. The hippocampus is particularly susceptible to epileptogenesis due to its circuitry. Status epilepticus animal models are commonly used to study the process. Epileptogenesis occurs in acute, subacute, and chronic stages. Acute changes include increased expression of immediate early genes and post-translational modifications of proteins. Subacute changes involve neuronal death, alterations in neurotrophic factors and inflammation. Chronic changes include mossy fiber sprouting and neurotransmission alterations.
The document describes research into discovering small molecule ligands that bind to the RhoA GTPase activator protein ARHGAP11A. Differential scanning fluorimetry was used to test 65 compounds for their ability to stabilize ARHGAP11A. Compounds ARG16 and ARG37 increased the protein's melting temperature in a concentration-dependent manner. Microscale thermophoresis confirmed ARG37 directly binds ARHGAP11A with a dissociation constant of 45.5 μM. Virtual screening of 5.9 million compounds led to experimental validation of 11 hits, including ARG037, that interact with ARHGAP11A.
This document discusses neuroactive steroids, which are steroids synthesized in the brain or other endocrine glands that rapidly alter neuronal excitability through interaction with receptors. They can have inhibitory or excitatory effects and are involved in many neurological and psychiatric conditions. Neuroactive steroids are also implicated in sex differences in brain disorder susceptibility. While their roles are increasingly understood, key questions remain regarding their regulatory mechanisms and impact on specific brain conditions and gender differences. Further research is needed to clarify their molecular mechanisms of action and therapeutic potential.
Murphy et al, AJP Cell Physiol 296_ C746–C756, 2009.Beth Murphy
Fasting enhances the response of hypothalamic arcuate nucleus neuropeptide Y (NPY) neurons that are inhibited by glucose (NPY-GI neurons) to decreases in extracellular glucose. Using hypothalamic explants from fed and fasted rats, the authors showed that fasting enhanced NPY release in response to lowered glucose concentrations. They also demonstrated that fasting caused NPY-GI neurons to depolarize, or become more electrically active, in response to smaller decreases in glucose levels. This increased responsiveness was mediated by the cellular energy sensor AMPK. During fasting, decreased leptin and glucose activate AMPK in NPY-GI neurons, making them more sensitive to fluctuations in glucose.
Nicholas Young, Sphingosine 1-phosphate Receptor Subtype Influence over Gliob...Nicholas Young
My talk presenting my thesis work per invitation of Research and Development Division of Genzyme Corporation to the Lipid Storage Disorders Department. October 5, 2007. Boston, MA: "Sphingosine 1-phosphate Receptor Subtype Influence over Glioblastoma Multiforme Pathology". My PhD was earned through the Integrated Biomedical Sciences, September 2007, The Ohio State University, College of Medicine Columbus, OH. Area of focus for my PhD: Biochemical and Molecular Disease Mechanisms. Dissertation title: Sphingosine 1-phosphate Receptor Subtype Influence Over Glioblastoma Multiforme Malignant Behavior"
Melatonin inhibits nitric oxide (NO)-induced relaxation in porcine coronary arteries by interfering with the NO/cGMP signaling pathway. Preliminary results show that melatonin selectively inhibits NO-induced relaxation via MT2 receptors localized in vascular smooth muscle cells. Melatonin inhibits the NO-induced increase in cGMP levels by potentially increasing phosphodiesterase type 5 (PDE5) activity and phosphorylation. The study aims to further elucidate the mechanisms of melatonin's inhibitory effects on NO/cGMP signaling and large conductance calcium-activated potassium (BKCa) channels.
a presentation on GABA including its synthesis, storage and degradation, types of receptors, and implications in various neuropsychiatric disorder, and finally a small chart on the drugs acting on GABA system.
This document discusses GABA, the major inhibitory neurotransmitter in the mammalian central nervous system. It covers GABA's synthesis, receptors (GABA-A and GABA-B), and role in neuropsychiatric conditions like anxiety disorders, mood disorders, schizophrenia, and epilepsy. Specifically, it notes that GABA serves an important regulatory role by reducing neuronal activity in areas like the amygdala and cortico-striatal-thalamo-cortical loop. Dysfunction of GABA signaling has been linked to these conditions.
This document discusses the management of seizures. It covers the approach to evaluating a patient with seizures, including common diagnostic tests. It then classifies traditional and newer antiepileptic drugs, describing their mechanisms of action and uses in treating different seizure disorders. The document discusses in detail several commonly used antiepileptic drugs, including phenytoin, carbamazepine, phenobarbital, vigabatrin, lamotrigine, felbamate, gabapentin, pregabalin, topiramate, and valproic acid. It also addresses status epilepticus, drug interactions, teratogenic effects, surgical treatment options, and newer drugs in development.
This document provides an overview of neurotransmitters and receptors. It discusses the mechanisms of fast neurotransmission mediated by neurotransmitters directly activating ligand-gated ion channels, as well as neuromodulation mediated by neurotransmitters binding to G-protein coupled receptors. The document outlines the major neurotransmitters - glutamate, GABA, glycine, acetylcholine - and covers their synthesis, release, reuptake, degradation and receptor systems. It also touches on the pharmacology of receptor agonists and antagonists.
