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

Experiences lead to lasting structural and functional changes in neurons, forming the basis for learning and memory. These persistent modifications are known as memory engrams. A critical step in engram formation is the allocation of neurons during learning, a process shown to depend on their relative excitability. Consequently, mechanisms that regulate excitation and inhibition can directly influence memory encoding. Nogo-A is widely known for inhibiting structural plasticity but has more recently been identified as a negative regulator of synaptic plasticity, stabilizing both excitatory and inhibitory synaptic transmission in a cell-type-specific manner. Notably, global deletion of Nogo-A in male mice enhances spatial learning. This study aimed to bridge the gap between the known cell-type-specific effects of Nogo-A in vitro and the behavioral improvements observed in constitutive knockouts (KO). A 3-day Morris water maze task followed by c-Fos immunohistochemistry was used to assess spatial learning and engram activation. Male constitutive Nogo-A KO mice successfully acquired the task, while their wildtype (WT) littermates and both female genotypes did not. Furthermore, mice with excitatory or PV+ inhibitory interneuron-specific deletion of Nogo-A showed no improvements in learning the task in comparison to their control groups, regardless of sex. Consistent with these behavioral findings, only male constitutive KO mice showed elevated c-Fos expression in CA1, CA3, and DG, suggesting enhanced recruitment of hippocampal neurons during memory formation. These findings suggest that combined Nogo-A deletion across multiple neuronal populations is required to improve spatial learning and that male mice may benefit more strongly from this effect. Patch-clamp recordings in CA3 pyramidal neurons of excitatory Nogo-A KO mice revealed a shift in the excitatory/inhibitory balance toward excitation, without changes to inhibitory input. Despite this excitatory bias, learning and c-Fos activation remained unchanged in cell-type-specific KO mice, implying that the synaptic changes were insufficient to drive improved memory formation under current conditions. Developmental compensations may also have masked potential effects. To overcome this limitation, a virus-based strategy for the acute, region-specific deletion of Nogo-A was developed for future studies.