Association Between SNAP-25 Gene Polymorphisms and Cognition in Autism: Functional Consequences and Potential Therapeutic Strategies

Overview

Journal Transl Psychiatry

Specialties Psychiatry
Public Health

Date 2015 Jan 29

PMID 25629685

Citations 45

Authors

D Braida

F R Guerini

L Ponzoni

I Corradini

S De Astis

L Pattini

E Bolognesi

R Benfante

D Fornasari

M Chiappedi

A Ghezzo

M Clerici

M Matteoli

M Sala

Affiliations

Soon will be listed here.

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.

Citing Articles

Single-cell delineation of the microbiota-gut-brain axis: Probiotic intervention in Chd8 haploinsufficient mice.

Ji P, Wang N, Yu Y, Zhu J, Zuo Z, Zhang B Cell Genom. 2025; 5(2):100768.

PMID: 39914389 PMC: 11872533. DOI: 10.1016/j.xgen.2025.100768.

SNARE protein SNAP25 regulates the chloride-transporter KCC2 in neurons.

Raveendran V, Serranilla M, Asgarihafshejani A, de Saint-Rome M, Cherednychenko M, Mullany S iScience. 2024; 27(11):111156.

PMID: 39507243 PMC: 11539599. DOI: 10.1016/j.isci.2024.111156.

The Relationship between SNAP25 and Some Common Human Neurological Syndromes.

Shu J, Peng F, Li J, Liu Y, Li X, Yuan C Curr Pharm Des. 2024; 30(30):2378-2386.

PMID: 38963116 DOI: 10.2174/0113816128305683240621060024.

Behavioral transcriptomic effects of triploidy and probiotic therapy (Bifidobacterium, Lactobacillus, and Lactococcus mixture) on juvenile Chinook salmon (Oncorhynchus tshawytscha).

Frank C, Sadeghi J, Heath D, Semeniuk C Genes Brain Behav. 2024; 23(3):e12898.

PMID: 38817102 PMC: 11140169. DOI: 10.1111/gbb.12898.

SNAP-25 Polymorphisms in Autism Spectrum Disorder: A Pilot Study towards a Possible Endophenotype.

Mensi M, Guerini F, Marchesi M, Chiappedi M, Bolognesi E, Borgatti R Pediatr Rep. 2023; 15(4):766-773.

PMID: 38133436 PMC: 10747488. DOI: 10.3390/pediatric15040068.

References

Jeans A, Oliver P, Johnson R, Capogna M, Vikman J, Molnar Z . A dominant mutation in Snap25 causes impaired vesicle trafficking, sensorimotor gating, and ataxia in the blind-drunk mouse. Proc Natl Acad Sci U S A. 2007; 104(7):2431-6. PMC: 1793901. DOI: 10.1073/pnas.0610222104. View

Bruno K, Freet C, Twining R, Egami K, Grigson P, Hess E . Abnormal latent inhibition and impulsivity in coloboma mice, a model of ADHD. Neurobiol Dis. 2006; 25(1):206-16. PMC: 1761697. DOI: 10.1016/j.nbd.2006.09.009. View

Bredy T, Wu H, Crego C, Zellhoefer J, Sun Y, Barad M . Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn Mem. 2007; 14(4):268-76. PMC: 2216532. DOI: 10.1101/lm.500907. View

Bronk P, Deak F, Wilson M, Liu X, Sudhof T, Kavalali E . Differential effects of SNAP-25 deletion on Ca2+ -dependent and Ca2+ -independent neurotransmission. J Neurophysiol. 2007; 98(2):794-806. DOI: 10.1152/jn.00226.2007. View

Meador K . The basic science of memory as it applies to epilepsy. Epilepsia. 2007; 48 Suppl 9:23-5. DOI: 10.1111/j.1528-1167.2007.01396.x. View

Pozzi D, Condliffe S, Bozzi Y, Chikhladze M, Grumelli C, Proux-Gillardeaux V . Activity-dependent phosphorylation of Ser187 is required for SNAP-25-negative modulation of neuronal voltage-gated calcium channels. Proc Natl Acad Sci U S A. 2007; 105(1):323-8. PMC: 2224210. DOI: 10.1073/pnas.0706211105. View

