Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder

Abstract

The striatum comprises two neurochemical compartments: striosomes and the matrix. Striosomal and matrix compartments receive inputs from limbic system-related and sensorimotor cortices, respectively. Here, we investigate the impact on the corticostriosomal pathway in the valproic acid (VPA)-induced autism spectrum disorder mouse model. VPA administration during the neurogenesis time windows of striosomes, but not the matrix, resulted in aberrant compartmentation [, maternal VPA injections at embryonic day (E)12.75 decreased μ-opioid receptor-positive striosomes, but increased calbindin-positive matrix in the rostral striatum]. VPA treatment also impaired the aggregation of cells pulse labeled with 5-bromo-2'-deoxyuridine at E12.75 into striosomal cell clusters, which suggests defective segregation of striosomal cells from matrix cells. This possibility was supported by our findings that VPA treatment altered the expression of ephrinA5 and EphA4, two molecules that are related to compartmental segregation. In the VPA neocortex, Foxp2-positive neurons were decreased in layer VI, but increased in layer V, which projects to the striosomal compartment. We also investigated VPA effects on the corticostriosomal pathway. VPA treatment decreased the putative corticostriosomal synapses of striosomal neurons and induced an aberrant pattern of isolation stress-induced ultrasonic vocalizations. Of interest, risperidone treatments conjointly improved ultrasonic vocalizations and restored the striosomal compartment in VPA pups. Collectively, dysfunctional corticostriatal pathways, particularly the aberrant striosomal compartment, may be involved in autism spectrum disorder pathophysiology.-Kuo, H.-Y., Liu, F.-C. Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder.

mTOR Suppresses Macroautophagy During Striatal Postnatal Development and Is Hyperactive in Mouse Models of Autism Spectrum Disorders

“…We found a decrease in frequency and increase in amplitude of mEPSCs, which may indicate a reduction in the number of spines and an increase in the strength of the synaptic connection in the striatum of mice prenatally exposed to VPA. This synaptic phenotype is in line with a previous publication reporting a reduction of corticostriatal synapses in the rostral striatum of VPA treated mice (Kuo and Liu, 2017). Moreover, decreased mEPSCs frequency in VPA treated mice is also present in the cerebellar cortex (Wang et al, 2018).…”

“…For the VPA experiments, pregnant female breeders received a single subcutaneous injection of VPA at the dose of 600 mg/kg during gestational day 12 (Lauber et al, 2016;Kuo and Liu, 2017;Wang et al, 2018). Control pregnant females received an equivalent dose of vehicle at gestational day 12.…”

Selective Postnatal Excitation of Neocortical Pyramidal Neurons Results in Distinctive Behavioral and Circuit Deficits in Adulthood

“…A key unanswered question posed by these studies is whether the transformation to weaker CS connectivity in the adult is related to the prior, stronger connectivity between projection pyramidal neurons to the striatum in development, or whether it is an independent process. In support of the former prediction, non-genetic insults during development that increase neocortical excitability, such as exposure in utero to the antiepileptic drug valproic acid, induce ASD phenotypes in both humans and mice (Roullet, Lai and Foster, 2013;Nicolini and Fahnestock, 2018), and in mice result in aberrant development of CS pathways (Kuo and Liu, 2017).…”

Abnormal empathy-like pro-social behaviour in the valproic acid model of autism spectrum disorder

“…In that case, it is likely that ultrasonic vocalizations emitted by the rat in the restrainer would be essential to communicate its distress [25]. It is possible that VPA animals do not recognize this call, since they present an aberrant pattern of ultrasonic vocalization in situations of stress [26] and an altered auditory processing of these vocalizations [17]. Animals exposed to VPA could also have decreased attention towards the…”