Cell Death and Differentiation 2015-09-01

Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis.

G Fossati, R Morini, I Corradini, F Antonucci, P Trepte, E Edry, V Sharma, A Papale, D Pozzi, P Defilippi, J C Meier, R Brambilla, E Turco, K Rosenblum, E E Wanker, N E Ziv, E Menna, M Matteoli

Index: Cell Death Differ. 22 , 1425-36, (2015)

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Abstract

Impairment of synaptic function can lead to neuropsychiatric disorders collectively referred to as synaptopathies. The SNARE protein SNAP-25 is implicated in several brain pathologies and, indeed, brain areas of psychiatric patients often display reduced SNAP-25 expression. It has been recently found that acute downregulation of SNAP-25 in brain slices impairs long-term potentiation; however, the processes through which this occurs are still poorly defined. We show that in vivo acute downregulation of SNAP-25 in CA1 hippocampal region affects spine number. Consistently, hippocampal neurons from SNAP-25 heterozygous mice show reduced densities of dendritic spines and defective PSD-95 dynamics. Finally, we show that, in brain, SNAP-25 is part of a molecular complex including PSD-95 and p140Cap, with p140Cap being capable to bind to both SNAP-25 and PSD-95. These data demonstrate an unexpected role of SNAP-25 in controlling PSD-95 clustering and open the possibility that genetic reductions of the protein levels - as occurring in schizophrenia - may contribute to the pathology through an effect on postsynaptic function and plasticity.