title: Association between SNAP-25 gene polymorphisms and cognition in autism: functional consequences and potential therapeutic strategies.
abstract: 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.
authors: 1] Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy [2] Fondazione IRCCS Don Gnocchi, Milan, Italy.
authors: D
authors: D
authors: Braida
authors: Fondazione IRCCS Don Gnocchi, Milan, Italy.
authors: F R
authors: FR
authors: Guerini
authors: 1] Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy [2] Fondazione Fratelli Confalonieri, Milan, Italy.
authors: L
authors: L
authors: Ponzoni
authors: CNR-Neuroscience Institute, Milan, Italy.
authors: I
authors: I
authors: Corradini
authors: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
authors: S
authors: S
authors: De Astis
authors: Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.
authors: L
authors: L
authors: Pattini
authors: Fondazione IRCCS Don Gnocchi, Milan, Italy.
authors: E
authors: E
authors: Bolognesi
authors: CNR-Neuroscience Institute, Milan, Italy.
authors: R
authors: R
authors: Benfante
authors: 1] Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy [2] CNR-Neuroscience Institute, Milan, Italy.
authors: D
authors: D
authors: Fornasari
authors: Child Neuropsychiatry Unit, National Neurological Institute C. Mondino, Pavia, Italy.
authors: M
authors: M
authors: Chiappedi
authors: 1] Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy [2] Associazione Nazionale Famiglie di Persone con Disabilitá Affettiva e/o Relazionale (ANFFAS), Macerata, Italy.
authors: A
authors: A
authors: Ghezzo
authors: 1] Fondazione IRCCS Don Gnocchi, Milan, Italy [2] Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy.
authors: M
authors: M
authors: Clerici
authors: 1] Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy [2] Humanitas Clinical and Research Center, Rozzano, Italy.
authors: M
authors: M
authors: Matteoli
authors: 1] Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy [2] CNR-Neuroscience Institute, Milan, Italy.
authors: M
authors: 000000019310958X
authors: M
authors: Sala
mesh_terms: D000293:Adolescent; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002648:Child; D003071:Cognition; D004569:Electroencephalography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006579:Heterozygote; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D017397:Prefrontal Cortex / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D012919:Social Behavior; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics* / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D000697:Central Nervous System Stimulants; D004791:Enzyme Inhibitors; C494208:SNAP25 protein, human; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D014635:Valproic Acid; D000661:Amphetamine
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