Dougherty Bartley Lucas Hablitz Dobrunz Cowell 2014Elizabeth Lucas
This document summarizes a research article that studied the effects of lacking the transcriptional coactivator PGC-1α in mice. The summary is:
The study found that mice lacking PGC-1α exhibited increased amplitudes and decreased frequency of spontaneous inhibitory postsynaptic currents in motor cortex pyramidal neurons. Upon repetitive stimulation at gamma frequency, decreased GABA release was observed. PV-positive interneurons in PGC-1α−/− mice displayed reductions in intrinsic excitability and excitatory input without changes in morphology. The results indicate PGC-1α is required for normal inhibitory neurotransmission and cortical PV interneuron function. Deficiencies in PGC-1α may contribute to cortical hyperexcit
This document discusses glutamate receptors, including their history, types, roles, and drugs that act on them. It notes that glutamate is the major excitatory neurotransmitter in the central nervous system. There are two main types of glutamate receptors: ionotropic receptors which are ligand-gated ion channels including NMDA, AMPA, and kainate receptors, and metabotropic G protein-coupled receptors divided into groups 1, 2, and 3. The roles of glutamate receptors include synaptic plasticity, learning and memory, and excitotoxicity. Many drugs have been developed that act as agonists or antagonists at glutamate receptors and are being investigated for conditions like Alzheimer's, Parkinson
This document discusses amyloid-beta (Aβ) and tau in Alzheimer's disease (AD) pathogenesis. It states that Aβ accumulation triggers AD, and that Aβ oligomers interact with tau signaling pathways, leading to tau hyperphosphorylation and neurofibrillary tangles. Hyperphosphorylated tau then disrupts axonal transport. The document outlines various therapeutic targets for AD, including reducing Aβ accumulation, inhibiting tau hyperphosphorylation, and supporting acetylcholine and glutamate signaling.
The document outlines a research proposal to study the cellular mechanisms underlying cognitive deficits caused by traumatic brain injury (TBI). The central hypothesis is that TBI causes pathological alterations in GABAergic function that lead to imbalances in excitatory and inhibitory synaptic transmission in the hippocampus, resulting in hippocampal dysfunction and cognitive impairment. Three specific aims are described to characterize alterations in GABAergic function in the dentate gyrus and areas CA1 and CA3 of the hippocampus at one week and over months following TBI using electrophysiological and other techniques.
Decreases Expression of PGC-1α in the Alzheimer Disease Brain Impaire Mitocho...rana alhakimi
Alzheimer is the most neurodegenerative disorder in the aged people. It is characterized by senile, accumulation of amyloid plaque, neurofibrillary tangle and progressive decline in brain memory cells.
Alzheimer disease is associated with inflammatory response, synaptic damage and mitochondrial dysfunctions which are a prominent and early feature of Alzheimer disease.
The Role of DNA Methylation as an Epigenetic Mechanism of the Neuroadaptation...RachaelWong11
- DNA methylation and demethylation through enzymes like Dnmt and Tet act as an epigenetic mechanism underlying the neuroadaptations caused by cocaine use disorder.
- In the nucleus accumbens, acute cocaine exposure reduces Dnmt and Tet1 mRNA levels initially but Dnmt levels rise with prolonged withdrawal while Tet levels remain low, indicating permanent methylation changes. Knockdown of Tet1 enhances cocaine seeking while overexpression reduces it.
- Specifically in the nucleus accumbens shell, Dnmt3a2 regulates plasticity genes to form cocaine-cue associations; reducing Dnmt3a2 decreases reinstatement of cocaine seeking but can cause compensatory elevation of Dnmt3b which
74th ICREA Colloquium "Autoimmunity meets neurodegeneration: different pathwa...ICREA
Studies during the last 10 years have revealed a new category of brain diseases in which crucial neuronal receptors are attacked by autoantibodies. As a result of this attack there is a reduction of the target synaptic proteins leading to alterations in synaptic transmission. The clinical manifestations vary according to the receptor involved, and may resemble many of the symptoms caused by neurodegenerative diseases in which specific receptors are involved, including among others Parkinson, epilepsy, chronically progressive sleep disease, or schizophrenia.
Adult rats were induced into status epilepticus (SE) using lithium chloride and pilocarpine. Ganaxolone (GNX) and diazepam (DZP), alone and in combination, were administered 15 minutes after SE onset. GNX (6 mg/kg) and sub-therapeutic DZP (5 mg/kg) together produced a complete block of SE, indicating a synergistic antiepileptic effect. Pharmacokinetic analysis found no interaction between the drugs. GNX effects on EEG were similar to propofol. The results suggest GNX enhances DZP's antiepileptic activity at GABA-A receptors and could improve treatment of refractory SE.
neurosteroid and neuropeptide biosynthetic pathway mechanism of action marketed formulation applications classifications recent findings refrences prepred by jonaid ali a student of m pharm 2nd sem jamia hamdard new delhi.
Epileptogenesis is the process by which normal brain tissue is transformed into tissue capable of generating spontaneous recurrent seizures. It involves multiple mechanisms including genetic and acquired factors. The hippocampus is particularly susceptible to epileptogenesis due to its circuitry. Status epilepticus animal models are commonly used to study the process. Epileptogenesis occurs in acute, subacute, and chronic stages. Acute changes include increased expression of immediate early genes and post-translational modifications of proteins. Subacute changes involve neuronal death, alterations in neurotrophic factors and inflammation. Chronic changes include mossy fiber sprouting and neurotransmission alterations.
