MicroRNA Linked to Faulty Molecular Signaling in Brain Disorders

These syndromes all result from a disruption in the function of N-methyl-D-aspartate (NMDA) glutamate receptors, which are regulators of rapid neurotransmission and synaptic plasticity.

Investigators at Scripps Florida (Jupiter, FL, USA) used both chemical and genetic tools to study the molecular mechanisms associated with NMDA-related behavior problems in mouse models. A population of normal mice was treated with dizocilpine, a known NMDA antagonist that has been reported to cause changes in human patients that resemble acute psychosis. A second study group comprised mice with a mutation in the Grin1gene, which results in a substantial decrease in NMDA expression levels.

Results published in the February 5, 2009, online edition of the journal Proceedings of the [U.S.] National Academy of Sciences (PNAS) revealed that disruption of NMDA receptor signaling by either chemical or genetic means reduced levels of the brain-specific microRNA, miR-219, in the prefrontal cortex (PFC) of the mice. The PFC is the area of the brain associated with memory, personality, and decision-making.

Further results showed that miR-219 targeted a key component of the NMDA signaling cascade, CaMKII-gamma, a calcium/calmodulin-dependent protein kinase. MiR-219 depressed the levels of CaMKII-gamma in vitro, while inhibition of miR-219 with specific antibodies in vivo altered its expression. Calcium is an integral component of the signal transduction pathway, where it modulates release of neurotransmitters from neurons. A disruption of calcium flow through NMDA would interfere with normal synaptic plasticity, a situation common to a number of brain disorders.

"We have shown the involvement of miR-219 in the signaling cascade, and with this important calcium kinase, and that makes miR-219 even more of a target of interest for potential drug development," said senior author Dr. Claes Wahlestedt, professor of molecular neurosciences at Scripps Florida. "These two facts alone mean that we should look at this microRNA far more than we have in the past."

"In the study we asked the question, which noncoding RNA players might have something to do with NMDA signaling in the prefrontal cortex part of the brain?" said Dr. Wahlestedt. "As we discovered, miRNA-219, which is a brain-specific microRNA, plays an integral part in the NMDA signaling process. Our findings strongly support the idea that this previously uncharacterized microRNA significantly modulates NMDA signaling and associated behavioral problems."

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