Epileptiform Activity and Cognitive Deficits in SNAP-25+/− Mice are Normalized by Antiepileptic Drugs

Irene Corradini,Flavia Antonucci,Hans-Peter Lipp,Mario Clerici,Hans Welzl,Yuri Bozzi,Andrea Donzelli,Claudia Verderio,Maarten Loos,Matteo Caleo,Carolina Frassoni,Mariaelvina Sala,Daniela Braida,Roberta Martucci,Michela Matteoli,Linda Pattini,Silvia De Astis,Francesca Inverardi,David Wolfer

doi:10.1093/cercor/bhs316

Abstract

Synaptosomal-associated protein of 25 kDa (SNAP-25) is a protein that participates in the regulation of synaptic vesicle exocytosis through the formation of the soluble NSF attachment protein receptor complex and modulates voltage-gated calcium channels activity. The Snap25 gene has been associated with schizophrenia, attention deficit hyperactivity disorder, and bipolar disorder, and lower levels of SNAP-25 have been described in patients with schizophrenia. We used SNAP-25 heterozygous (SNAP-25(+/-)) mice to investigate at which extent the reduction of the protein levels affects neuronal network function and mouse behavior. As interactions of genotype with the specific laboratory conditions may impact behavioral results, the study was performed through a multilaboratory study in which behavioral tests were replicated in at least 2 of 3 distinct European laboratories. Reductions of SNAP-25 levels were associated with a moderate hyperactivity, which disappeared in the adult animals, and with impaired associative learning and memory. Electroencephalographic recordings revealed the occurrence of frequent spikes, suggesting a diffuse network hyperexcitability. Consistently, SNAP-25(+/-) mice displayed higher susceptibility to kainate-induced seizures, paralleled by degeneration of hilar neurons. Notably, both EEG profile and cognitive defects were improved by antiepileptic drugs. 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.

Highlights

Synapses are fundamental brain structures that mediate information transfer between neurons
We found that Synaptosomal-associated protein of 25 kDa (SNAP-25)+/− mice display hyperactivity and show an abnormal EEG profile associated with cognitive defects, both normalized by treatment with valproate (VLP)
To validate SNAP-25 levels and to minimize development-related artifacts possibly leading to erroneous data interpretation, both beta-III-Tubulin and alpha-Tubulin were used as a loading marker for SNAP-25 quantitation

Summary

Introduction

Synapses are fundamental brain structures that mediate information transfer between neurons. Case–control- or family-based studies indicated that the Snap gene is associated with attention deficit hyperactivity disorder (ADHD) (Barr et al 2000; Kustanovich et al 2003; Mill et al 2004; Faraone et al 2005; Feng et al 2005). Snap intronic single nucleotide polymorphisms (SNPs) have been linked to inattentive hyperactivity in a group of ADHD children (Zhang et al 2010), and associated with hyperactivity in autism spectrum disorders (Guerini et al 2011). Modifications of SNAP-25 levels occur in the brain of bipolar patients (Fatemi et al 2001; Scarr et al 2006), while one SNP variant in the promoter region, associated with higher SNAP-25 expression in prefrontal cortex, was linked with early onset of bipolar disorder (Etain et al 2010)

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Results

Conclusion