The document describes research into discovering small molecule ligands that bind to the RhoA GTPase activator protein ARHGAP11A. Differential scanning fluorimetry was used to test 65 compounds for their ability to stabilize ARHGAP11A. Compounds ARG16 and ARG37 increased the protein's melting temperature in a concentration-dependent manner. Microscale thermophoresis confirmed ARG37 directly binds ARHGAP11A with a dissociation constant of 45.5 μM. Virtual screening of 5.9 million compounds led to experimental validation of 11 hits, including ARG037, that interact with ARHGAP11A.
This document discusses neuroactive steroids, which are steroids synthesized in the brain or other endocrine glands that rapidly alter neuronal excitability through interaction with receptors. They can have inhibitory or excitatory effects and are involved in many neurological and psychiatric conditions. Neuroactive steroids are also implicated in sex differences in brain disorder susceptibility. While their roles are increasingly understood, key questions remain regarding their regulatory mechanisms and impact on specific brain conditions and gender differences. Further research is needed to clarify their molecular mechanisms of action and therapeutic potential.
Murphy et al, AJP Cell Physiol 296_ C746–C756, 2009.Beth Murphy
Fasting enhances the response of hypothalamic arcuate nucleus neuropeptide Y (NPY) neurons that are inhibited by glucose (NPY-GI neurons) to decreases in extracellular glucose. Using hypothalamic explants from fed and fasted rats, the authors showed that fasting enhanced NPY release in response to lowered glucose concentrations. They also demonstrated that fasting caused NPY-GI neurons to depolarize, or become more electrically active, in response to smaller decreases in glucose levels. This increased responsiveness was mediated by the cellular energy sensor AMPK. During fasting, decreased leptin and glucose activate AMPK in NPY-GI neurons, making them more sensitive to fluctuations in glucose.
Nicholas Young, Sphingosine 1-phosphate Receptor Subtype Influence over Gliob...Nicholas Young
My talk presenting my thesis work per invitation of Research and Development Division of Genzyme Corporation to the Lipid Storage Disorders Department. October 5, 2007. Boston, MA: "Sphingosine 1-phosphate Receptor Subtype Influence over Glioblastoma Multiforme Pathology". My PhD was earned through the Integrated Biomedical Sciences, September 2007, The Ohio State University, College of Medicine Columbus, OH. Area of focus for my PhD: Biochemical and Molecular Disease Mechanisms. Dissertation title: Sphingosine 1-phosphate Receptor Subtype Influence Over Glioblastoma Multiforme Malignant Behavior"
Melatonin inhibits nitric oxide (NO)-induced relaxation in porcine coronary arteries by interfering with the NO/cGMP signaling pathway. Preliminary results show that melatonin selectively inhibits NO-induced relaxation via MT2 receptors localized in vascular smooth muscle cells. Melatonin inhibits the NO-induced increase in cGMP levels by potentially increasing phosphodiesterase type 5 (PDE5) activity and phosphorylation. The study aims to further elucidate the mechanisms of melatonin's inhibitory effects on NO/cGMP signaling and large conductance calcium-activated potassium (BKCa) channels.
a presentation on GABA including its synthesis, storage and degradation, types of receptors, and implications in various neuropsychiatric disorder, and finally a small chart on the drugs acting on GABA system.
This document discusses GABA, the major inhibitory neurotransmitter in the mammalian central nervous system. It covers GABA's synthesis, receptors (GABA-A and GABA-B), and role in neuropsychiatric conditions like anxiety disorders, mood disorders, schizophrenia, and epilepsy. Specifically, it notes that GABA serves an important regulatory role by reducing neuronal activity in areas like the amygdala and cortico-striatal-thalamo-cortical loop. Dysfunction of GABA signaling has been linked to these conditions.
This document discusses the management of seizures. It covers the approach to evaluating a patient with seizures, including common diagnostic tests. It then classifies traditional and newer antiepileptic drugs, describing their mechanisms of action and uses in treating different seizure disorders. The document discusses in detail several commonly used antiepileptic drugs, including phenytoin, carbamazepine, phenobarbital, vigabatrin, lamotrigine, felbamate, gabapentin, pregabalin, topiramate, and valproic acid. It also addresses status epilepticus, drug interactions, teratogenic effects, surgical treatment options, and newer drugs in development.
This document provides an overview of neurotransmitters and receptors. It discusses the mechanisms of fast neurotransmission mediated by neurotransmitters directly activating ligand-gated ion channels, as well as neuromodulation mediated by neurotransmitters binding to G-protein coupled receptors. The document outlines the major neurotransmitters - glutamate, GABA, glycine, acetylcholine - and covers their synthesis, release, reuptake, degradation and receptor systems. It also touches on the pharmacology of receptor agonists and antagonists.
