The retinal light response is modulated by an mGluR5-mediated retrograde signal from ON-bipolar cells to photoreceptors

Abstract

The ON visual pathway is initiated by the deactivation of mGluR6, coupled to the opening of TRPM1 channels in retinal ON-bipolar cell dendrites. Here, we show that a second metabotropic glutamate receptor, mGluR5, is localized with TRPM1 and mGluR6 in the dendrites of ON-bipolar cells. To examine the function of mGluR5, we performed electroretinogram (ERG) recordings and found that the amplitude of the b-wave, which is primarily a measure of ON-bipolar cell light-driven activity, is reduced in mGluR5 knock-out mice compared to wild type. In the mGluR5-/- retina, we observed weaker mGluR6 immunofluorescence in the dendritic tips of ON-bipolar cells that could explain the smaller ERG b-wave. To observe the effect of mGluR5 without perturbing mGluR6 expression, wild type mice were injected with MTEP, an allosteric antagonist of mGluR5. MTEP increased the amplitude of the b-wave in response to dim stimuli and caused an inflection in the intensity-response plot for flashes in the mesopic range. In the brain, postsynaptic mGluR5 regulates presynaptic glutamate release via endocanabinoid-mediated retrograde signaling. Therefore, we tested the effect of the CB1 receptor antagonist, SR1417A, on the ERG and found that the b-wave was affected as by MTEP, including an inflection in the intensity-response. We further showed that the CB1 receptor agonist, ACEA, reversed the effects of MTEP. Together, our results indicate that mGluR5 plays a role in gain-control at the photoreceptor to ON-bipolar cell synapses, likely via an endocannabinoid-mediated retrograde feedback. Significance StatementLight-ON stimuli are transmitted from photoreceptors to ON-bipolar cells via three pathways, which are used under different light intensities, from dim to bright light. For each pathway, glutamate is the neurotransmitter released by rods and cones, and the postsynaptic role of the mGluR6-TRPM1 signaling cascade in ON-bipolar cells is well studied, with defects known to cause congenital stationary night blindness. We show here that mGluR5 is also present in ON-bipolar cell dendrites and regulates synaptic transmission between photoreceptors and ON-bipolar cells. In particular, we find that mGluR5 facilitates the transition between the different photoreceptor to ON-bipolar cell pathways via mGluR5-controlled retrograde release of endocannabinoids.