MicroRNAs suggest a new mechanism for altered brain gene expression in schizophrenia.

N europharmacologic and genetic association studies implicate dysregulation of NMDA receptor function in the pathophysiology of schizophrenia and bipolar disorder (1). In this issue of PNAS Kocerha et al. (2) suggest a novel molecular mechanism whereby a microRNA (miRNA) regulates signaling downstream from the NMDA receptor at the calcium/ calmodulin-dependent protein kinase II subunit (CaMKII ). They found that acute treatment of mice with the potent NMDA receptor antagonist dizocilpine resulted in down-regulation of miR-219 in mouse prefrontal cortex. Mice in which the expression of the critical NR1 subunit of the NMDA receptor was reduced by 95% (3) also showed a similar downregulation of miR-219. Treatment with the antipsychotic drugs haloperidol or clozapine attenuated the hyperactivity and stereotypies caused by dizocilpine and prevented the reduction in miR-219 in the prefrontal cortex. A search of miRNA target databases revealed that the mRNA encoding CaMKII was a possible target for miR-219 (several hundred putative mRNA targets were predicted by sequence complementarity). Treating neuronal-like cultured cells with a modified antisense construct to miR-219 to inactivate it increased the expression of CaMKII levels. Conversely, overexpressing miR-219 in cultured cortical neurons caused a robust reduction in CaMKII levels. Infusing the mouse brain with the antisense construct to miR-219 both attenuated the locomotor and stereotypic behaviors caused by dizocilpine and increased the expression of CaMKII in the prefrontal cortex. Kocerha et al. concluded that miR-219 plays an integral role in the behavioral manifestations associated with NMDA receptor hypofunction and thus might be relevant to the ‘‘locomotor deficits in acute schizophrenia.’’