Impact of Sema3A Interference on Cerebellum-Dependent Motor Associative Learning and Memory

Semaphorin 3A (Sema3A), a known axon chemorepulsive protein during development, is localised in perineuronal nets (PNNs) in the adult brain. PNNs are condensed aggregates of extracellular matrix molecules surrounding specific types of neurons, which regulate neuroplasticity and memory. However, the role of PNN-associated Sema3A in these processes remains unclear. To address this topic, we investigated the contribution of Sema3A to cerebellum-dependent learning and memory in adult mice using the eyeblink conditioning (EBC) paradigm. We interfered with Sema3A signalling by employing: (i) a molecular approach, in which secreted Sema3A receptors (neuropilin-1 bodies) were expressed in the anterior interposed nuclei (AIN) via viral vector injection; and (ii) a genetic approach, using mutant mice with impaired Sema3A signalling (K108N mice). Mice expressing neuropilin-1 bodies showed reduced EBC performance at the beginning of the memory retention phase. However, increased inflammation was found in the AIN of these mice, challenging the interpretation of these findings. K108N mice showed enhanced EBC performance at the beginning of the memory retention phase. No synaptic structural changes were detected in the AIN of K108N mice at the end of the EBC paradigm. Based on our findings in K108N mice, constitutively altered Sema3A signalling is associated with subtle improvement in cerebellar memory.