Fast Regulation of GABAAR 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(A)R diffusion, thereby decreasing their number at synaptic sites and the amplitude of GABAergic mIPSCs at CA3 hippocampal neurons. This increase in GABA(A)R diffusion rate is correlated with an increase in Ca2+ influx and requires the calcineurin-mediated dephosphorylation of the gamma(2) subunit at serine 327. These results suggest that Nogo-A signaling rapidly strengthens inhibitory GABAergic transmission by restricting the diffusion dynamics of GABA(A)Rs. 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.