Cell-type specific actions of Nogo-A in controlling spatial memory formation by modulating neuronal excitability

Learning and memory processes activate a specific ensemble of neurons distributed across different brain regions, the so-called engram, inducing in them lasting physical and chemical changes. The allocation of neurons to the engram depends on their relative excitability. Therefore, mechanisms regulating the balance between excitation (E) and inhibition (I) in the brain influence memory formation. Nogo-A negatively regulates neuronal plasticity and influences the E/I balance by promoting inhibitory, while suppressing excitatory synaptic transmission. Moreover, loss of function for Nogo-A results in alterations in different learning paradigms. This suggests that Nogo-A may influence learning and memory acquisition by modulating neuronal excitability and thus, their allocation to engrams. Nogo-A is expressed by excitatory and Parvalbumin-positive (PV+) inhibitory neurons throughout the hippocampus, but especially in the CA3 region, which is crucial for the acquisition of episodic spatial memory. This work aims to elucidate the cell type-specific effects of Nogo-A signalling on spatial learning and engram formation. Conditional knockout (KO) mice for Nogo-A in either excitatory or PV+ neurons were trained in the Morris water maze. While mice missing Nogo-A in excitatory neurons have reduced latency to reach the platform, this is increased by knocking Nogo-A out from PV+ neurons. Moreover, knockout of Nogo-A from excitatory neurons resulted in higher numbers of c-Fos expressing CA3 neurons. Current experiments use doxycycline-controlled labelling of hippocampal engram neurons during spatial learning to investigate the effects of Nogo-A on their allocation. The Nogo-A cell type-specific effects on neuronal excitability are being examined in electrophysiological recordings.