Gestational VPA exposure enhances facial stimulation-evoked cerebellar mossy fiber–granule cell transmission via GluN2A-contanning NMDA receptor in offspring mice

Abstract

Valproic acid (VPA) is one of the most efficient antiepileptic drugs, which exposed during gestation has been employed as an animal model for autism spectrum disorder (ASD). Numerous studies have demonstrated that the dysfunction of synaptic transmission of cerebellar cortical circuitry contributes to the social deficits and repetitive behaviors of ASD. In this study, we investigated the effect of VPA exposure during pregnancy on the tactile stimulation-evoked cerebellar mossy fibers-granule cell (MF-GC) synaptic transmission in the urethane-anesthetized mice. Three-chamber test showed that VPA-exposed mice exhibited significant reduction of social interaction comparted with control group. In vivo electrophysiological recordings revealed that a paired-facial stimulation evoked MF-GC synaptic, N1 and N2. The evoked MF-GC synaptic responses in VPA-exposed mice exhibited a significant increase in area under the curve (AUC) of N1, amplitude and AUC of N2 than that of VPA-untreated mice. Cerebellar surface application of a selective N-methyl-D-aspartate (NMDA) receptors blocker, D-APV, significantly depressed the facial stimulation-evoked MF-GC synaptic transmission. In presence of D-APV, AUC of N1, amplitude and AUC of N2 in VPA-exposed mice were no significant than that of VPA-untreated mice. Notably, blockade of GluN2A- but not GluN2B- subunit-containing NMDA receptor, significantly depressed the MF-GC synaptic transmission, and decreased AUC of N1, amplitude and AUC of N2 in VPA-exposed mice to a similar level of that in VPA-untreated mice. In addition, the expression of GluN2A subunit-containing NMDA receptor immunoreactivity in granule cell layer of VPA-treated mice was significantly higher than that in control mice. These results indicate gestational VPA exposure produces behaviors of ASD accompanied with an enhancement of the cerebellar MF-GC synaptic transmission by an increase of GluN2A-contanning NMDA receptor in offspring mice.