Retinoic Acid Receptor RAR alpha-Dependent Synaptic Signaling Mediates Homeostatic Synaptic Plasticity at the Inhibitory Synapses of Mouse Visual Cortex

Homeostatic synaptic plasticity is a synaptic mechanism through which the nervous system adjusts synaptic excitation and inhibition to maintain network stability. Retinoic acid (RA) and its receptor RAR alpha have been established as critical mediators of homeostatic synaptic plasticity. In vitro studies reveal that RA signaling enhances excitatory synaptic strength and decreases inhibitory synaptic strength. However, it is unclear whether RA-mediated homeostatic synaptic plasticity occurs in vivo, and if so, whether it operates at specific types of synapses. Here, we examine the impact of RA/RAR alpha signaling in the monocular zone of primary visual cortex (V1m) in mice of either sex. Exogenous RA treatment in acute cortical slices resulted in a reduction in mIPSCs oflayer 2/3 pyramidal neurons, an effect mimicked by visual deprivation induced by binocular enucleation in postcritical period animals. Postnatal deletion of RAR alpha blocked RA's effect on mIPSCs. Cell type-specific deletion of RAR alpha revealed that RA acted specifically on parvalbumin (PV)-expressing interneurons. RAR alpha deletion in PV interneurons blocked visual deprivation-induced changes in mIPSCs, demonstrating the critical involvement of RA signaling in PV interneurons in vivo. Moreover, visual deprivation- or RA-induced downregulation of synaptic inhibition was absent in the visual cortical circuit of constitutive and PV-specific Fmr1 KO mice, strongly suggesting a functional interaction between fragile X mental retardation protein and RA signaling pathways. Together, our results demonstrate that RA/RAR alpha signaling acts as a key component for homeostatic regulation of synaptic transmission at the inhibitory synapses of the visual cortex.