Braida D, Guerini F R, Ponzoni L, Corradini I, De Astis S, Pattini L, Bolognesi E, Benfante R, Fornasari D, Chiappedi M, Ghezzo A, Clerici M, Matteoli M, Sala M
1] Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy [2] Fondazione IRCCS Don Gnocchi, Milan, Italy.
Fondazione IRCCS Don Gnocchi, Milan, Italy.
Transl Psychiatry. 2015 Jan 27;5(1):e500. doi: 10.1038/tp.2014.136.
Synaptosomal-associated protein of 25 kDa (SNAP-25) is involved in different neuropsychiatric disorders, including schizophrenia and attention-deficit/hyperactivity disorder. Consistently, SNAP-25 polymorphisms in humans are associated with hyperactivity and/or with low cognitive scores. We analysed five SNAP-25 gene polymorphisms (rs363050, rs363039, rs363043, rs3746544 and rs1051312) in 46 autistic children trying to correlate them with Childhood Autism Rating Scale and electroencephalogram (EEG) abnormalities. The functional effects of rs363050 single-nucleotide polymorphism (SNP) on the gene transcriptional activity, by means of the luciferase reporter gene, were evaluated. To investigate the functional consequences that SNAP-25 reduction may have in children, the behaviour and EEG of SNAP-25(+/-) adolescent mice (SNAP-25(+/+)) were studied. Significant association of SNAP-25 polymorphism with decreasing cognitive scores was observed. Analysis of transcriptional activity revealed that SNP rs363050 encompasses a regulatory element, leading to protein expression decrease. Reduction of SNAP-25 levels in adolescent mice was associated with hyperactivity, cognitive and social impairment and an abnormal EEG, characterized by the occurrence of frequent spikes. Both EEG abnormalities and behavioural deficits were rescued by repeated exposure for 21 days to sodium salt valproate (VLP). A partial recovery of SNAP-25 expression content in SNAP-25(+/-) hippocampi was also observed by means of western blotting. A reduced expression of SNAP-25 is responsible for the cognitive deficits in children affected by autism spectrum disorders, as presumably occurring in the presence of rs363050(G) allele, and for behavioural and EEG alterations in adolescent mice. VLP treatment could result in novel therapeutic strategies.
25 kDa的突触体相关蛋白（SNAP-25）与包括精神分裂症和注意力缺陷多动障碍在内的多种神经精神疾病有关。同样，人类中的SNAP-25多态性与多动和/或低认知评分相关。我们分析了46名自闭症儿童的5个SNAP-25基因多态性（rs363050、rs363039、rs363043、rs3746544和rs1051312），试图将它们与儿童自闭症评定量表和脑电图（EEG）异常相关联。通过荧光素酶报告基因评估了rs363050单核苷酸多态性（SNP）对基因转录活性的功能影响。为了研究SNAP-25减少可能对儿童产生的功能后果，我们研究了SNAP-25(+/-)青春期小鼠（SNAP-25(+/+)）的行为和脑电图。观察到SNAP-25多态性与认知评分降低存在显著关联。转录活性分析表明，SNP rs363050包含一个调控元件，导致蛋白质表达下降。青春期小鼠中SNAP-25水平的降低与多动、认知和社交障碍以及异常脑电图有关，其特征是频繁出现尖峰。通过反复暴露于丙戊酸钠（VLP）21天，脑电图异常和行为缺陷均得到改善。通过蛋白质印迹法还观察到SNAP-25(+/-)海马体中SNAP-25表达含量的部分恢复。SNAP-25表达降低是自闭症谱系障碍患儿认知缺陷的原因，可能是在存在rs363050(G)等位基因的情况下发生的，也是青春期小鼠行为和脑电图改变的原因。VLP治疗可能会带来新的治疗策略。