Dougherty Bartley Lucas Hablitz Dobrunz Cowell 2014Elizabeth Lucas
This document summarizes a research article that studied the effects of lacking the transcriptional coactivator PGC-1α in mice. The summary is:
The study found that mice lacking PGC-1α exhibited increased amplitudes and decreased frequency of spontaneous inhibitory postsynaptic currents in motor cortex pyramidal neurons. Upon repetitive stimulation at gamma frequency, decreased GABA release was observed. PV-positive interneurons in PGC-1α−/− mice displayed reductions in intrinsic excitability and excitatory input without changes in morphology. The results indicate PGC-1α is required for normal inhibitory neurotransmission and cortical PV interneuron function. Deficiencies in PGC-1α may contribute to cortical hyperexcit
This document summarizes a study investigating the effects of positive allosteric modulators of mGlu5 and GABAB receptors in animal models related to the positive, negative, and cognitive symptoms of schizophrenia. Specifically, the study examined the compounds CDPPB (an mGlu5 PAM), GS39783 and CGP7930 (GABAB PAMs) in models of negative/cognitive symptoms like the forced swim test, social interaction test, and novel object recognition test. The study also looked at effects in a model of positive symptoms (DOI-induced head twitches) and a model of motor symptoms (haloperidol-induced catalepsy). Results showed that both mGlu5 and G
This document summarizes several newer antiepileptic drugs (AEDs) that aim to inhibit abnormal neuronal discharge through enhancing GABA action, inhibiting sodium channels, or inhibiting calcium channels. It describes the mechanisms, indications, side effects, and pharmacokinetics of specific AEDs including vigabatrin, lamotrigine, felbamate, topiramate, gabapentin, pregabalin, tiagabine, levetiracetam, zonisamide, stiripentol, lacosamide, rufinamide, eslicarbazepine, ezogabine, and perampanel. It also discusses several drugs currently in development pipelines as well as concludes
Ms. Comenencia, a graduate student from the University of Puerto Rico at Cayey, gave a seminar on her research into the modulation of GABAa receptor trafficking by neurosteroids. Her research focuses on how neuroactive steroids can alter the GABAa receptor and affect its presence in brain cell membranes. Preliminary findings suggest increasing the level of GABAa receptors in membranes through neurosteroid modulation may help reduce side effects of conditions like autism and epilepsy.
Dr. kristen park kcnq2 Cure professional track - learn more at kcnq2cure.orgscottyandjim
Dr. Kristen Park speaking at 2014 Denver KCNQ2 Cure summit professionals track at Children's Hospital of Colorado. More information at www.kcnq2cure.org
GABA is the primary inhibitory neurotransmitter in the central nervous system. It is synthesized from glutamate and acts by binding to GABA-A and GABA-B receptors, allowing chloride ions to enter neurons and reduce excitability. Disruptions to GABA signaling are associated with disorders like epilepsy, anxiety, sleep disorders, and addiction. While drugs targeting GABA receptors are used to treat some of these, further research is still needed to better understand GABA's role in health and disease.
The document outlines the structural organization and functional circuits of the limbic system. It discusses key limbic structures like the hippocampus, amygdala, cingulate cortex, and their interconnections. It describes the medial and basolateral circuits of the limbic system and their roles in cognitive and emotional/affective processing. It also covers the neurophysiology of the limbic system including the roles of the neurotransmitter GABA and limbic system circuits like the Papez circuit. Finally, it discusses how the GABA system and limbic structures are involved in several neuropsychiatric disorders.
The document summarizes recent advances in understanding and treating Alzheimer's disease. It discusses both non-modifiable and modifiable risk factors for the disease. The major signs and symptoms include progressive memory loss and cognitive decline. Alzheimer's is confirmed through neuronal plaques and tangles seen in the brain. Recent treatment strategies aim to reduce amyloid plaques through vaccines, antibodies, and inhibitors of beta- and gamma-secretase. Other approaches include tau phosphorylation inhibitors, therapies for mitochondrial dysfunction, and cholinesterase inhibitors. Animal models continue to be important for studying the human APP, ApoE, and presenilin genes involved in Alzheimer's pathology.
The document discusses the role of glutamate neurotransmission in various psychiatric and substance use disorders. It notes that a paradigm shift from focusing on monoamine hypotheses to a neuroplasticity hypothesis centered around glutamate may help advance treatment for depression. It also discusses how thinking about schizophrenia and addiction from a glutamate perspective provides new receptor targets and conceptual opportunities. The document provides details on glutamate regulation and interactions with dopamine systems. It reviews evidence that drugs of abuse interact with and cause long-lasting changes to glutamate transmission. Two case reports are presented showing lamotrigine's effectiveness in reducing substance craving and symptoms by potentially impacting glutamate neurotransmission.
IJERA (International journal of Engineering Research and Applications) is International online, ... peer reviewed journal. For more detail or submit your article, please visit www.ijera.com
1) Sodium valproate is currently the first choice treatment for generalized epilepsy. It prevents high-frequency neuronal firing by modulating gamma-aminobutyric acid (GABA) and sodium ion concentrations in the brain.
2) Phenobarbital was historically one of the first treatments for epilepsy. It reduces seizure risk by enhancing the effects of the inhibitory neurotransmitter GABA in the brain.
3) Both drugs have been shown to effectively control seizures and reduce recurrence in clinical trials and animal studies, though they can cause side effects like sedation, vomiting, and liver toxicity.
1. Brandon Turner Receptors & Channels May 10, 2012
Investigating the Roles of GABAergic Inhibitory Currents in Epilepsy
Introduction
Epilepsy is one of the more common neurological disorders in humans and is
characterized by the occurrence of repeated seizures. Seizures themselves result from an area of
the brain exhibiting large amounts of depolarizing currents/over activity. For this reason, past
research has focused on an up-regulation of excitatory neurotransmission, such as AMPA
receptors, to be the cause of such over activity (Rogawski, 2011). However, treatment of seizures
with anti-convulsant that target excitability has proved to be less effective than desired. More
recent research has discussed the role of inhibitory currents, notably those mediated by the γ-
amino butyric acid (GABAA) type A receptor, which is responsible for the majority of the fast
inhibitory signaling in the brain. The GABAA receptor exists as a heteropentamer usually
comprised of two pairs of α and β subunits and a variable subunit (γ, δ, ρ, π, ε), each of which
may have several subtypes (α [1-6], β [1-3], etc). With such subunit variability and differences of
subunit expression levels in specific brain regions, the pharmacology of the GABAA receptor has
a high degree of variance. The receptor binds several allosteric potentiating ligands, such as
benzodiazepines (BZDs), which require the γ subunit, and neurosteroids which bind directly to
the α subunit.
