Gestational VPA Exposure Impairs the Facial Stimulation‐Induced Cerebellar MF‐GC LTP by Enhancing mGluR1/5‐CB1 Receptor Cascade in Offspring Mice

The abnormalities in cerebellar circuit function within the Crus I/II lobules in autism spectrum disorder (ASD) are widely recognized as critical contributors to impairments in motor behavior and social interaction. We here investigated the impact of prenatal valproic acid (VPA) exposure on facial stimulation-evoked synaptic plasticity at cerebellar mossy fiber-granule cell (MF-GC) synapses in urethane-anesthetized offspring mice in vivo. When the GABAA receptor was blocked, 20 Hz facial stimulation induced MF-GC LTP in control mice, whereas the same stimulation paradigm triggered MF-GC LTD in VPA-treated offspring. Blockade of N-methyl-D-aspartate receptors abolished LTP in control mice while unmasking LTD in VPA-treated offspring. Notably, the facial stimulation-induced LTD observed in VPA-treated offspring was abolished by blocking group I metabotropic glutamate receptors, but not by the selective blockade of either mGluR1 or mGluR5 alone. Blockade of cannabinoid receptor 1 (CB1) or inhibition of diacylglycerol lipase (DGL) prevented the induction of LTD. Pharmacologically activating mGluR1/5 or CB1 produced MF-GC LTD and overwhelmed the facial stimulation-induced LTD in VPA-treated offspring mice. Conversely, mGluR1/5 activation failed to induce LTD in control mice. Moreover, 20 Hz facial stimulation induced MF-GC LTP in the absence of mGluR1/5 or CB1 receptor activity in VPA-treated offspring mice. Immunohistochemical analyses revealed that the expression levels of mGluR1/5 were significantly higher in the cerebellar GCs of VPA-treated offspring compared to those of control mice. These results indicate that 20 Hz facial stimulation induces MF-GC LTD by enhancing the mGluR1/5-DGL-CB1 receptor signaling cascade, thereby resulting in impairment of MF-GC LTP in VPA-treated offspring mice.