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GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions.
Gerhard DM, Pothula S, Liu RJ, Wu M, Li XY, Girgenti MJ, Taylor SR, Duman CH, Delpire E, Picciotto M, Wohleb ES, Duman RS
(2020) J Clin Invest 130: 1336-1349
MeSH Terms: Animals, Antidepressive Agents, Female, GABAergic Neurons, Gene Knockout Techniques, Glutamate Decarboxylase, Interneurons, Ketamine, Male, Mice, Mice, Transgenic, Parvalbumins, Receptors, N-Methyl-D-Aspartate, Sex Characteristics, Somatostatin
Show Abstract · Added March 18, 2020
A single subanesthetic dose of ketamine, an NMDA receptor (NMDAR) antagonist, produces rapid and sustained antidepressant actions in depressed patients, addressing a major unmet need for the treatment of mood disorders. Ketamine produces a rapid increase in extracellular glutamate and synaptic formation in the prefrontal cortex, but the initial cellular trigger that initiates this increase and ketamine's behavioral actions has not been identified. To address this question, we used a combination of viral shRNA and conditional mutation to produce cell-specific knockdown or deletion of a key NMDAR subunit, GluN2B, implicated in the actions of ketamine. The results demonstrated that the antidepressant actions of ketamine were blocked by GluN2B-NMDAR knockdown on GABA (Gad1) interneurons, as well as subtypes expressing somatostatin (Sst) or parvalbumin (Pvalb), but not glutamate principle neurons in the medial prefrontal cortex (mPFC). Further analysis of GABA subtypes showed that cell-specific knockdown or deletion of GluN2B in Sst interneurons blocked or occluded the antidepressant actions of ketamine and revealed sex-specific differences that are associated with excitatory postsynaptic currents on mPFC principle neurons. These findings demonstrate that GluN2B-NMDARs on GABA interneurons are the initial cellular trigger for the rapid antidepressant actions of ketamine and show sex-specific adaptive mechanisms to GluN2B modulation.
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15 MeSH Terms
A Role for Dystonia-Associated Genes in Spinal GABAergic Interneuron Circuitry.
Zhang J, Weinrich JAP, Russ JB, Comer JD, Bommareddy PK, DiCasoli RJ, Wright CVE, Li Y, van Roessel PJ, Kaltschmidt JA
(2017) Cell Rep 21: 666-678
MeSH Terms: Animals, Biomarkers, Dystonia, GABAergic Neurons, Genetic Predisposition to Disease, Interneurons, Male, Mice, Mutant Strains, Molecular Chaperones, Mutation, Nerve Net, Presynaptic Terminals, Proprioception, Spinal Cord, Transcription Factors
Show Abstract · Added November 7, 2017
Spinal interneurons are critical modulators of motor circuit function. In the dorsal spinal cord, a set of interneurons called GABApre presynaptically inhibits proprioceptive sensory afferent terminals, thus negatively regulating sensory-motor signaling. Although deficits in presynaptic inhibition have been inferred in human motor diseases, including dystonia, it remains unclear whether GABApre circuit components are altered in these conditions. Here, we use developmental timing to show that GABApre neurons are a late Ptf1a-expressing subclass and localize to the intermediate spinal cord. Using a microarray screen to identify genes expressed in this intermediate population, we find the kelch-like family member Klhl14, implicated in dystonia through its direct binding with torsion-dystonia-related protein Tor1a. Furthermore, in Tor1a mutant mice in which Klhl14 and Tor1a binding is disrupted, formation of GABApre sensory afferent synapses is impaired. Our findings suggest a potential contribution of GABApre neurons to the deficits in presynaptic inhibition observed in dystonia.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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15 MeSH Terms
Reduced ethanol drinking following selective cortical interneuron deletion of the GluN2B NMDA receptors subunit.
