Aberrant Development and Synaptic Transmission of Cerebellar Cortex in a VPA Induced Mouse Autism Model

Abstract

Autistic spectral disorder (ASD) is a prevalent neurodevelopmental disease that affects multiple brain regions. Both clinical and animal studies have revealed the possible involvement of the cerebellum in ASD pathology. In this study, we generated a rodent ASD model through a single prenatal administration of valproic acid (VPA) into pregnant mice, followed by cerebellar morphological and functional studies of the offspring. Behavioral studies showed that VPA exposure led to retardation of critical motor reflexes in juveniles and impaired learning in a tone-conditioned complex motor task in adults. These behavioral phenotypes were associated with premature migration and excess apoptosis of the granular cell (GC) precursor in the cerebellar cortex during the early postnatal period, and the decreased cell density and impaired dendritic arborization of the Purkinje neurons. On acute cerebellar slices, suppressed synaptic transmission of the Purkinje cells were reported in the VPA-treated mice. In summary, converging evidence from anatomical, electrophysiological and behavioral abnormalities in the VPA-treated mice suggest cerebellar pathology in ASD and indicate the potential values of motor dysfunction in the early diagnosis of ASD.

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

“…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). Reduction in excitatory striatal inputs is also observed in genetic mouse models of ASD (Fuccillo, 2016).…”

“…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.…”

“…Control pregnant females received an equivalent dose of vehicle at gestational day 12. Only male mice of the offspring were utilized for these experiments (in Figures 5-7) (Lauber et al, 2016;Kuo and Liu, 2017;Wang et al, 2018).…”

Psilocybin rescues sociability deficits in an animal model of autism

“…Through this long-standing clinical use, it has been observed that pregnant mothers treated with VPA are at an increased risk of giving birth to children that are diagnosed with ASD 20 . In mice, prenatal VPA exposure also results in offspring exhibiting many ASD-like behavioural phenotypes [21][22][23][24] , including altered social behaviour [25][26][27] . Here we explored the potential of psilocybin to ameliorate altered sociability in the prenatal VPA mouse model of autism.…”

“…More detailed mechanistic studies will be needed in future to understand the molecular and circuit underpinnings of this therapeutic potential. The dose and the embryonic day of VPA administration were based on previously published reports [21][22][23] . Prenatally exposed VPA animals showed significantly lower body weight than the prenatal saline control at weaning age (controls = 15.01 g, VPA = 12.09 g; P = 0.0002; n = 24/group; Extended Data Fig.…”