Stabilizers and negative modulators of synaptic transmission and plasticity: the Nogo-A signaling system

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The ability of the brain to perform learning and memory processes depend on a tightly regulated balance between excitatory and inhibitory synaptic transmission. Among the molecules involved in regulating the excitation/inhibition balance of the CNS network, the myelin-associated neurite growth inhibitor Nogo-A is of special interest. Indeed, our work performed during the previous funding period shows that Nogo-A signaling via its receptors S1PR2 and NgR1 reciprocally modulates the strength of excitatory and inhibitory synaptic transmission at a fast time scale by controlling the synaptic localization of AMPA and GABAA receptors, respectively. In particular, loss-of-function for Nogo-A results in the strengthening of excitation paired to the weakening of inhibition. These results, and our preliminary data indicate that Nogo-A regulates neuronal excitability. This is interesting in the context of the cellular and molecular mechanisms regulating the encoding of new memory and specifically the probability of each neuron to be allocated to a particular memory trace. In fact while all principal neurons in a specific brain region are activated during memory encoding, only a small portion of them is recruited into any memory in a competition process based on the levels of neuronal excitability. Interestingly, Nogo-A signalling has been shown, by us and others to modulate activity-dependent synaptic plasticity as well as learning and memory processes.In this project we plan to investigate the cellular and molecular mechanisms and the behavioural consequences of the modulation of the E/I balance by Nogo-A signalling. We will combine electrophysiological, imaging and behavioral methods to assess whether Nogo-A signalling via its receptors regulates memory processes (i.e. spatial memory and context-dependent fear conditioning) by controlling neuronal allocation during encoding in the hippocampus and amygdala. Moreover, we aim at addressing the physio-pathological relevance of Nogo-A in modulating neuronal excitability and memory allocation using different behavioral paradigms in a model of post-traumatic stress disorder.These experiments will provide insights into the core mechanisms regulating synaptic transmission and neuronal excitability as well as into the behavioural consequences of Nogo-A signalling under physiological and pathophysiological conditions.