Radke AK, Jury NJ, Delpire E, Nakazawa K, Holmes A
(2017) Alcohol 58: 47-51
MeSH Terms: Alcohol Drinking, Animals, Cerebral Cortex, Choice Behavior, Ethanol, Female, Gene Deletion, Interneurons, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Protein Subunits, Receptors, N-Methyl-D-Aspartate
Show Abstract · Added May 3, 2017
N-Methyl-d-aspartate receptors (NMDAR) are involved in the regulation of alcohol drinking, but the contribution of NMDAR subunits located on specific neuronal populations remains incompletely understood. The current study examined the role of GluN2B-containing NMDARs expressed on cortical principal neurons and cortical interneurons in mouse ethanol drinking. Consumption of escalating concentrations of ethanol was measured in mice with GluN2B gene deletion in either cortical principal neurons (GluN2B) or interneurons (GluN2B), using a two-bottle choice paradigm. Results showed that GluN2B, but not GluN2B, mice consumed significantly less ethanol, at relatively high concentrations, than non-mutant controls. In a second paradigm in which mice were offered a 15% ethanol concentration, without escalation, GluN2B mice were again no different from controls. These findings provide novel evidence for a contribution of interneuronal GluN2B-containing NMDARs in the regulation of ethanol drinking.
Copyright © 2016 Elsevier Inc. All rights reserved.
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15 MeSH Terms
Optogenetic versus electrical stimulation of dopamine terminals in the nucleus accumbens reveals local modulation of presynaptic release.
Melchior JR, Ferris MJ, Stuber GD, Riddle DR, Jones SR
(2015) J Neurochem 134: 833-44
MeSH Terms: Acetylcholine, Animals, Artifacts, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Channelrhodopsins, Cholinergic Neurons, Dopamine, Dopaminergic Neurons, Electric Stimulation, GABA-B Receptor Antagonists, GABAergic Neurons, Gene Knock-In Techniques, Interneurons, Male, Mice, Mice, Inbred C57BL, Microelectrodes, Nerve Tissue Proteins, Nucleus Accumbens, Optogenetics, Phosphinic Acids, Presynaptic Terminals, Promoter Regions, Genetic, Propanolamines, Synapses, Tyrosine 3-Monooxygenase, Ventral Tegmental Area, gamma-Aminobutyric Acid
Show Abstract · Added March 30, 2020
The nucleus accumbens is highly heterogeneous, integrating regionally distinct afferent projections and accumbal interneurons, resulting in diverse local microenvironments. Dopamine (DA) neuron terminals similarly express a heterogeneous collection of terminal receptors that modulate DA signaling. Cyclic voltammetry is often used to probe DA terminal dynamics in brain slice preparations; however, this method traditionally requires electrical stimulation to induce DA release. Electrical stimulation excites all of the neuronal processes in the stimulation field, potentially introducing simultaneous, multi-synaptic modulation of DA terminal release. We used optogenetics to selectively stimulate DA terminals and used voltammetry to compare DA responses from electrical and optical stimulation of the same area of tissue around a recording electrode. We found that with multiple pulse stimulation trains, optically stimulated DA release increasingly exceeded that of electrical stimulation. Furthermore, electrical stimulation produced inhibition of DA release across longer duration stimulations. The GABAB antagonist, CGP 55845, increased electrically stimulated DA release significantly more than light stimulated release. The nicotinic acetylcholine receptor antagonist, dihydro-β-erythroidine hydrobromide, inhibited single pulse electrically stimulated DA release while having no effect on optically stimulated DA release. Our results demonstrate that electrical stimulation introduces local multi-synaptic modulation of DA release that is absent with optogenetically targeted stimulation.
© 2015 International Society for Neurochemistry.
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MeSH Terms
Activation of Metabotropic Glutamate Receptor 7 Is Required for Induction of Long-Term Potentiation at SC-CA1 Synapses in the Hippocampus.
