INVESTIGATING THE ROLE OF THE ADHD-ASOCIATED <EM>SNORC</EM> GENE IN BRAIN FUNCTION AND BEHAVIOUR USING A KNOCKOUT MOUSE MODEL

Attention-Deficit/Hyperactivity Disorder (ADHD) is among the most heritable neuropsychiatric disorders and shows marked sex differences in prevalence. Previously, we identified ADHD-risk alleles associated with increased methylation of the SNORC (Small NOvel Rich in Cartilage) promoter and reduced SNORC expression (Pineda-Cirera et al. Transl Psychiatry 2019,9:242). SNORC encodes a glycosylated transmembrane protein that is highly expressed in the human brain, but its function remains largely uncharacterized. Here, we investigated the role of Snorc in mice and assessed potential sex differences. In wild-type (WT) mice, Snorc was expressed across multiple brain regions, with the highest levels observed in the nucleus accumbens (NA) and dorsal striatum (DS). In the DS, females showed approximately seven-fold higher expression than males. We then used a homozygous Snorc KO mouse model to evaluate alterations in behaviour and brain gene expression. Transcriptomic analyses of NA and DS using RNA-seq revealed limited global changes but identified differential expression of six genes. Three genes were consistently altered in both regions and in both sexes: : Wdfy1 (downregulated), and Ngef and Gm38312 (upregulated). Three additional genes, 5033417F24Rik, Mlph, and D2hgdh, showed differences in expression between KO and WT mice only in females. Behavioural testing included fear conditioning, cocaine self-administration and relapse, and novel object recognition. Snorc KO mice displayed hypolocomotion, reduced exploration, increased anxiety (particularly in males), impaired object recognition, and altered impulsivity and drug-seeking behaviour. Together, these findings suggest a sex-dependent role for Snorc in molecular and behavioural processes relevant to ADHD.