Evidence for functional GABA_A but not GABA_C receptors in mouse cone photoreceptors

Abstract

At the first retinal synapse, horizontal cells (HCs) contact both photoreceptor terminals and bipolar cell dendrites, modulating information transfer between these two cell types to enhance spatial contrast and mediate color opponency. The synaptic mechanisms through which these modulations occur are still debated. The initial hypothesis of a GABAergic feedback from HCs to cones has been challenged by pharmacological inconsistencies. Surround antagonism has been demonstrated to occur via a modulation of cone calcium channels through ephaptic signaling and pH changes in the synaptic cleft. GABAergic transmission between HCs and cones has been reported in some lower vertebrates, like the turtle and tiger salamander. In these reports, it was revealed that GABA is released from HCs through reverse transport and target GABA receptors are located at the cone terminals. In mammalian retinas, there is growing evidence that HCs can release GABA through conventional vesicular transmission, acting both on autaptic GABA receptors and on receptors expressed at the dendritic tips of the bipolar cells. The presence of GABA receptors on mammalian cone terminals remains equivocal. Here, we looked specifically for functional GABA receptors in mouse photoreceptors by recording in the whole-cell or amphotericin/gramicidin-perforated patch clamp configurations. Cones could be differentiated from rods through morphological criteria. Local GABA applications evoked a Cl− current in cones but not in rods. It was blocked by the GABAA receptor antagonist bicuculline methiodide and unaffected by the GABAC receptor antagonist TPMPA [(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid]. The voltage dependency of the current amplitude was as expected from a direct action of GABA on cone pedicles but not from an indirect modulation of cone currents following the activation of the GABA receptors of HCs. This supports a direct role of GABA released from HCs in the control of cone activity in the mouse retina.

Horizontal Cell Feedback to Cone Photoreceptors in Mammalian Retina: Novel Insights From the GABA-pH Hybrid Model

“…GABARs containing ρ-subunits have a high affinity for GABA and are non-desensitizing (Farrant and Kaila, 2007), consistent reports of a GABA-activated conductance in mammalian horizontal cells (Feigenspan and Weiler, 2004;Liu et al, 2013). The GABARs recently found in mouse cones (Deniz et al, 2019) do not include the ρ subunitcontaining type shown here.…”

“…Many physiological recordings in the normal mammalian retina do not show a direct action of GABAergic agents on cones (Verweij et al, 2003 ; Crook et al, 2009 ; Kemmler et al, 2014 ; Szikra et al, 2014 ; Grove et al, 2019 ), but there is evidence for GABAR subunit expression by mammalian photoreceptors (Greferath et al, 1993 ; Grigorenko and Yeh, 1994 ; Picaud et al, 1998 ; Vardi et al, 1998 ; Chaffiol et al, 2017 ). However, in cultured retinal explants (and possibly in rd1 mice lacking rods), cones may be reprogrammed and respond to GABA application (Picaud et al, 1998 ; Pattnaik et al, 2000 ), and one report indicates GABA activation of TPMPA-insensitive GABAR Cl − channels in wild-type mouse cones (Deniz et al, 2019 ). Further complicating the functional role for photoreceptor Cl − flux, during surround light stimulation that hyperpolarizes horizontal cells, the resulting disinhibition of Ca V channels in cones in fish (Verweij et al, 1996 ) and macaque (Verweij et al, 2003 ) is accompanied by an increase in Ca 2+ -activated Cl − conductance.…”

Vesicular Release of GABA by Mammalian Horizontal Cells Mediates Inhibitory Output to Photoreceptors

“…Cone terminals of pig and rat were reported to show GABA A ρ subunit (ρ subunit) immunoreactivity suggesting the presence of a GABA A ρ receptor (Picaud et al, 1998b;Pattnaik et al, 2000). However, Deniz et al (2019) reported bicuculinesensitive, but not TPMPA-sensitive, GABA evoked currents in mouse cone photoreceptors in retinal slices, suggesting the presence of ionotropic GABA A receptors, but not those comprising ρ-subunits. Rod photoreceptors from cultured pig retina and in mouse retinal slices were reported to exhibit no response to GABA (Picaud et al, 1998b;Deniz et al, 2019).…”