Sex- and cell type-specific Nogo-A regulation of neuronal excitation in fear memory processes

Memory engrams are neural ensembles whose enduring structural remodeling and strengthened synaptic connectivity underlie the storage and recall of memories. The fear engram generated during aversive learning relies on both the plasticity of the neuronal network for its formation and the stability for persistence. Since the allocation of neurons to a specific engram depends on their excitability, molecules regulating the excitation / inhibition balance (E/I balance) in the brain are key players in engram formation. Nogo-A has been shown to influence the E/I balance, restrict activity-dependent functional and structural plasticity and modulate learning and memory formation. However, whether Nogo-A controls the memory engram formation is still unknown. In this thesis, behavioral experiments were combined with immunohistochemical analysis, genetic tools, Ca2+ imaging and electrophysiology to address this question. Moreover, the cell type-specific role of Nogo-A in memory engram formation was assessed by comparing conditional knockout (cKO) mice - missing Nogo-A either in parvalbumin (PV)-expressing interneurons or in excitatory neurons – with wildtype controls in an amygdala- and hippocampus-dependent contextual fear conditioning paradigm. Mice lacking Nogo-A in excitatory neurons exhibit an increased freezing time accompanied by a significantly higher number of cFOS expressing neurons in the basolateral amygdala (BLA). The effect on fear memory of deleting Nogo-A from excitatory neurons could only be observed in female mice, suggesting a sex- and cell type-specific effect of Nogo-A in this context. However, the improved spatial learning in the novel object location test was observed equally in both male and female Nogo-A cKO mice. Moreover, deletion of Nogo-A from excitatory neurons resulted in increased field excitatory postsynaptic potentials in female mice, indicating a higher neuronal excitability. Conversely, cKO mice lacking Nogo-A in PV-expressing interneuron showed the opposite effects in all of the above experimental paradigms, although with a small effect size. 2-Photon Ca2+-imaging experiments showed an increase in the synchrony of Ca2+-events under basal conditions in CA3 neurons in organotypic slice cultures lacking Nogo-A in excitatory neurons. Additionally, following chemical induction of long-term potentiation, the frequency as well as the amplitudes of Ca2+-events were found to be enhanced. Overall, Nogo-A signaling regulates fear memory processes in a sex- and cell type-specific manner as well as plasticity and excitability in the hippocampus.