Vesicular Release of GABA by Mammalian Horizontal Cells Mediates Inhibitory Output to Photoreceptors
Open Access
- 1 December 2020
- journal article
- review article
- Published by Frontiers Media SA in Frontiers in Cellular Neuroscience
Abstract
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.Keywords
Funding Information
- National Institutes of Health
- U.S. Department of Veterans Affairs
- Research to Prevent Blindness
This publication has 177 references indexed in Scilit:
- Extrasynaptic GABAA Receptors: Their Function in the CNS and Implications for DiseaseNeuron, 2012
- Rod Vision Is Controlled by Dopamine-Dependent Sensitization of Rod Bipolar Cells by GABANeuron, 2011
- v-SNARE Composition Distinguishes Synaptic Vesicle PoolsNeuron, 2011
- SV2 Acts via Presynaptic Calcium to Regulate Neurotransmitter ReleaseNeuron, 2010
- Syntaxin-4 Defines a Domain for Activity-Dependent Exocytosis in Dendritic SpinesCell, 2010
- Immunocytochemical identification of proteins involved in dopamine release from the somatodendritic compartment of nigral dopaminergic neuronsNeuroscience, 2009
- Plasmalemmal and vesicular γ-aminobutyric acid transporter expression in the developing mouse retinaJournal of Comparative Neurology, 2008
- Syntaxin 3b is a t-SNARE specific for ribbon synapses of the retinaJournal of Comparative Neurology, 2008
- Anatomical and neurochemical characterization of dopaminergic interplexiform processes in mouse and rat retinasJournal of Comparative Neurology, 2008
- Robust syntaxin-4 immunoreactivity in mammalian horizontal cell processesVisual Neuroscience, 2007