SHORT-TERM ENVIRONMENTAL ENRICHMENT DURING ADOLESCENCE RESCUES SOCIO-COGNITIVE DEFICITS IN MICE LACKING Α5-NACHRS

Proper cholinergic signaling is crucial for establishing functional neural networks during development, and its disruption often leads to socio-cognitive impairments linked to neurodevelopmental disorders. This study investigated how the deletion of the ALPHA5 nicotinic acetylcholine receptor (ALPHA5-nAChR) subunit, a key modulator of neural circuits, influences behaviour; and whether short-term environmental enrichment (EE) can influence the pathological phenotype. To document sex and developmental differences in these manipulations, we examined WT and ALPHA5 knockout (ACNA5) mice of both sexes and applied the environmental manipulation at two distinct developmental windows. Animals were assigned to either standard housing (SH) or a two-week EE protocol starting either after weaning (PND21) or during late adolescence (PND45). Behavioural testing revealed that ACNA5 mice in SH exhibited significant impairments in spatial memory, assessed via the novel object location task, and reduced sociability in the three-chamber test. Notably, short-term EE was sufficient to rescue these deficits regardless of the timing of the intervention, as both PND35 and PND60 ACNA5 mice of both sexes showed significant improvements in spatial memory performance and social interaction preference. These findings indicate that the ALPHA5-nAChR subunit is critical for the development of socio-cognitive traits, yet the brain retains high levels of experience-dependent plasticity throughout adolescence. This suggests that brief environmental interventions offer a powerful, non-pharmacological strategy to rescue cognitive and social impairments associated with cholinergic dysfunction.