Retinal glia regulate development of the circadian photoentrainment circuit

Circadian photoentrainment depends on intrinsically photosensitive retinal ganglion cells (ipRGCs), which convey environmental light information to the hypothalamus. While the anatomy and function of mature ipRGCs are well characterized, the mechanisms guiding their developmental integration into the circadian circuit remain unclear. Here, using transsynaptic rabies tracing in mice, we show that Müller glia are primary upstream partners of developing hypothalamus-projecting ipRGCs, suggesting a role for glia-neuron communication in the assembly of the photoentrainment pathway. We further show that disrupting SNARE function specifically in Müller glia during early postnatal development impairs ATP release, induces ipRGC hyper-responsiveness to light, and results in defective photoentrainment. In contrast, visual acuity and the pupillary light reflex, which are mediated by different RGC/ipRGC subtypes, remain unaffected. These results indicate a critical and circuit-specific role for Müller glia in shaping the development and function of the retinal pathway underlying circadian photoentrainment.