Nogo-A signaling reciprocally modulates excitatory and inhibitory synaptic transmission

Abstract

Nogo-A is among the molecules crucial for maintaining the balance between plasticity and stability of synaptic contacts. Indeed, Nogo-A restricts both functional and structural plasticity by signaling via the binding of its two inhibitory domains to their cognate receptors. This study especially examined the Nogo-A signaling in reciprocally regulating excitatory and inhibitory signal transmission at a fast time scale. Whole-cell patch clamp during Nogo-A loss-of-function showed that Nogo-A signaling, especially via the S1PR2 regulates the strength of excitatory and inhibitory synaptic transmission in hippocampal neurons in a bidirectional manner, thus altering excitation/ inhibition balance. This reciprocal modulation of excitatory and inhibitory transmission by Nogo-A signaling is associated to alterations in the dynamics of neurotransmitter receptors at synapses. Within minutes, loss-of-function for Nogo-A signaling results in higher excitatory glutamate transmission by increasing the surface localization of synaptic AMPA receptors (AMPAR). Especially the AMPAR subunit GluA1 is recruited to the postsynaptic site, while GluA2 remains unaltered under conditions of Nogo-A inhibition. Furthermore, Nogo-A signaling regulates inhibitory GABAergic synaptic transmission by regulating GABAA receptor (GABAAR) clustering. Moreover, this study explored the downstream signaling mediating the effects of Nogo-A in regulating inhibitory synaptic transmission. While, upon Nogo-A loss-of-function changes in the clustering of the GABAAR-binding postsynaptic protein Gephyrin were not observed, an increase in intracellular Ca2+ and the activation of the Ca2+-dependent phosphatase Calcineurin are required for the decrease in the amount of GABAARs at synapses. Indeed, after blocking of Nogo-A function Calcineurin dephosphorylation of the GABAAR ɣ2 subunit at serine 327 results in a decrease in the synaptic localization of GABARs. These results indicate a crucial role for the ability of Nogo-A signaling to modulate Ca2+ dynamics and consequently limit GABAAR mobility. The rise in intracellular Ca2+ upon Nogo-A inhibition is due to influx across the plasma membrane rather that to its release from the internal stores. Overall, the data presented in this thesis show that Nogo-A acutely modulates the excitation/ inhibition balance in primary hippocampal neurons by controlling the synaptic localization respectively of GluA1 and GABAARs.