The involvement of such receptors in epilepsy is bound to be highly complex. Indeed,
many factors can contribute to epilepsy via GABAergic currents, such as environmental
intoxicants like RDX (Williams et al 2011), developmental defects involving time of onset of
seizures (Briggs SW and Galanopoulou AS, 2011), regulation of GABA transport both, synaptic
2. 2
and extrasynaptic (Chiu et al 2005), neuronal migration (Bozzi et al 2012), or inherent genetic
factors (Gurba et al 2012, Macdonald et al 2009). It has also been shown that GABA subunit
composition changes during the course of seizures and epileptogenesis (Loup et al 2000).
Despite these problems, neurosteroids and benzodiazepines are known to be effective
anticonvulsants if administered with proper timing, yet some types of epilepsy, such as temporal
lobe epilepsy (TLE), remain resistant to such treatment. Clearly the role of GABAA in epilepsy is
not straightforward and requires additional investigation if a more conclusive understanding of
the disease and its treatment are to be found. In this review, I will focus on changes in
GABAergic inhibitory current due to developmental changes, GABA concentration variations in
multiple forms of epilepsy, and on receptor specific changes in temporal lobe epilepsy in the
hopes of directing future research to develop anticonvulsants targeting these receptors that more
accurately despite the inherent complexity of their role in epileptogenesis.
Developmental Malformations in GABAergic Systems
Developmental miscues can result in a host of neurological disorders that include many
subtypes of epilepsy. Some of these include genetic defects that decrease the migration of
GABAergic neurons to their proper positions, including interneurons of the cortex and
hippocampus. Two of these factors, Dlx and Reelin, have been shown in knockout and mutation
studies to impair the migration of such inhibitory neurons to the cortex and proper layer in the
hippocampus, respectively (Bozzi et al 2012), and have been implicated several forms of
epilepsy. Many other factors have been shown to induce epilepsy in model animals as well, all
concerning cellular circuits and positioning in the brain. Notably, Velisek et al have recently
shown that haploinsufficiency of BRD2 (Bromodomain- containing gene 2) in mice contributes
to lack of GABAergic neurons in the neocortex and striatum and a deficiency in GABAergic
3. 3
signaling in other regions of the brain associated with idiopathic generalized epilepsies. Clearly,
developmental factors and genetic regulation can play into developing epilepsy by removing
inhibition in different brain regions.
Other changes in normal neuronal function, most notably seizures at an early age, can
induce epilepsy in adult animal models. Depending on age, GABAA currents can be either
depolarizing (early age) or hyperpolarizing. Recently, this has been shown to be linked to the
concentration of Cl- within the cell, which affects GABAA subunit compositions (Succol et al
2012). The authors used both electrophysiological and immunostaining to show that changes in
intracellular chloride concentrations affected EGABA depending on the expression levels of
KCC2, a potassium/chloride cotransporter. Consistent with this data, it has been shown that
disruption of KCC2 funciton can contribute to early life seizures and that these seizures
themselves can alter GABAA subunit composition as well (Reviewed by Briggs SW,
Galanopoulou AS, 2011). It may be that a rapid influx of chloride ions due to compensatory
inhibition during seizures may contribute to the changes in GABAA receptor subunit
composition, or that changes in chloride trafficking may result in a reversion to immature-like
expression and function of GABAA receptors, causing them to be depolarizing rather than
inhibitory. Further research into the temporal allocation of shifts in chloride gradients,
transporter activity, and subunit composition during the ictal period of seizures may provide
insight into epileptogenesis.
Changes in Extracellular and Synaptic GABA Concentrations
Changes in GABA concentrations at the synapse due to disruptions in transport or
synthesis could contribute to altered levels of GABAA signaling, which could, in turn, contribute
4. 4
to epileptic phenotypes. As reviewed by Pavlov et al, 2012, “Reversal of GABA transport in
certain subpopulations of neurons or individual cells in epileptic tissue cannot be ruled out. Some
interneurons in chronic epilepsy may become metabolically more active, express more GAD and
have elevated intracellular GABA concentrations.” This speaks the idea that overexpression of
GAD (Glutamate Decarboxylase), which converts Glutamate to GABA, could raise intracellular
GABA and reverse transportation, which is largely dependent on voltage and concentration
gradients (Pavlov et al, 2012). Consistent with this, impaired GABA uptake by GABA
transporter deficiency has been shown to cause tremors and ataxia in mice (Chiu et al 2005).
Despite the possible negative roles of GAT impairment in epilepsy, it has been shown that GAT
impairment functions to increase tonic inhibition in epileptic rats (Frahm et al, 2003) by
increasing available GABA to the extrasynaptic, high affinity and slow desensitizing receptors.
In this sense, GABA transporters could serve as a possible drug target for anticonvulsants should
allosteric up-regulation be possible.
