CAUSES AND CONSEQUENCES OF REDUCED EXPRESSION OF SNAP-25 IN NEURONAL NETWORKS

Synaptosomal-associated protein of 25 kDa (SNAP-25) is a protein that participates in the regulation of synaptic vesicle exocytosis and modulates voltage-gated calcium channels activity. Altered levels of SNAP-25 expression have been associated to different neurological and neuropsychiatric conditions, such as schizophrenia, ADHD, and bipolar disorder, and lower levels of SNAP-25 have been described in patients with schizophrenia. I used Snap-25 heterozygous (Snap-25+/−) mice, expressing reduced levels of SNAP-25, to investigate at which extent the reduction of the protein expression affects neuronal network function and mouse behaviour. Snap-25+/− mice displayed a moderate hyperactivity, which disappeared in the adult animals and showed an impairment in associative learning and recognition memory. Electroencephalographic recordings revealed the occurrence of frequent spikes, suggesting a diffuse network hyperexcitability. Moreover, SNAP-25+/− mice displayed higher susceptibility to kainate-induced seizures. Notably, treatment with antiepileptic drugs improve both EEG profile and cognitive defects. The abnormal EEG profile observed in SNAP-25+/- mice could contribute to the learning and memory defects. Based on the results i have obtained, showing the occurrence of cognitive disabilities in mice expressing reduced levels of SNAP-25 i conducted a functional analysis on SNP rs363050, which associates with low performance IQ and is located on intron 1 of the Snap-25 gene, to investigate whether the presence of the parental or minor allele may affect the expression of SNAP-25. The presence of minor allele resulted in a reduction of the transcription capability, while the parental allele did not increase the basal activity of an heterologous promoter. These results indicate that reduction of SNAP-25 expression is associated to generation of epileptiform discharges and cognitive dysfunctions, which can be effectively treated by antiepileptic drugs and support the evidence that the rs363050 polymorphism might have a role in modulating Snap-25 gene expression levels.