The State of the Dopaminergic and Glutamatergic Systems in the Valproic Acid Mouse Model of Autism Spectrum Disorder

Abstract

Autism Spectrum Disorder (ASD) is a progressive neurodevelopmental disorder mainly characterized by deficits in social communication and stereotyped behaviors and interests. Here, we aimed to investigate the state of several key players in the dopamine and glutamate neurotransmission systems in the valproic acid (VPA) animal model that was administered to E12.5 pregnant females as a single dose (450 mg/kg). We report no alterations in the number of mesencephalic dopamine neurons or in protein levels of tyrosine hydroxylase in either the striatum or the nucleus accumbens. In females prenatally exposed to VPA, levels of dopamine were slightly decreased while the ratio of DOPAC/dopamine was increased in the dorsal striatum, suggesting increased turn-over of dopamine tone. In turn, levels of D1 and D2 dopamine receptor mRNAs were increased in the nucleus accumbens of VPA mice suggesting upregulation of the corresponding receptors. We also report decreased protein levels of striatal parvalbumin and increased levels of p-mTOR in the cerebellum and the motor cortex of VPA mice. mRNA levels of mGluR1, mGluR4, and mGluR5 and the glutamate receptor subunits NR1, NR2A, and NR2B were not altered by VPA, nor were protein levels of NR1, NR2A, and NR2B and those of BDNF and TrkB. These findings are of interest as clinical trials aiming at the dopamine and glutamate systems are being considered.

Early cellular and synaptic changes in dopaminoceptive forebrain regions of juvenile mice following gestational exposure to valproate

“…At variance with our findings (Ádám et al, 2020, present study), no difference was found in either the abundance of DAergic neurons of SN or VTA, or the expression of TH in CPu or NAc, in mice prenatally exposed to VPA (Maisterrena et al, 2022). The apparent controversy may be due to the different age of animals (P7 in our study, and P21 in the cited study), and to methodological differences in preparing samples for WB.…”

“…The cited authors used whole lysates for WB, whereas we prepared crude synaptosome fraction from the primary lysate, which, in our opinion, represents synaptic and membrane-bound TH more specifically. Interestingly, Maisterrena et al (2022) reported an upregulation of DA receptors, indicating an underlying reduction of ligand (DA), which may have had occurred (unnoticed, in that case) prior to the age (P21) at which their samples for immunoblotting were collected. Similarly, upregulation of first D2 (at P35-40), then D1 receptors (at P90-95) was observed in the NAc of rats born to VPA-exposed mothers, (with no data on P7 animals), by Schiavi et al (2019), together with characteristic behavioral and electrophysiological responses.…”

The cortico-striatal circuitry in autism-spectrum disorders: a balancing act

“…Gene variants associated with dopaminergic markers and receptors have been identified in ASD ( De Krom et al, 2009 ; Staal et al, 2012 ; Gangi et al, 2016 ; Mariggiò et al, 2021 ). Several ASD animal models show increased gene expression of dopamine D2 receptors in iMSNs ( Maisterrena et al, 2022 Chhabra et al, 2023 ; reviewed in Gandhi and Lee, 2021 ). Increased striatal levels of dopamine D2 receptors was documented in Rett syndrome ( Chiron et al, 1993 ) and more recently, increased striatal D2 receptor gene expression has been reported in ASD post-mortem brains ( Brandenburg et al, 2020 ).…”

“…In mice, knock-down of neuroligin 2, another ASD-associated gene, results in a reduction in the density of dopaminergic synapses and an increase in the number of GABAergic synapses onto MSN ( Uchigashima et al, 2016 ). In the valproic model of ASD, dopamine levels are decreased and dopamine turnover is increased in the dorsal striatum while dopamine receptor expression is increased in the nucleus accumbens ( Maisterrena et al, 2022 ). These convergent findings suggest that altered dopaminergic modulation of corticostriatal inputs onto MSNs is a key pathophysiological feature of ASD.…”

Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders

“…Accordingly, several animal models of ASD, including both pharmacological models and genetic models generated by mutations in genes found in patients with ASD, show glutamatergic alterations. Excitotoxicity, altered glutamate homeostasis, and receptor subunit expression and regulation were reported in the brain of a valproic acid model, one of the most widely used animal models of ASD [ 30 , 31 , 32 , 33 ]. Similarly, Shank mutant mice clearly exhibit glutamatergic impairments [ 34 , 35 , 36 , 37 ].…”