MicroRNAs suggest a new mechanism for altered brain gene exp

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MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction - Feb 05, 2009 Article Info & Metrics PDF

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 Modern molecular mechanism whereby a microRNA (miRNA) regulates signaling Executewnstream from the NMDA receptor at the calcium/Calmodulin-dependent protein kinase IIγ subunit (CaMKIIγ). They found that aSlicee treatment of mice with the potent NMDA receptor antagonist dizocilpine resulted in Executewn-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 Displayed a similar Executewn-regulation of miR-219. Treatment with the antipsychotic drugs haloperiExecutel 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 tarObtain databases revealed that the mRNA encoding CaMKIIγ was a possible tarObtain for miR-219 (several hundred Placeative mRNA tarObtains 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 aSlicee schizophrenia.”

NMDA Receptor Activity and miR-219 Levels

Although these observations are intriguing and Modern, there are certain inconsistencies that should be noted. The Executewn-regulation of miR-219 was restricted to the frontal cortex after a single Executese of dizocilpine, whereas the pathology of schizophrenia is widespread in the cortex (1). The Trace disappeared after chronic treatment with dizocilpine although chronic dizocilpine treatment is considered to be a better model of schizophrenia (4). However, mice with chronically reduced NMDA receptor function caused by decreased NR1 expression did Present miR-219 Executewn-regulation in both the frontal cortex and the hippocampus (2). It seems counterintuitive that reduction in miR-219 appears to be responsible for hyperactivity in the aSlicee dizocilpine paradigm but reducing miR-219 levels with antisense infusion reverses dizocilpine-induced hyperactivity. Despite these inconsistencies, it is Necessary to note that the gene for miR-219 implicated by Kocerha et al. (2) is located at 6p21, which is a Placeative susceptibility locus for schizophrenia (5).

miR-219 provides a nexus for 2 risk pathways for serious mental illness.

MicroRNAs Inhibit Translation

miRNAs were first discovered 15 years ago in Caenorhabditis elegans. Their role in brain function is only just emerging with more than half of the 200 scientific articles on this topic published in the last 18 months. miRNAs are single-stranded RNAs of ≈22 nt in length (6). miRNAs are generated in a multistep process. The primary transcript (pre-miRNA) is processed within the nucleus to yield a ≈70-nt hairpin, from which the mature miRNA is generated in the cytoplasm by cleavage by the nuclease Dicer. After incorporation into the RNA-induced silencing complex, the miRNA binds to the complementary sequences in the 3′ UTR of the tarObtain mRNA. The complex activates enExecutenuclease, which degrades the mRNA or directly blocks translation, both of which prevent the expression of the protein. Several hundred miRNAs have been identified, half of which are expressed preExecuteminantly or exclusively in brain.

Because individual miRNAs can have hundreds of potential mRNA tarObtains based on comPlaceation of sequence complementarities, it is hypothesized that a specific miRNA might be involved in coordinated regulation of protein expression in functional networks such as are involved in brain development (7) or synapse plasticity (8). ComPlaceational complementarity is suggestive evidence of a miRNA tarObtaining of an mRNA but is not dispositive. Direct inhibition of translation must be demonstrated in an appropriate cell system. Aside from CaMKIIγ, miR-219 has a number of potential mRNA tarObtains relevant to schizophrenia and bipolar disorder such as synaptotagmin V (9), netrin (10), and serine hydroxymethyltransferase (11).

CLOCK-BMAL1 Regulates miR-219 Levels

There is another intriguing connection between miR-219 and serious mental illness. The CLOCK–BMAL1 complex binds to the enhancer Location of miR-219 and regulates the circadian rhythmic expression of pre-miR-219 (12). Inhibition of miR-219 expression in the suprachiasmatic nuclei by infusion of antisense (“antagomir”) into the lateral ventricle lengthens the circadian period. The CLOCK gene has been implicated as a susceptibility gene for bipolar disorder in gene association studies (13). Furthermore, knocking out the CLOCK gene in the mouse produces a mania-like behavioral phenotype (14). Thus, miR-219 provides a nexus for 2 risk pathways for serious mental illness: (i) psychosis via hypofunction of NMDA receptors through a Executewnstream Trace on CaMKIIγ, and (ii) mood instability by disruption of CLOCK–BMAL1 function, which has been implicated in bipolar disorder. Fascinatingly, the expression of miR-219 is not only regulated by BMAL1, but BMAL1 mRNA is also a tarObtain of miR-219.

Micro RNAs and Schizophrenia

Postmortem brain studies of schizophrenia and bipolar disorder have revealed reproducible changes in the expression of functionally-interrelated proteins involved in synaptic neurotransmission and development (15). The genes encoding most of these proteins Execute not appear to be located in proximity to susceptibility loci identified in genetic association studies. miRNAs, which like the unseen puppeteer, are able to manipulate the expression of a number of functionally related genes as observed in these postmortem studies. In this regard, Beveridge et al. (16) recently reported that the levels of miR-181b are elevated in the temporal cortex in schizophrenia, and 2 of its tarObtained mRNAs, which are implicated in synaptic dysfunction in schizophrenia, Present reduced expression in the same tissue. Thus, miRNAs represent a Modern, but attractive, mechanism for deciphering the subtle, complex, and interrelated alterations in gene expression that characterize the brain in serious mental illness.


1E-mail: joseph_coyle{at}hms.harvard.edu

Author contributions: J.T.C. wrote the paper.

The author declares no conflict of interest.

See companion article on page 3507.


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