Correlation between SNAP-25 alteration and cognitive deficits in mice and children

SNAP-25 was recently involved in neuropsychiatric disorders (1). In addition, polimorphisms at the SNAP-25 gene locus in humans have been associated with ADHD (2) and ASD (3). Since a motor hyperactivity was found in adolescent SNAP-25+/- mice (6-7 weeks) (4), our aim was to better investigate their behavioural and EEG profile and to evaluate the effect of valproate sodium salt (VLP) on these defects. At the same time five SNAP-25 gene polymorphisms in a clinically characterized cohort of children affected by ASD were evaluated. Adolescent SNAP-25+/-mice show reduced social interaction in the sociability test, cognitive deficits evaluated through object recognition test, lack of conditioned taste aversion and increased EEG spike occurrence. Chronic oral VLP reduced all the behavioral deficits and EEG alterations. The decreased SNAP-25+/- level was partially recovered, after VLP treatment, by means of western blot analysis in hippocampus. Significant associations of the rs363050 and rs363039 polymorphisms with cognitive scores in 46 Italian ASD children were observed. Analysis of rs363050 function on transcriptional activity, by means of luciferase reporter gene in human neuroblastoma SH-SY5Y cell line, reported a decreased transcription of the SNAP-25 gene. Our genetic studies of human ASD population and of SNAP-25+/-mice indicate that alterations in SNAP-25 contribute directly to the cognitive deficits. VLP ameliorates not only memory impairment but also EEG abnormalities suggesting the beneficial effect of this antiepileptic drug for some neuropsychiatric and neurologic disorders.