Chronic valproate restores hyperactivity, cognitive deficits and epileptiform activity in adolescent SNAP-25 heterozygous (SNAP-25+/−) mice

SNAP-25 is a protein that participates in the regulation of synaptic vesicle exocytosis through the formation of the SNARE complex and modulates voltage gated calcium channels activity. The Snap25 gene has been associated with schizophrenia, ADHD and bipolar disorders and low levels of SNAP-25 have been described in the brain of schizophrenic patients. Recently, we have behaviorally characterized adult SNAP-25+/−mice and found the occurrence of frequent spikes during 24-hour electroencephalographic (EEG) recordings, associative memory deficits and impaired social behavior, compared to the littermates (Corradini et al., 2012). Notably, acute treatment (250 mg/kg) with valproate sodium salt (VLP) rescued these impairments. A motor hyperactivity and a lack of response to amphetamine, specifically occurring in adolescent SNAP-25+/- mice (6-7 weeks), was also shown. On this basis, our aim was :1) to better investigate adolescent SNAP-25+/- mice (6-7 weeks old ) for memory and EEG profile ; 2) to evaluate the effect of VLP given chronically on behavioral and EEG defects. We found that adolescent SNAP-25+/−mice show reduced social interaction in the sociability test, cognitive deficits evaluated through object recognition test and lack of conditioned taste aversion. Furthermore, adolescent mice showed increased EEG spike occurrence and altered relative spectral power, in terms of reduced alpha (8-13 Hz) and beta (13-25Hz) and increased delta (0.1-4 Hz) activity during 2-hours recordings. Chronic VLP (0.1% dissolved in plain water for 3 weeks) reduced all the behavioral deficits. EEG spectral power alteration and enhanced spike activity were absent until two weeks from drug cessation. Experiments are in progress to investigate the possible effect of VLP on the expression of SNAP-25 by means of Western Blotting analysis of wild-type and heterozygous mice cortices. Behavioural SNAP-25+/- mice profile appears to recapitulate some of the core symptoms of ADHD. Repeated treatment with VLP ameliorated all the behavioral and EEG impairments suggesting the beneficial effect of this antiepileptic drug for some of ADHD-like behavioral features