Much of the regulation of extrasynaptic GABA concentrations is dependent on the
function of GABA transporters in astrocytes. GAT-3, which is primarily found in astrocytes,
contributes substantially to extracellular GABA levels and can induce increased tonic inhibition
in the presensce of glutamate (Heja et al 2009). In vivo studies have also shown that uptake of
glutamate in hippocampal astrocytes is necessary for GABA release by GAT-2,3 and can convert
excess amounts of glutamate excitatory signaling to inhibition in an epileptic model (Heja et al
2012). Due to increased variability of GABAA subunits during seizures, increased tonic GABA
can initiate a negative feedback loop and prevent the spread of excess excitation to other brain
regions without the need of specifically designed drugs for the variant receptors. However, this
may not serve as an effective treatment for epilepsy, as past studies have demonstrated in vitro
5. 5
that increased extra-cellular GABA concentrations are not enough to mitigate the hyper-
excitability of hippocampal neurons in an epileptic model (Yeh et al 2005).
Since extracellular GABA levels and tonic inhibition seem to be inefficient at preventing
seizures, investigation of vesicular GABA transporters (VGAT) may provide insight into
mechanisms for preventing seizures. It has recently been shown that epileptic neurons, as
induced by excess exposure to glutamate, express a truncated form of VGAT that accumulates at
non-synaptic sites (Gomes et al 2011). However, removal of VGAT from vesicles contributes to
increased synaptic GABA concentrations, suggesting that VGAT truncation may serve as a
mechanism to increase inhibition in their model of temporal lobe epilepsy rather than furthering
the progression of the disease. Given that synaptic GABAA receptors desensitize more rapidly
than extrasynaptic receptors, it would seem that enhancing GABA at the synapse may also prove
to be ineffective at alleviating epileptogenesis. Since the level of GABA transport appears to be
providing negative feedback in epileptic models, their dysfunction could contribute to
epileptogenesis. However, due to their regulation by both voltage and concentration gradients,
modifying these transporters would prove difficult at the least, suggesting that changes in
receptor expression and subunit concentration could provide more insight into understanding
epileptogenesis and drug design.
GABA Receptor Expression and Composition Prior to and Following Seizures
Temporal lobe epilepsy (TLE) is among the most common forms of epilepsy in adults
and is mainly thought to arise from alterations in excitation/inhibition in the hippocampus (Joshi
et al 2011). Those with the disease normally display a loss of both CA1 and CA3 pyramidal
neurons and changes in receptor expression in dentate gyrus cells (DGCs). These changes have
6. 6
been shown by S. Joshi et al to lower neurosteroid sensitivity, which they attribute to changes in
seizure susceptibility of women dependent on the menstrual cycle (known to cause alterations in
the levels of endogenous neurosteroids in the brain). Indeed, recent studies have shown using
radiolabeled ligand binding that rats with temporal lobe epilepsy show decreased binding in the
cerebral cortex and further show that this corresponds to a decrease in expression of α1, γ, δ,
GABAB receptors, and GAD, the enzyme that converts glutamate to GABA (Mathew et al
2012). Past studies have also shown that changes in CA1 and CA3 cells include a marked
decrease in α1 subunit expression and an increase in α2/3 expression (Loup et al 2000). Also,
Rajasekaran et al had recently shown that the low affinity of neurosteroids for epileptic GABAA
receptors is likely due to lower incorporation of the δ subunit, which is down-regulated in TLE.
How intracellular mechanisms contribute to subunit regulation is currently not well understood,
but recent studies have shown that δ subunit incorporation is largely dependent on intracellular
[Cl-]. Increased intracellular [Cl] in the presence of a KCC2 knockdown decreased the amount of
δ subunit incorporated into receptors, as shown by immunostaining, present at the membrane, as
well as increasing the incorporation of α3 subunits and decreasing the incorporation of α1
subunits (Succol et al 2012). The authors focused on this shift of subunit incorporation primarily
to elucidate the shift of GABAA from depolarizing to hyperpolarizing during neuronal
development, which they showed to be mediated by KCC2 up-regulation. However, this could
also point to a method of altered subunit expression in epileptic animals, but whether the KCC2
ion transporter is involved is not known.
In addition to differential regulation of GABAA subunits during epilepsy, there is also a
loss of synaptic GABAA receptors that may be due to changes in gephyrin and collybistin
scaffolding. Past studies have shown that gephyrin preferentially binds to α2 and α3 subunits,
7. 7
while collybistin binds preferentially to α2 only. They assert that the subunit and the scaffolding
proteins form a trimeric complex via co-immunoprecipitation and that disruption of this
interaction may lead to epilepsy, as seen in a genetic mutation causing a change in the SH3
domain of collybistin which is known to cause mental disability and seizures (Saiepour et al
2010). More recent studies have also shown that gephyrin is able to bind to α1 subunits as well,
also using immunoprecipitation (Mukherjee et al 2011). Since α1-3 containing receptors are the
primary receptors found at synaptic sites, changes in gephyrin binding, expression, or
localization may contribute to loss of these receptors at the synapse and change the
pharmacological properties of these sites during epilepsy. Congruent with this idea, other studies
have shown that induction of status epilepticus alters gephyrin and neuroligin-2 expresssion, but
these did not have an effect on GABAA clustering . Mechanisms underlying the lack of
correlation between the two remain unexplained, but other studies have shown that such a
relationship does exist. Forstera et al had recently demonstrated that splicing of gephyrin exons
is altered in brain regions undergoing TLE or cellular stress which corresponded to a loss of α2
subunit containing receptors at the synapse. It is possible that a decrease of gephyrin binding and
the reported up-regulation of α2 GABAA subunits could contribute to an unnatural clustering of
these receptors at extra-synaptic sites, which normally contain α4 α6 subunits, specifically.