Klar R, Walker AG, Ghose D, Grueter BA, Engers DW, Hopkins CR, Lindsley CW, Xiang Z, Conn PJ, Niswender CM
(2015) J Neurosci 35: 7600-15
MeSH Terms: Animals, CA1 Region, Hippocampal, CA3 Region, Hippocampal, Channelrhodopsins, Electric Stimulation, Excitatory Amino Acid Agonists, Excitatory Amino Acid Antagonists, Hippocampus, In Vitro Techniques, Inhibitory Postsynaptic Potentials, Interneurons, Long-Term Potentiation, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Parvalbumins, Patch-Clamp Techniques, Receptors, Metabotropic Glutamate
Show Abstract · Added February 18, 2016
Of the eight metabotropic glutamate (mGlu) receptor subtypes, only mGlu7 is expressed presynaptically at the Schaffer collateral (SC)-CA1 synapse in the hippocampus in adult animals. Coupled with the inhibitory effects of Group III mGlu receptor agonists on transmission at this synapse, mGlu7 is thought to be the predominant autoreceptor responsible for regulating glutamate release at SC terminals. However, the lack of mGlu7-selective pharmacological tools has hampered direct testing of this hypothesis. We used a novel, selective mGlu7-negative allosteric modulator (NAM), ADX71743, and a newly described Group III mGlu receptor agonist, LSP4-2022, to elucidate the role of mGlu7 in modulating transmission in hippocampal area CA1 in adult C57BL/6J male mice. Interestingly, although mGlu7 agonists inhibit SC-CA1 EPSPs, we found no evidence for activation of mGlu7 by stimulation of SC-CA1 afferents. However, LSP4-2022 also reduced evoked monosynaptic IPSCs in CA1 pyramidal cells and, in contrast to its effect on SC-CA1 EPSPs, ADX71743 reversed the ability of high-frequency stimulation of SC afferents to reduce IPSC amplitudes. Furthermore, blockade of mGlu7 prevented induction of LTP at the SC-CA1 synapse and activation of mGlu7 potentiated submaximal LTP. Together, these data suggest that mGlu7 serves as a heteroreceptor at inhibitory synapses in area CA1 and that the predominant effect of activation of mGlu7 by stimulation of glutamatergic afferents is disinhibition, rather than reduced excitatory transmission. Furthermore, this mGlu7-mediated disinhibition is required for induction of LTP at the SC-CA1 synapse, suggesting that mGlu7 could serve as a novel therapeutic target for treatment of cognitive disorders.
Copyright © 2015 the authors 0270-6474/15/357600-16$15.00/0.
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20 MeSH Terms
Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes.
Brown JA, Ramikie TS, Schmidt MJ, Báldi R, Garbett K, Everheart MG, Warren LE, Gellért L, Horváth S, Patel S, Mirnics K
(2015) Mol Psychiatry 20: 1499-507
MeSH Terms: Animals, Behavior, Animal, Brain, Disease Models, Animal, Electrophysiology, Exploratory Behavior, Fear, Gene Silencing, Glutamate Decarboxylase, Interneurons, Ketamine, Male, Mice, Mice, Inbred C3H, Mice, Transgenic, Parvalbumins, Receptors, N-Methyl-D-Aspartate, Schizophrenia, Sensory Gating, Synaptic Transmission
Show Abstract · Added February 12, 2015
Reduced expression of the Gad1 gene-encoded 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of schizophrenia. GAD67 downregulation occurs in multiple interneuronal sub-populations, including the parvalbumin-positive (PVALB+) cells. To investigate the role of the PV-positive GABAergic interneurons in behavioral and molecular processes, we knocked down the Gad1 transcript using a microRNA engineered to target specifically Gad1 mRNA under the control of Pvalb bacterial artificial chromosome. Verification of construct expression was performed by immunohistochemistry. Follow-up electrophysiological studies revealed a significant reduction in γ-aminobutyric acid (GABA) release probability without alterations in postsynaptic membrane properties or changes in glutamatergic release probability in the prefrontal cortex pyramidal neurons. Behavioral characterization of our transgenic (Tg) mice uncovered that the Pvalb/Gad1 Tg mice have pronounced sensorimotor gating deficits, increased novelty-seeking and reduced fear extinction. Furthermore, NMDA (N-methyl-d-aspartate) receptor antagonism by ketamine had an opposing dose-dependent effect, suggesting that the differential dosage of ketamine might have divergent effects on behavioral processes. All behavioral studies were validated using a second cohort of animals. Our results suggest that reduction of GABAergic transmission from PVALB+ interneurons primarily impacts behavioral domains related to fear and novelty seeking and that these alterations might be related to the behavioral phenotype observed in schizophrenia.
