Modulation of Off response output from mouse retinal ganglion cells by mGluR6, CB1, and GABAc receptors
The retina is a sensory tissue that converts optical images into neural signals known as light responses. Light responses are transmitted from photoreceptors to bipolar cells to retinal ganglion cells (RGCs) in parallel pathways specific for either light increments or light decrements. This improves vision by doubling the retina’s dynamic range and increasing contrast sensitivity. Research has shown that Off pathways, which are sensitive to light decrements, are likely modulated by the activity of metabotropic glutamate receptor 6 (mGluR6) receptors, cannabinoid 1 receptors (CB1Rs), and γ-aminobutyric acid C (GABAC) receptors. In this dissertation, I investigate how these neurotransmitter receptors modulate Off responses in the retina by performing whole-cell recordings of mouse RGCs. On bipolar cells express mGluR6 receptors, a type of glutamate receptor that hyperpolarizes bipolar cells when bound to glutamate. Previous research has shown that these receptors modulate Off responses under dark adaptation, but effects under light adaptation were unclear. My research has shown that mGluR6 receptor agonist DL-2-amino-4-phosphonobutyric acid (APB) decreases light-evoked Off responses under light adaptation by disrupting dopaminergic transmission between amacrine cells and Off bipolar cells. CB1Rs are localized to many cell types including cone and bipolar cell axon terminals, each of which release glutamate. Research primarily in brain has shown that cannabinoid receptor activation prevents neurotransmitter release from the presynapse. This has led to the hypothesis that CB1R activation would decrease glutamate release in Off pathways and attenuate Off responses. My research shows that CB1R agonists differentially modulate Off responses. Based on my results, I suggest that CB1R agonists increase light-evoked Off responses in one population of RGCs by reducing GABA transmission between GABAergic amacrine cells and Off bipolar cells. GABAergic amacrine cells feed back onto bipolar cell axon terminals that express GABAC receptors. Previous research has shown that GABAC receptor antagonist (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) alters On responses, but effects on Off responses are unclear. I show that TPMPA modulates kinetics of both On and Off responses recorded from On-Off RGCs. All together, the results in this dissertation indicate that mGluR6 receptors, CB1Rs, and GABAC receptors modulate Off responses, and therefore vision.