However, Forstera et al report that no concurrent mutations in gephyrin are concurrent with
temporal lobe epilepsy in humans, which may indicate that collybistin-gephyrin clustering, along
with their association with GABAA receptors is complex and requires additional study. Whether
these changes in protein scaffolding are reflect potential feedback mechanisms to stop
epileptogenesis or a method in which seizures are generated will require additional research and
8. 8
holds promise in understanding how spatial localization of inhibitory receptors may contribute to
TLE.
Most studies have alluded to the involvement of hippocampal neurons in the pathogenesis
of TLE, but, due to the aberrant shuffling of subunits and inherent neuro-plasticity that
accompanies seizures many forms of TLE have remained resistant to anti-convulsants. As
previously described, GABAA receptors in the hippocampus display lowered sensitivity to both
benzodiazepines and neurosteroids, possibly due to increases in α4 containing receptors, which
are insensitive to BZDs, and a decrease in δ containing receptors, which have a high sensitivity
to neurosteroids (Joshi et al 2011). A recent study has shown that other brain regions may be
involved in the propagation of excitatory signaling from the hippocampus and are involved in the
development of seizures. The thalamus, particularly the Thalamic Parafascicular Nucleus, has
been shown to be directly involved in the development of seizures (Langlois et al 2010).
Specifically, they show in vivo that inhibition of NMDA receptors and/or the presence of
GABAA antagonists injected into the TPN was sufficient to prevent behavioral effects following
the creation of an epileptic center in the hippocampus. In agreement with these findings, similar
data was published using muscimol to activate GABAA receptors in the mediodorsal region of
the thalamus and similar results were observed, most notably being the attenuation of seizure
duration (Sloan et al 2011). Although changes in receptor signaling and expression may be
present in the thalamus as well, it provides a novel target for preventing TLE behavioral effects
that circumvents the complex problem of receptor subunit regulation, shuffling, or changes in
ligand concentrations. Until the generation of seizures is fully understood, the thalamus may be
the best option for treating patients with TLE and provides a novel target for specific drugs that
could serve as anti-convulsants for TLE patients.
9. 9
Conclusion
Comprehending epilepsy from the molecular to the physiological level is a difficult gap
to bridge, but the numerous studies already done have shown many changes at both levels, both
before and after the occurrence of seizures. The myriad of developmental factors that could
contribute to the onset of epilepsy are not well understood beyond their number, yet the
numerous in ways in which they affect the nervous system, as per neuronal development and
migration or receptor/transporter mutations that cause aberrant signaling in mature neurons. This
significantly narrows the mechanisms in which developmental disorders can contribute to
epileptogenesis, but correcting neuronal migration in the brain is unlikely, while finding methods
that can target malformed regions and restore them to their normal inhibitory function by anti-
convulsant drugs is much more likely. GABA transporters, however, seem to serve a role as
increasing GABAergic current in epileptic areas of the brain and their selective modulation by
allosteric drugs would also prove arduous due to their voltage sensitivity and dependence on
intra/extra cellular GABA concentrations. It is possible that an increase in GAD activity may in
neurons or astrocytes may be able to shunt the concentration of GABA to favor increased
exportation, but it has been shown that increased ambient GABA at the synapse or in extra-
synaptic regions have been ineffective at preventing seizures. A more novel target would be
selective modulation of GABAA receptors to increase tonic and phasic inhibition, but the regions
affected by seizure generation display irregular GABAA subunit composition and pharmacology,
further complicating the effect of anti-convulsants. Also, TLE is markedly insensitive to anti-
convulsant drugs, perhaps due to this or the inability of such drugs to act in the epileptic centers.
Yet new research suggests that inhibiting the progression of seizures to other areas of the brain
via increased inhibition or decreased excitation in the thalamus may be an effective way of
10. 10
mitigating seizure genesis at a behavioral level. Although working in the hippocampus to
discover the origin of TLE genesis, preventing the spread of seizures from here by increased
inhibition in the thalamus may be the most effective direction to work with until the exact
mechanism of the marked increase in excitability of hippocampal neurons is discovered and
more specific drugs can be developed.
11. 11
References
Bozzi Y, Casarosa S and Caleo M. Epilepsy as a neurodevelopmental disorder (2012). Front.
Psych. 3(19): DOI: 10/3389/fpsyt.2012.00019.
Briggs SW and Galanopoulou AS. Altered GABA signaling in early life epilepsies (2011).
Neural Plasticity. 2011: DOI: 10.1155/2011/527605
Chiu CS, Brickley S, Jensen K. Southwell A, Mckinney S, Cull-Candy S, Mody I and Lester
HA. GABA transporter deficiency causes tremor, ataxia, nervousness, and increased
GABA-induced tonic conductance in cerebellum (2005). Journ. Neurosci. 25(12): 3234 –
3245.
Forstera B, Belaidi AA, Juttner R, Bernert C, Tsokos M, Lehmann TN, Horn P, Dehnicke C,
Schwarz G and Meir JC. Irregular RNA splicing curtails postsynaptic gephyrin in the
cornu ammonis of patients with epilepsy. Brain. 133:3778-3794.
