Alteration of mTOR signalling pathway in rats prenatally exposed to valproic acid

• Autorzy: Adamczyk A. , Cieslik M. , Gassowska-Dobrowolska M. , Jesko H. , Filipkowski R.K. , Boguszewski P.M.
• Języki publikacji: EN

Abstrakty

EN

INTRODUCTION: Autism is a neurodevelopmental disorder characterised by impaired social interaction, deficits in communication and stereotyped behaviours with synaptic dysfunction suggested as the major causative factor. However, the molecular mechanisms of synapses impairment remain unclear. The most recent studies point to mTOR, a regulator of protein synthesis at spines, as a potential molecular basis of autism. AIM(S): Here, we investigated whether the Akt/mTOR pathway is damaged in rats prenatally exposed to valproic acid (VPA), an animal model exhibiting autistic-like behaviour. METHOD(S): Pregnant Wistar rats were injected i.p. with a single dose of 400 mg/kg VPA on embryonic day 12.5. Autism‑like behaviours were verified by measuring ultrasonic vocalizations and elevated plus maze test. Gene expression and protein levels were analysed using real-time PCR and western blot methods, respectively. RESULTS: Our behavioural investigations have shown impaired communication and increased anxiety in VPA group. Along with the behavioural changes we observed alteration of mTOR signalling in the cerebral cortex, hippocampus and cerebellum of autistic model rats. Enhancement of phospho-mTOR protein level was the most pronounced in the hippocampus, where the phosphorylation of mTOR targets was observed: increased p-4E-BP1, and reduced phospho-p70S6K. These changes were accompanied by an increase in p-Akt protein level. Activation of mTOR in the cerebellum caused an increase of p-4E-BP1, but not of p70S6K. The mild but significant rise in phosphorylated mTOR in the cerebral cortex did not lead to any changes in p70 or 4E-BP1 phosphorylation. Synaptosomes isolated from VPA subjects revealed significant abnormalities in their ultrastructure including unidentified electron-dense matrix material as well as fragile and malformed the post-synaptic densities. CONCLUSIONS: These results suggested that altered signalling via Akt/mTOR/p70S6K/p-4E-BP1 may result in disturbed spine protein synthesis and thereby lead to synaptic dysfunction. FINANCIAL SUPPORT: Supported from MMRC statutory theme 8.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2017
• Tom: 77
• Numer: Suppl.1
• Opis fizyczny: p.61

Twórcy

autor

Adamczyk A.

• Department of Cellular Signalling, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland

autor

Cieslik M.

• Department of Cellular Signalling, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland

autor

Gassowska-Dobrowolska M.

• Department of Cellular Signalling, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland

autor

Jesko H.

• Department of Cellular Signalling, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland

autor

Filipkowski R.K.

• Behavior and Metabolism Research Laboratory, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland

autor

Boguszewski P.M.

• Laboratory of Animal Models, Neurobiology Center, Nencki Institute of Experimental Biology Polish Academy of Sciences, Warsaw, Poland