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20 MeSH Terms
Loss of dopamine D2 receptors increases parvalbumin-positive interneurons in the anterior cingulate cortex.
Graham DL, Durai HH, Garden JD, Cohen EL, Echevarria FD, Stanwood GD
(2015) ACS Chem Neurosci 6: 297-305
MeSH Terms: Animals, Cell Count, Depression, Emotions, Female, GABAergic Neurons, Glutamate Decarboxylase, Green Fluorescent Proteins, Gyrus Cinguli, Immunohistochemistry, In Situ Hybridization, Fluorescence, Interneurons, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Neuropsychological Tests, Parvalbumins, Receptors, Dopamine D2
Show Abstract · Added January 20, 2015
Disruption to dopamine homeostasis during brain development has been implicated in a variety of neuropsychiatric disorders, including depression and schizophrenia. Inappropriate expression or activity of GABAergic interneurons are common features of many of these disorders. We discovered a persistent upregulation of GAD67+ and parvalbumin+ neurons within the anterior cingulate cortex of dopamine D2 receptor knockout mice, while other GABAergic interneuron markers were unaffected. Interneuron distribution and number were not altered in the striatum or in the dopamine-poor somatosensory cortex. The changes were already present by postnatal day 14, indicating a developmental etiology. D2eGFP BAC transgenic mice demonstrated the presence of D2 receptor expression within a subset of parvalbumin-expressing cortical interneurons, suggesting the possibility of a direct cellular mechanism through which D2 receptor stimulation regulates interneuron differentiation or survival. D2 receptor knockout mice also exhibited decreased depressive-like behavior compared with wild-type controls in the tail suspension test. These data indicate that dopamine signaling modulates interneuron number and emotional behavior and that developmental D2 receptor loss or blockade could reveal a potential mechanism for the prodromal basis of neuropsychiatric disorders.
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19 MeSH Terms
Microcircuitry of agranular frontal cortex: testing the generality of the canonical cortical microcircuit.
Godlove DC, Maier A, Woodman GF, Schall JD
(2014) J Neurosci 34: 5355-69
MeSH Terms: Action Potentials, Animals, Brain Mapping, Evoked Potentials, Visual, Female, Frontal Lobe, Interneurons, Macaca mulatta, Macaca radiata, Male, Pyramidal Cells, Reaction Time, Synaptic Potentials, Visual Cortex
Show Abstract · Added February 12, 2015
We investigated whether a frontal area that lacks granular layer IV, supplementary eye field, exhibits features of laminar circuitry similar to those observed in primary sensory areas. We report, for the first time, visually evoked local field potentials (LFPs) and spiking activity recorded simultaneously across all layers of agranular frontal cortex using linear electrode arrays. We calculated current source density from the LFPs and compared the laminar organization of evolving sinks to those reported in sensory areas. Simultaneous, transient synaptic current sinks appeared first in layers III and V followed by more prolonged current sinks in layers I/II and VI. We also found no variation of single- or multi-unit visual response latency across layers, and putative pyramidal neurons and interneurons displayed similar response latencies. Many units exhibited pronounced discharge suppression that was strongest in superficial relative to deep layers. Maximum discharge suppression also occurred later in superficial than in deep layers. These results are discussed in the context of the canonical cortical microcircuit model originally formulated to describe early sensory cortex. The data indicate that agranular cortex resembles sensory areas in certain respects, but the cortical microcircuit is modified in nontrivial ways.
