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

Abstract

Neuropharmacologic 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 IIγ subunit (CaMKIIγ). 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 down-regulation 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 CaMKIIγ 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 CaMKIIγ levels. Conversely, overexpressing miR-219 in cultured cortical neurons caused a robust reduction in CaMKIIγ 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 CaMKIIγ 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.”