Gosso M, de Geus E, Polderman T, Boomsma D, Heutink P, Posthuma D . Common variants underlying cognitive ability: further evidence for association between the SNAP-25 gene and cognition using a family-based study in two independent Dutch cohorts. Genes Brain Behav. 2007; 7(3):355-64. DOI: 10.1111/j.1601-183X.2007.00359.x. View

Weickert C, Miranda-Angulo A, Wong J, Perlman W, Ward S, Radhakrishna V . Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia. Hum Mol Genet. 2008; 17(15):2293-309. PMC: 2465798. DOI: 10.1093/hmg/ddn130. View

Catterall W, Few A . Calcium channel regulation and presynaptic plasticity. Neuron. 2008; 59(6):882-901. DOI: 10.1016/j.neuron.2008.09.005. View

10.

Wu X, Chen P, Dallas S, Wilson B, Block M, Wang C . Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. Int J Neuropsychopharmacol. 2008; 11(8):1123-34. PMC: 2579941. DOI: 10.1017/S1461145708009024. View

11.

Matteoli M, Pozzi D, Grumelli C, Condliffe S, Frassoni C, Harkany T . The synaptic split of SNAP-25: different roles in glutamatergic and GABAergic neurons?. Neuroscience. 2008; 158(1):223-30. DOI: 10.1016/j.neuroscience.2008.03.014. View

12.

Corradini I, Verderio C, Sala M, Wilson M, Matteoli M . SNAP-25 in neuropsychiatric disorders. Ann N Y Acad Sci. 2009; 1152:93-9. PMC: 2706123. DOI: 10.1111/j.1749-6632.2008.03995.x. View

13.

Sudhof T, Rothman J . Membrane fusion: grappling with SNARE and SM proteins. Science. 2009; 323(5913):474-7. PMC: 3736821. DOI: 10.1126/science.1161748. View

14.

Tuchman R, Moshe S, Rapin I . Convulsing toward the pathophysiology of autism. Brain Dev. 2008; 31(2):95-103. PMC: 2734903. DOI: 10.1016/j.braindev.2008.09.009. View

15.

Mula M, Trimble M . Antiepileptic drug-induced cognitive adverse effects: potential mechanisms and contributing factors. CNS Drugs. 2009; 23(2):121-37. DOI: 10.2165/00023210-200923020-00003. View

16.

Manfredi I, Zani A, Rampoldi L, Pegorini S, Bernascone I, Moretti M . Expression of mutant beta2 nicotinic receptors during development is crucial for epileptogenesis. Hum Mol Genet. 2009; 18(6):1075-88. DOI: 10.1093/hmg/ddp004. View

17.

Guerini F, Bolognesi E, Manca S, Sotgiu S, Zanzottera M, Agliardi C . Family-based transmission analysis of HLA genetic markers in Sardinian children with autistic spectrum disorders. Hum Immunol. 2009; 70(3):184-90. DOI: 10.1016/j.humimm.2008.12.009. View

18.

Forero D, Arboleda G, Vasquez R, Arboleda H . Candidate genes involved in neural plasticity and the risk for attention-deficit hyperactivity disorder: a meta-analysis of 8 common variants. J Psychiatry Neurosci. 2009; 34(5):361-6. PMC: 2732742. View

19.

Callaerts-Vegh Z, Hoyer D, Kelly P . Selective effects of benzodiazepines on the acquisition of conditioned taste aversion compared to attenuation of neophobia in C57BL/6 mice. Psychopharmacology (Berl). 2009; 206(3):389-401. DOI: 10.1007/s00213-009-1614-4. View

20.

Ghezzo A, Guerini F, Bolognesi E, Matteoli M, Manca S, Sotgiu S . Neuropsycological gender differences in healthy individuals and in pediatric neurodevelopmental disorders. A role for SNAP-25. Med Hypotheses. 2009; 73(6):978-80. DOI: 10.1016/j.mehy.2009.05.045. View