Fast Regulation of GABA_AR Diffusion Dynamics by Nogo-A Signaling

Precisely controlling the excitatory and inhibitory balance is crucial for the stability and information-processing ability of neuronal networks. However, the molecular mechanisms maintaining this balance during ongoing sensory experiences are largely unclear. We show that Nogo-A signaling reciprocally regulates excitatory and inhibitory transmission. Loss of function for Nogo-A signaling through S1PR2 rapidly increases GABA_AR diffusion, thereby decreasing their number at synaptic sites and the amplitude of GABAergic mIPSCs at CA3 hippocampal neurons. This increase in GABA_AR diffusion rate is correlated with an increase in Ca²⁺ influx and requires the calcineurin-mediated dephosphorylation of the γ2 subunit at serine 327. These results suggest that Nogo-A signaling rapidly strengthens inhibitory GABAergic transmission by restricting the diffusion dynamics of GABA_ARs. Together with the observation that Nogo-A signaling regulates excitatory transmission in an opposite manner, these results suggest a crucial role for Nogo-A signaling in modulating the excitation and inhibition balance to restrict synaptic plasticity.