TY - JOUR T1 - Targeted deletion of vesicular GABA transporter from retinal horizontal cells eliminates feedback modulation of photoreceptor calcium channels JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0148-15.2016 SP - ENEURO.0148-15.2016 AU - Arlene A. Hirano AU - Xue Liu AU - Jim Boulter AU - James Grove AU - Luis Pérez de Sevilla Müller AU - Steven Barnes AU - Nicholas C. Brecha Y1 - 2016/02/29 UR - http://www.eneuro.org/content/early/2016/02/28/ENEURO.0148-15.2016.abstract N2 - The cellular mechanisms underlying feedback signaling from horizontal cells to photoreceptors, important for formation of receptive field surrounds of early visual neurons, remain unsettled. Mammalian horizontal cells express a complement of synaptic proteins that are necessary and sufficient for calcium-dependent exocytosis of inhibitory neurotransmitters at their contacts with photoreceptor terminals, suggesting that they are capable of releasing GABA via vesicular release. To test if horizontal cell vesicular release is involved in feedback signaling, we perturbed inhibitory neurotransmission in these cells by targeted deletion of the vesicular GABA transporter (VGAT), the protein responsible for uptake of inhibitory transmitter by synaptic vesicles. To manipulate horizontal cells selectively, an iCre mouse line with Cre recombinase expression controlled by connexin57 (Cx57) regulatory elements was generated. In Cx57-iCre mouse retina, only horizontal cells expressed Cre protein and its expression occurred in all retinal regions. After crossing with a VGATflox/flox mouse line, VGAT was selectively eliminated from horizontal cells, which was confirmed immunohistochemically. Voltage-gated ion channel currents in horizontal cells of Cx57-VGAT-/- mice were the same as Cx57-VGAT+/+ controls, as were the cells’ responses to the ionotropic glutamate receptor agonist, kainate, but the response to the GABAA receptor agonist, muscimol, in Cx57-VGAT-/- mice was larger. In contrast, feedback inhibition of photoreceptor calcium channels, which in control animals is induced by horizontal cell depolarization, was completely absent in Cx57-VGAT-/- mice. The results suggest that vesicular release of GABA from horizontal cells is required for feedback inhibition of photoreceptors.Significance Statement: Feedback inhibition by horizontal cells regulates the photoreceptor calcium channels responsible for the release of the neurotransmitter, glutamate. This feedback inhibition contributes to the formation of the receptive field surrounds of early visual neurons, important for contrast sensitivity and color opponency in vision. The cellular mechanisms underlying feedback inhibition are not fully understood. One disputed mechanism for mammalian horizontal cell inhibitory output involves the vesicular release of the inhibitory neurotransmitter, GABA. By deleting selectively the transporter that normally loads GABA into vesicles in horizontal cells, we show that horizontal cells lose their ability to modulate photoreceptor calcium signals. These findings implicate a role for the vesicular release of GABA in mediating inhibitory feedback. ER -