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Mood regulation. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment.

ABSTRACT: The lateral habenula (LHb), a key regulator of monoaminergic brain regions, is activated by negatively valenced events. Its hyperactivity is associated with depression. Although enhanced excitatory input to the LHb has been linked to depression, little is known about inhibitory transmission. We discovered that ?-aminobutyric acid (GABA) is co-released with its functional opponent, glutamate, from long-range basal ganglia inputs (which signal negative events) to limit LHb activity in rodents. At this synapse, the balance of GABA/glutamate signaling is shifted toward reduced GABA in a model of depression and increased GABA by antidepressant treatment. GABA and glutamate co-release therefore controls LHb activity, and regulation of this form of transmission may be important for determining the effect of negative life events on mood and behavior.

SUBMITTER: Shabel SJ

PROVIDER: S-EPMC4305433 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Mood regulation. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment.

Shabel Steven J SJ Proulx Christophe D CD Piriz Joaquin J Malinow Roberto R

Science (New York, N.Y.) 20140918 6203

The lateral habenula (LHb), a key regulator of monoaminergic brain regions, is activated by negatively valenced events. Its hyperactivity is associated with depression. Although enhanced excitatory input to the LHb has been linked to depression, little is known about inhibitory transmission. We discovered that γ-aminobutyric acid (GABA) is co-released with its functional opponent, glutamate, from long-range basal ganglia inputs (which signal negative events) to limit LHb activity in rodents. At ...[more]

PMID: 25237099

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Project description:Feedback inhibition by horizontal cells regulates rod and cone photoreceptor calcium channels that control their release of the neurotransmitter glutamate. This inhibition contributes to synaptic gain control and the formation of the center-surround antagonistic receptive fields passed on to all downstream neurons, which is important for contrast sensitivity and color opponency in vision. In contrast to the plasmalemmal GABA transporter found in non-mammalian horizontal cells, there is evidence that the mechanism by which mammalian horizontal cells inhibit photoreceptors involves the vesicular release of the inhibitory neurotransmitter GABA. Historically, inconsistent findings of GABA and its biosynthetic enzyme, L-glutamate decarboxylase (GAD) in horizontal cells, and the apparent lack of surround response block by GABAergic agents diminished support for GABA's role in feedback inhibition. However, the immunolocalization of the vesicular GABA transporter (VGAT) in the dendritic and axonal endings of horizontal cells that innervate photoreceptor terminals suggested GABA was released via vesicular exocytosis. To test the idea that GABA is released from vesicles, we localized GABA and GAD, multiple SNARE complex proteins, synaptic vesicle proteins, and Cav channels that mediate exocytosis to horizontal cell dendritic tips and axonal terminals. To address the perceived relative paucity of synaptic vesicles in horizontal cell endings, we used conical electron tomography on mouse and guinea pig retinas that revealed small, clear-core vesicles, along with a few clathrin-coated vesicles and endosomes in horizontal cell processes within photoreceptor terminals. Some small-diameter vesicles were adjacent to the plasma membrane and plasma membrane specializations. To assess vesicular release, a functional assay involving incubation of retinal slices in luminal VGAT-C antibodies demonstrated vesicles fused with the membrane in a depolarization- and calcium-dependent manner, and these labeled vesicles can fuse multiple times. Finally, targeted elimination of VGAT in horizontal cells resulted in a loss of tonic, autaptic GABA currents, and of inhibitory feedback modulation of the cone photoreceptor Cai, consistent with the elimination of GABA release from horizontal cell endings. These results in mammalian retina identify the central role of vesicular release of GABA from horizontal cells in the feedback inhibition of photoreceptors.

Dataset Information

Mood regulation. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment.

Publications

Mood regulation. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment.

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