Marinesco–Sjögren Syndrome (MSS) is a rare autosomal recessive disorder characterized by cerebellar ataxia, cataracts, myopathy, and intellectual disability. While MSS patients show no macroscopic brain alterations, the neurobiological mechanisms underlying cognitive impairments remain poorly understood. This study investigated cognitive deficits and underlying mechanisms in the woozy mouse model (Sil1^wz), a preclinical MSS model.

Using Open Field Test (OFT) and Light Dark Box Test (LDBT), we observed genotype- and age-dependent decreases in locomotor activity, confirming cerebellar ataxia and muscular deficits. 16-week-old Sil1^wz mice spent more time in the OFT centre, suggesting cognitive impairments rather than anxiety-like behaviour, supported by LDBT results.

Molecular analysis revealed altered gene expression in the prefrontal cortex and hippocampus across multiple neurotransmitter systems. The cholinergic system showed increased Chrna3 expression in both regions, with age-dependent hippocampal changes in transporters and enzymes. The serotonergic system exhibited time-dependent inverse expression of Htr2a and Tph2 in prefrontal cortex, while the dopaminergic system showed increased Ddc and Drd1 expression in hippocampus. Glutamatergic and GABAergic systems displayed significant alterations, particularly increased Grin2b expression.

Correlation analysis revealed complex relationships between gene expression and behaviour, with opposite trends between brain regions. Prefrontal cortex cholinergic and GABAergic systems correlated positively with locomotor parameters but negatively with immobility, while hippocampal patterns were inverse.

This study provides the first comprehensive characterization of cognitive deficits in the MSS mouse model, highlighting disrupted excitatory–inhibitory neurotransmission balance in key brain regions. These findings offer insights into pathophysiological mechanisms and potential therapeutic targets for MSS cognitive impairments.