Schizophrenia is characterized by affective, cognitive, neuromorphological, and 
molecular abnormalities that may have a neurodevelopmental origin. MicroRNAs 
(miRNAs) are small noncoding RNA sequences critical to neurodevelopment and 
adult neuronal processes by coordinating the activity of multiple genes within 
biological networks. We examined the expression of 854 miRNAs in prefrontal 
cortical tissue from 100 control, schizophrenic, and bipolar subjects. The 
cyclic AMP-responsive element binding- and NMDA-regulated microRNA miR-132 was 
significantly down-regulated in both the schizophrenic discovery cohort and a 
second, independent set of schizophrenic subjects. Analysis of miR-132 target 
gene expression in schizophrenia gene-expression microarrays identified 26 genes 
up-regulated in schizophrenia subjects. Consistent with NMDA-mediated 
hypofunction observed in schizophrenic subjects, administration of an NMDA 
antagonist to adult mice results in miR-132 down-regulation in the prefrontal 
cortex. Furthermore, miR-132 expression in the murine prefrontal cortex exhibits 
significant developmental regulation and overlaps with critical 
neurodevelopmental processes during adolescence. Adult prefrontal expression of 
miR-132 can be down-regulated by pharmacologic inhibition of NMDA receptor 
signaling during a brief postnatal period. Several key genes, including DNMT3A, 
GATA2, and DPYSL3, are regulated by miR-132 and exhibited altered expression 
either during normal neurodevelopment or in tissue from adult schizophrenic 
subjects. Our data suggest miR-132 dysregulation and subsequent abnormal 
expression of miR-132 target genes contribute to the neurodevelopmental and 
neuromorphological pathologies present in schizophrenia.