Transcriptomic Analysis in the Striatum Reveals an Involvement of Nurr1 in Social Behavior of Prenatally Valproic Acid-Exposed Mice

Abstract BackgroundThe striatum of the basal ganglia is the major subcortical component of the mammalian forebrain. Magnetic resonance imaging (MRI) studies have implicated surface deformation of the striatum in the brains of patients with autism spectrum disorders (ASD) and their correlation with behavioral phenotypes. MethodsUsing RNA sequencing (RNA-Seq), we analyzed transcriptome alteration in striatal tissues from 10-week-old prenatally valproic acid (VPA)-exposed BALB/c male mice. To investigate the relationship of Nurr1 with synaptic and social deficit, we activated the expression level of nuclear receptor related 1 protein (Nurr1) by i.p. injection of amodiaquine (AQ) for 2 weeks. Furthermore, we employed lentiviral system to inhibit the Nurr1 expression and provide evidence for the role of Nurr1 in social behavior. ResultsTranscriptomic analysis showed higher levels of genes related to synaptic function of neurons in striatal tissues from the prenatally VPA-exposed mice. Among those genes, Nurr1 expression was significantly upregulated. The treatment with AQ, which has been known to be a ligand for Nurr1, to saline-exposed mice mimicked social deficits and synaptic abnormality observed in prenatally VPA-exposed mice. Moreover, viral inhibition of Nurr1 markedly improved social deficits in prenatally VPA-exposed mice. LimitationsThis study did not identify the mechanism of how Nurr1 activation regulates striatum-related circuit. Identification of the mechanism will provide explanation for behavioral impairments in prenatally VPA-exposed mice.ConclusionsTaken together, these results suggest that the increase in Nurr1 expression in the striatum is a mechanism related to the changes in synaptic deficits and behavioral phenotypes of VPA-induced ASD mouse model.