Alterations in Tau Protein Level and Phosphorylation State in the Brain of the Autistic-Like Rats Induced by Prenatal Exposure to Valproic Acid

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficient social interaction and communication besides repetitive, stereotyped behaviours. A characteristic feature of ASD is altered dendritic spine density and morphology associated with synaptic plasticity disturbances. Since microtubules (MTs) regulate dendritic spine morphology and play an important role in spine development and plasticity the aim of the present study was to investigate the alterations in the content of neuronal α/β-tubulin and Tau protein level as well as phosphorylation state in the valproic acid (VPA)-induced rat model of autism. Our results indicated that maternal exposure to VPA induces: (1) decrease the level of α/β-tubulin along with Tau accumulation in the hippocampus and cerebral cortex; (2) excessive Tau phosphorylation and activation of Tau-kinases: CDK5, ERK1/2, and p70S6K in the cerebral cortex; (3) up-regulation of mTOR kinase-dependent signalling in the hippocampus and cerebral cortex of adolescent rat offspring. Moreover, immunohistochemical staining showed histopathological changes in neurons (chromatolysis) in both analysed brain structures of rats prenatally exposed to VPA. The observed changes in Tau protein together with an excessive decrease in α/β-tubulin level may suggest destabilization and thus dysfunction of the MT cytoskeleton network, which in consequence may lead to the disturbance in synaptic plasticity and the development of autistic-like behaviours.

Proteomic-Based Approach Reveals the Involvement of Apolipoprotein A-I in Related Phenotypes of Autism Spectrum Disorder in the BTBR Mouse Model

“…Our results have shown significant abnormalities of P-ERK and CDK5 in the brains of BTBR mice, which could be rescued by SKI-II intervention. In contrast to our study, other studies have demonstrated that ERK1/2 and CDK5 are both activated in the hippocampus of VPA rats [ 51 ], possibly because different ASD models have different variations. Targeting the ApoA-I-SphK pathway will shed new light on therapeutic interventions.…”

Sex Differences in Animal Models of Sodium-Valproate-Induced Autism in Postnatal BALB/c Mice: Whole-Brain Histoarchitecture and 5-HT2A Receptor Biomarker Evidence

“…In this study, 5-HT2A receptor protein immunoreactivity was detected by immunohistochemistry (IHC), using a previously described procedure [ 31 ]. Briefly, endogenous peroxidase was blocked by incubation with 3% H 2 O 2 for 15 min, and sections were incubated overnight at 4 °C in a humidity chamber with primary antibody (1:500 polyclonal anti5-HT2A, catalogue no.…”

Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms

“…While levels of endogenous or total tau differ across examinations of patients with epilepsy, increased levels of p-tau in the brain are found across many seizure disorders ( Thom et al, 2011 ). These include patients with TLE, Dravet syndrome, Nodding syndrome ( Thom et al, 2011 ; Pollanen et al, 2018 ; Hotterbeekx et al, 2019 ), Niemann-Pick type C disease (NPC) ( Auer et al, 1995 ; Love et al, 1995 ; Suzuki et al, 1995 ; Malnar et al, 2014 ), focal cortical dysplasia IIB (FCDIIb) ( Sen et al, 2007 ; Iyer et al, 2014 ), and tuberous sclerosis complex (TSC) ( Sarnat and Flores-Sarnat, 2015 ; Liu et al, 2020 ), as well as animal models of post-traumatic epilepsy (PTE) ( Cho et al, 2020 ; Alyenbaawi et al, 2021 ), Lafora disease ( Epm2a –/– ) ( Ganesh et al, 2002 ; Puri et al, 2009 ; Machado-Salas et al, 2012 ), and ASD ( Gassowska-Dobrowolska et al, 2021 ). It should be noted that tau aggregation in the brain is associated with older age and is generally uncommon in healthy young adults ( Braak et al, 2011 ; Crary et al, 2014 ).…”