Genetic control of circuit function: Vsx1 and Irx5 transcription factors regulate contrast adaptation in the mouse retina

Transcriptional programs guide the specification of neural cell types in the developing nervous system. However, it is unclear whether such programs also control specific aspects of neural circuit function at maturity. In the mammalian retina, Vsx1 and Irx5 transcription factors are present in a subset of bipolar interneurons that convey signals from photoreceptors to ganglion cells. The biased expression of Vsx1 and Irx5 in hyperpolarizing OFF compared with depolarizing ON bipolar cells suggests that these transcription factors may selectively regulate signal processing in OFF circuits. To test this hypothesis, we generated mice lacking both Vsx1 and Irx5. Bipolar cells in these mice were morphologically normal, but the expression of cell-specific markers in some OFF but not ON bipolar cells was reduced or absent. To assess visual function in Vsx1^-/-Irx5^-/- retinas, we recorded light responses from ensembles of retinal ganglion cells (RGCs). Wefirst identified functional RGC types in control mice and describe their response properties and adaptation to temporal contrast using a simple linear-nonlinear model. We found that space-time receptive fields of RGCs are unchanged in Vsx1^-/-Irx5 ^-/- mice compared with control retinas. In contrast, response threshold, gain, and range were lowered in a cell-type-specific manner in OFF but not ON RGCs in Vsx1^-/-Irx5^-/- retinas. Finally, we discovered that the ability to adapt to temporal contrast is greatly reduced in OFF RGCs in the double mutant, suggesting that Vsx1 and Irx5 control specific aspects of visual function in circuits of the mammalian retina.