Frahm C, Stief F, Zuschratter W, Draguh A. Unaltered control of extracellular GABA-
concentration through GAT-1 in the hippocampus of rats after pilocarpine-induced status
epilepticus (2003). Epilepsy Res. 52: 243-252
Gomes JR, Lobo AC, Melo CV, Inacio AR, Takano J, Iwata N, Saido TC, de Almeida LP,
Wieloch T and Duarte CB. Cleavage of the vesicular GABA transporter under
excitotoxic conditions is followed by accumulation of the truncated transporter in
nonsynaptic sites (2011). 31(12): 4622 – 4635.
Gurba KN, Hernandez CC, Hu N and Macdonald RL. The GABRB3 mutation, G32R, associated
with childhood absence epilepsy alters α1β3γ2L GABAA receptor expression and channel
gating (2012). Journ. Biol. Chem. 287, 12083-12097.
Heja L, Barabas P, Nyitrai G, Kekesi KA, Lasztoczi B, Toke O, Tarkanyi G, Madsen K,
Schousboe A, Dobolyi A, Palkovits M and Kardos J. Glutamate uptake triggers
transporter-mediated GABA release from astrocytes (2009). PLoS ONE. 4(9): e7153.
DOI:10.1371/jounal.pone.0007153.
Heja L, Nyitrai G, Kekesi O, Dobolyi A, Szabo P, Fiath R, Ulbert I, Pal-Szenthe B, Palkovits M
and Kardos J. Astrocytes convert network excitation to tonic inhibition of neurons
(2012). BMC Biology. 10(26): http://www.biomedcentral.com/1741-7007/10/26.
Jackson J, Chugh D, Nilsson P, Wood J, Carlstrom K, Lindvall O and Ekdahl CT. Altered
synaptic properties during integration of adult-born hippocampal neurons following a
seiaure insult (2012). PLoS One. 7(4). E35557.
Joshi S, Rajasekaran K, Kapur J. GABAergic transmission in temporal lobe epilepsy: The role of
neurosteroids (2011). Exp Neurol. Doi:10.1016/j.expneurol.2011.10.028
Langlois M, Polack PO, Bernard H, David O, Charpier S, Depaulis A, and Deransart C.
Involvement of the Thalamic Parafascicular Nucleus in Mesial Temporal Lobe Epilepsy
(2010). Journ. Neurosci. 300(49):16523-16535
12. 12
Loup F, Wieser HG, Yonekawa Y, Aguzzi A and Fritschy JM. Selective alterations in GABA A
subtypes in human temporal lobe epilepsy (2000). Journ. Neurosci. 20(14): 5401 – 5419.
Mathew J, Balakrishnan S, Antony S, Abraham PM and Paulose CS. Decreased GABA receptor
in the cerebral cortex of epileptic rats: effect of Bacopa monnieri and Bacoside-A (2012).
Journal of Biomedical Science. 19:25. http://www.jbiomedsci.com/content/19/1/25.
Mukherjee J, Kretschmannova K, Gouzer G, Maric HM, Ramsden S, Tretter V, Harvey K,
Davies PA, Triller A, Schindelin H and Moss SJ. The residence time of GABAARs at
inhibitory synapses is determined by direct binding of the receptor α1 subunit to gephyrin
(2011). Journ. Neurosci. 32(41):14677-14687.
Pavlov I & Walker MC. Tonic GABAA receptor-mediated signaling in temporal lobe epilepsy
(2012). Neuropharm. Doi:10.1016/j.neuropharm.2012.04.003
Rajasekaran K, Joshi S, Sun C, Mtchedlishvilli Z and Kapur J. Receptors with low affinity for
neurosteroids and GABA contribute to tonic inhibition of granule cells in epileptic
animals (2010). Neurobio. Disease. 40: 490-501.
Rogawski MA. Revisiting AMPA receptors as an antiepileptic drug target (2011). Epilep. Curr.
11(2): 56-63.
Saiepour L, Fuchs C, Patrizi A, Sassoe-Pognetto M, Harvey RJ and Harvey K. Complex role of
collybistin and gephyrin in GABAA receptor clustering (2010). Journ. Biol. Chem.
285(38): 29623-29631.
Sloan DM, Zhang DX, and Bertram EH III. Increased GABAergic inhibition in the midline
thalamus affects signaling and seizure spread in the hippocampus-prefrontal cortex
pathway (2011). Epilepsia. 52(3):523-530.
Succol F, Fiumelli H, Benfanati F, Cancedda L and Barberis A. Intracellular chloride
concentration influences the GABAA receptor subunit composition (2012). Nature
Comm. 3:738. DOI: 10.1038/ncomms1744.
Velisek L, Shang E, Velskova J, Chachau T, Macchiarulo S, Maglakelidze G, Wolgemuth DJ
and Greenberg DA. GABAergic neuron defecit as an idiopathic generalized epilepsy
mechanism: The role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy (2011).
PLoS One. 6(8): E23656.
Williams LR, Aroniadou-Anderjaska V, Qashu F, Finne H, Pidoplichko V, Bannon DI and Braga
MFM. RDX binds to the GABAA receptor-convulsant site and blocks GABAA receptor-
mediated currents in the amygdale: A mechanism for RDX-induced seizures. Envir.
Health. Persp. 119(3): 357 – 363.
Yeh JH, Jeng CJ, Chen YW, Lin HM, Wu YS and Tang CY. Selective enhancement of tonic
inhibition by increasing ambient GABA is insufficient to suppress excitotoxicity in
hippocampal neurons (2005). Biochem. Biophys. Res. Comm. 338: 1417-1425.