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Differential distribution of proteins regulating GABA synthesis and reuptake in axon boutons of subpopulations of cortical interneurons.

ABSTRACT: Subclasses of ?-aminobutyric acid (GABA) interneurons differentially influence cortical network activity. The contribution of differences in GABA synthesis and reuptake in axon boutons to cell type-specific functions is unknown. GABA is synthesized within boutons by glutamic acid decarboxylase 65 (GAD65) and GAD67, while GAT1 is responsible for GABA reuptake. Using an imaging methodology capable of determining the colocalization frequency of different immunocytochemical labels in the same bouton and the quantification of the fluorescence intensity of each label in these same structures, we assessed the bouton levels of GAD65, GAD67, and GAT1 in parvalbumin-expressing chandelier (PV(ch)) and basket (PV(b)) neurons and cannabinoid 1 receptor-expressing basket (CB1r(b)) neurons in the monkey prefrontal cortex. We show that PV(ch) boutons almost exclusively contained GAD67, relative to GAD65, whereas CB1r(b) boutons contained mostly GAD65. In contrast, both GAD65 and GAD67 were easily detected in PV(b) boutons. Furthermore, in comparison with PV(ch) boutons, CB1r(b) boutons expressed low to undetectable levels of GAT1. Our findings provide a new basis for the distinctive functional roles of these perisomatic-innervating interneurons in cortical circuits. In addition, they strongly suggest that altered levels of GAD67 or GAD65, as seen in some psychiatric diseases, would have cell type-specific consequences on the modulation of GABA neurotransmission.

SUBMITTER: Fish KN

PROVIDER: S-EPMC3183419 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Differential distribution of proteins regulating GABA synthesis and reuptake in axon boutons of subpopulations of cortical interneurons.

Fish Kenneth N KN Sweet Robert A RA Lewis David A DA

Cerebral cortex (New York, N.Y. : 1991) 20110321 11

Subclasses of γ-aminobutyric acid (GABA) interneurons differentially influence cortical network activity. The contribution of differences in GABA synthesis and reuptake in axon boutons to cell type-specific functions is unknown. GABA is synthesized within boutons by glutamic acid decarboxylase 65 (GAD65) and GAD67, while GAT1 is responsible for GABA reuptake. Using an imaging methodology capable of determining the colocalization frequency of different immunocytochemical labels in the same bouton ...[more]

PMID: 21422269

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Project description:UNLABELLED:Although synapsins regulate GABA release, it is unclear which synapsin isoforms are involved. We identified the synapsin isoforms that regulate GABA release via rescue experiments in cultured hippocampal neurons from synapsin I, II, and III triple knock-out (TKO) mice. In situ hybridization indicated that five different synapsin isoforms are expressed in hippocampal interneurons. Evoked IPSC amplitude was reduced in TKO neurons compared with triple wild-type neurons and was rescued by introducing any of the five synapsin isoforms. This contrasts with hippocampal glutamatergic terminals, where only synapsin IIa rescues the TKO phenotype. Deconvolution analysis indicated that the duration of GABA release was prolonged in TKO neurons and this defect in release kinetics was rescued by each synapsin isoform, aside from synapsin IIIa. Because release kinetics remained slow, whereas peak release rate was rescued, there was a 2-fold increase in GABA release in TKO neurons expressing synapsin IIIa. TKO neurons expressing individual synapsin isoforms showed normal depression kinetics aside from more rapid depression in neurons expressing synapsin IIIa. Measurements of the cumulative amount of GABA released during repetitive stimulation revealed that the rate of mobilization of vesicles from the reserve pool to the readily releasable pool and the size of the readily releasable pool of GABAergic vesicles were unaffected by synapsins. Instead, synapsins regulate release of GABA from the readily releasable pool, with all isoforms aside from synapsin IIIa controlling release synchrony. These results indicate that synapsins play fundamentally distinct roles at different types of presynaptic terminals. SIGNIFICANCE STATEMENT:Synapsins are a family of proteins that regulate synaptic vesicle (SV) trafficking within nerve terminals. Here, we demonstrate that release of the inhibitory neurotransmitter GABA is supported by many different synapsin types. This contrasts with the release of other neurotransmitters, which typically is supported by only one type of synapsin. We also found that synapsins serve to synchronize the release of GABA in response to presynaptic action potentials, which is different from the synapsin-dependent trafficking of SVs in other nerve terminals. Our results establish that different synapsins play fundamentally different roles at nerve terminals releasing different types of neurotransmitters. This is an important clue to understanding how neurons release their neurotransmitters, a process essential for normal brain function.

Dataset Information

Differential distribution of proteins regulating GABA synthesis and reuptake in axon boutons of subpopulations of cortical interneurons.

Publications

Differential distribution of proteins regulating GABA synthesis and reuptake in axon boutons of subpopulations of cortical interneurons.

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