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14 MeSH Terms
Temporal identity transition from Purkinje cell progenitors to GABAergic interneuron progenitors in the cerebellum.
Seto Y, Nakatani T, Masuyama N, Taya S, Kumai M, Minaki Y, Hamaguchi A, Inoue YU, Inoue T, Miyashita S, Fujiyama T, Yamada M, Chapman H, Campbell K, Magnuson MA, Wright CV, Kawaguchi Y, Ikenaka K, Takebayashi H, Ishiwata S, Ono Y, Hoshino M
(2014) Nat Commun 5: 3337
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cells, Cultured, Cerebellum, GABAergic Neurons, Immunohistochemistry, Interneurons, Mice, Nerve Tissue Proteins, Oligodendrocyte Transcription Factor 2, Purkinje Cells, Stem Cells, Transcription Factors
Show Abstract · Added March 14, 2014
In the cerebellum, all GABAergic neurons are generated from the Ptf1a-expressing ventricular zone (Ptf1a domain). However, the machinery to produce different types of GABAergic neurons remains elusive. Here we show temporal regulation of distinct GABAergic neuron progenitors in the cerebellum. Within the Ptf1a domain at early stages, we find two subpopulations; dorsally and ventrally located progenitors that express Olig2 and Gsx1, respectively. Lineage tracing reveals the former are exclusively Purkinje cell progenitors (PCPs) and the latter Pax2-positive interneuron progenitors (PIPs). As development proceeds, PCPs gradually become PIPs starting from ventral to dorsal. In gain- and loss-of-function mutants for Gsx1 and Olig1/2, we observe abnormal transitioning from PCPs to PIPs at inappropriate developmental stages. Our findings suggest that the temporal identity transition of cerebellar GABAergic neuron progenitors from PCPs to PIPs is negatively regulated by Olig2 and positively by Gsx1, and contributes to understanding temporal control of neuronal progenitor identities.
3 Communities
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13 MeSH Terms
Modulation of behavioral networks by selective interneuronal inactivation.
Schmidt MJ, Horvath S, Ebert P, Norris JL, Seeley EH, Brown J, Gellert L, Everheart M, Garbett KA, Grice TW, Caprioli RM, Mirnics K
(2014) Mol Psychiatry 19: 580-7
MeSH Terms: Amphetamine, Animals, Anxiety, Behavior, Brain, Central Nervous System Stimulants, Cholecystokinin, Glutamate Decarboxylase, Interneurons, Male, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neuropeptide Y, Olfactory Perception, Proteomics, Social Behavior, gamma-Aminobutyric Acid
Show Abstract · Added March 20, 2014
Gamma-aminobutyric acid (GABA)-ergic disturbances are hallmark features of schizophrenia and other neuropsychiatric disorders and encompass multiple interneuronal cell types. Using bacterial artificial chromosome-driven, miRNA silencing technology we generated transgenic mouse lines that suppress glutamic acid decarboxylase 1 (GAD1) in either cholecystokinin (CCK)- or neuropeptide Y (NPY)-expressing interneurons. In situ lipidomic and proteomic analyses on brain tissue sections revealed distinct, brain region-specific profiles in each transgenic line. Behavioral analyses revealed that suppression of GAD1 in CCK+ interneurons resulted in locomotor and olfactory sensory changes, whereas suppression in NPY+ interneurons affected anxiety-related behaviors and social interaction. Both transgenic mouse lines had altered sensitivity to amphetamine albeit in opposite directions. Together, these data argue that reduced GAD1 expression leads to altered molecular and behavioral profiles in a cell type-dependent manner, and that these subpopulations of interneurons are strong and opposing modulators of dopamine system function. Furthermore, our findings also support the hypothesis that neuronal networks are differentially controlled by diverse inhibitory subnetworks.
2 Communities
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18 MeSH Terms