Autoradiographic localization of α5 subunit-containing GABAA receptors in rat brain

Sur, Cyrille; Fresu, Luigia Grazia; Howell, Owain W.; McKernan, Ruth M.; Atack, John

doi:10.1016/s0006-8993(99)01152-x

Cited by 147 publications

(125 citation statements)

References 16 publications

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Section: Discussionmentioning

confidence: 99%

“…The a5GABA A subunit shows a high affinity for GABA as well as a restricted pattern of expression, predominately in the HPC, with less expression in the cortex and thalamus (Heldt and Ressler, 2007;Ramos et al, 2004;Sur et al, 1999). In the adult HPC, a5GABA A R are located extrasynaptically, primarily in the dendritic fields of CA1, CA3, dentate gyrus, and subiculum (Sur et al, 1999). In addition, a5GABA A R expression and binding is greater in the ventral HPC, mainly stratum lacunosum-moleculare, in comparison with the dorsal HPC (Sarantis et al, 2008;Sotiriou et al, 2005), suggesting that targeted agonism of this GABA subunit would alter ventral HPC activity selectively.…”

Section: Discussionmentioning

confidence: 99%

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A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia

Gill

Lodge

Cook

et al. 2011

Neuropsychopharmacol

150

181

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We have shown previously that aberrant hippocampal (HPC) output underlies the dopamine (DA) dysfunction observed in the methylazoxymethanol acetate (MAM) developmental model of schizophrenia in the rodent. This alteration of HPC activity was proposed to result from a reduction in parvalbumin (PV)-expressing GABAergic interneurons and consequent destabilization of the output of pyramidal neurons, as well as disrupted activation across a broad neural network. In vivo extracellular recordings were performed in the ventral tegmental area (VTA) and ventral HPC of saline-(SAL) and MAM-treated animals. A novel benzodiazepine-positive allosteric modulator (PAM), selective for the a5 subunit of the GABA A receptor, SH-053-2 0 F-R-CH3, was tested for its effects on the output of the HPC, leading to dopamine system hyperactivity in MAM-treated animals. In addition, the effect of SH-053-2 0 F-R-CH3 on the hyperactive locomotor response to amphetamine in MAM animals was examined. We demonstrate that treatment with the a5GABA A R PAM reduced the number of spontaneously active DA neurons in the VTA of MAM animals to levels observed in SAL rats, both when administered systemically and when directly infused into the ventral HPC. Moreover, HPC neurons in both SAL and MAM animals showed diminished cortical-evoked responses following a5GABA A R PAM treatment. In addition, the increased locomotor response to amphetamine observed in MAM rats was reduced following a5GABA A R treatment. This study supports a novel treatment of schizophrenia that targets abnormal HPC output, which in turn normalizes dopaminergic neuronal activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia

Gill

Lodge

Cook

et al. 2011

Neuropsychopharmacol

150

181

View full text Add to dashboard Cite

show abstract

“…In the hippocampus, ␣5 subunit-containing GABA A Rs (␣5GABA A Rs) primarily populate the extrasynaptic regions of CA1 pyramidal neurons (Sur et al, 1999;Pirker et al, 2000), in which they generate a tonic inhibitory conductance (Caraiscos et al, 2004;Scimemi et al, 2005;Glykys and Mody, 2006;Glykys et al, 2008). These receptors are targets for memory-blocking drugs (Cheng et al, 2006;Martin et al, 2009); however, their physiological relevance requires additional clarification.…”

Section: Introductionmentioning

confidence: 99%

α5GABA_AReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory

Martin¹,

Zurek²,

MacDonald³

et al. 2010

J. Neurosci.

164

138

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Synaptic plasticity, which is the neuronal substrate for many forms of hippocampus-dependent learning, is attenuated by GABA type A receptor (GABA A R)-mediated inhibition. The prevailing notion is that a synaptic or phasic form of GABAergic inhibition regulates synaptic plasticity; however, little is known about the role of GABA A R subtypes that generate a tonic or persistent inhibitory conductance. We studied the regulation of synaptic plasticity by ␣5 subunit-containing GABA A Rs (␣5GABA A Rs), which generate a tonic inhibitory conductance in CA1 pyramidal neurons using electrophysiological recordings of field and whole-cell potentials in hippocampal slices from both wild-type and null mutant mice for the ␣5 subunit of the GABA A R (Gabra5 ؊/؊ mice). In addition, the strength of fearassociated memory was studied. The results showed that ␣5GABA A R activity raises the threshold for induction of long-term potentiation in a highly specific band of stimulation frequencies (10 -20 Hz) through mechanisms that are predominantly independent of inhibitory synaptic transmission. The deletion or pharmacological inhibition of ␣5GABA A Rs caused no change in baseline membrane potential or input resistance but increased depolarization during 10 Hz stimulation. The encoding of hippocampus-dependent memory was regulated by ␣5GABA A Rs but only under specific conditions that generate moderate but not robust forms of fear-associated learning. Thus, under specific conditions, ␣5GABA A R activity predominates over synaptic inhibition in modifying the strength of both synaptic plasticity in vitro and certain forms of memory in vivo.

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“…Each subunit consists of four α-helical transmembrane (TM) domains and a large extracellular amino-terminal domain that harbours the neurotransmitter binding sites and the signature 'cysteine-loop'. Receptors are constructed from a family of 19 different subunits (α [1][2][3][4][5][6] , β [1][2][3] , γ [1][2][3] , π, θ, ε, δ, andρ [1][2][3] ) plus a few splice variants. The most common stoichiometry in vivo is two α, two β and one γ subunit [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…For instance, studies on genetically modified mice have demonstrated that the widely distributed α 1 -containing GABA A Rs mediate the sedative and amnesic effects of the benzodiazepines (BZDs) whereas α 2 -and α 3 -containing receptors, located mainly in the forebrain, mediate their anticonvulsant and anxiolytic effects [2,5]. The high density of α 5 -containing GABA A Rs (α 5 GABA A Rs) in the hippocampus suggests this subunit may be implicated in cognition, learning and memory [2,6,7]. In addition to the BZDs, other drugs or drug classes such as propofol, barbiturates and neurosteroids are also clinically important GABA A R modulators for indications including anaesthesia, anxiolysis, sedation or epilepsy.…”

Section: Introductionmentioning

confidence: 99%

Selective Modulators of α<sub>5</sub>-Containing GABA<sub>A</sub> Receptors and their Therapeutic Significance

Soh

Lynch

2015

CDT

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Autoradiographic localization of α5 subunit-containing GABAA receptors in rat brain

Cited by 147 publications

References 16 publications

A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia

A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia

α5GABA_AReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory

Selective Modulators of α<sub>5</sub>-Containing GABA<sub>A</sub> Receptors and their Therapeutic Significance

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Autoradiographic localization of α5 subunit-containing GABAA receptors in rat brain

Cited by 147 publications

References 16 publications

A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia

A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia

α5GABAAReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory

Selective Modulators of α<sub>5</sub>-Containing GABA<sub>A</sub> Receptors and their Therapeutic Significance

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Product

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α5GABA_AReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory