MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction

Abstract

cerebral cortex ͉ glutamatergic signaling ͉ regulatory RNA N MDA receptors (NMDA-R) control many executive brain functions, such as working memory, and their dysfunction is implicated in a host of brain disorders (1-4). Notably, hypofunctional NMDA-R signaling, particularly in the prefrontal cortex (PFC), has been implicated in the cognitive and behavioral disturbances characteristic of schizophrenia (5), autism (6, 7), attention deficit hyperactivity disorder (ADHD) (8, 9), mood disorders (10), and other psychiatric illnesses. The cellular mechanisms by which disrupted NMDA-R transmission drives behavioral pathology are still unclear, although several of the major proteins involved in this pathway, such as calcium/calmodulin-dependent protein kinase II (CaMKII) (11), have been identified. In this study, we examine whether neurobehavioral abnormalities associated with NMDA-R hypofunction can be attributed to a novel class of regulatory RNA molecules, microRNAs (miRNAs).miRNAs have attracted much attention as regulators of neuronal development and synaptic plasticity (12-15). Furthermore, psychiatric disorders such as schizophrenia, autism, and Tourette's syndrome are associated with dysregulated levels of miRNAs (16)(17)(18)(19)(20). miRNAs are small (Ϸ22 nt) noncoding transcripts that can control expression of protein-coding mRNAs at the posttranscriptional level (21). Pleiotropic miRNAs can control gene expression by binding to complementary sequences in the 3Ј untranslated region (3Ј UTR) of target mRNA transcripts to facilitate their degradation and/or inhibit their translation (15,22,23). Understanding this layer of gene regulation therefore promises to enrich our knowledge of brain function and pathology. Dizocilpine is a highly selective phencyclidine-like NMDA-R antagonist that can rapidly produce schizophrenia-like behavioral deficits in humans and rodents (24). We examined whether a psychotomimetic dose of dizocilpine (0.5 mg/kg, i.p.) altered miRNA expression in brain regions of C57BL/6 mice, by using miRNA microarray profiling as an initial screening approach. Our analysis was focused on the PFC because of the considerable evidence linking this brain region with behavioral pathology in psychiatric illnesses (19). We extracted the small RNAs from the PFC of the mice 15 min after administration of a single dose of dizocilpine, i.e., a time-point at which dizocilpine-induced behavioral disturbances such as hyperlocomotion and stereotypy are readily observed (25). Of note, there was a robust reduction of miR-219 out of 182 miRNAs detectable by microarray in PFC tissues (Table S1). miR-219 is a conserved miRNA expressed in both rodent and human brains, but not in other tissues (26,27). These data demonstrate that concentrations of a brain-specific miRNA, which may play a role in regulating NMDA-R function, are altered during states of NMDA-R hypofunction.In support of the microarray data, RT-PCR analyses demonstrated that miR-219 levels were significantly reduced by Ϸ50% (a change from an average cycle th...

Differential expression of miRNAs in the nervous system of a rat model of bilateral sciatic nerve chronic constriction injury

“…Aberrant miRNA expression has also been linked to a variety of diseases, including several nervous system diseases (32)(33)(34). For example, miR-219 modulates N-methyl-D-aspartate (NMDA) receptor-mediated neurobehavioral dysfunction, which is implicated in schizophrenia and autism (35), and the expression of the sensory organ-specific miR-183 family has been shown to be altered following spinal nerve ligation (14). Moreover, Table I.…”

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

“…For instance, 2′-O-methyl oligonucleotides have been shown to inhibit let-7b and miR-124, thereby inducing proliferation of neural stem cells [131]. Treatment with LNA antisense oligonucleotides decreased the levels of miR-21 in glioblastoma cell lines [132] and miR-219 in cortex [128,133]. Similarly, peptide nucleic acids (PNAs) delivered into neurons decreased miR-326 activity and caused an increase in expression of synaptic plasticity genes [134].…”

P1–234: Circulating miRNA biomarkers for Alzheimer's disease

“…In schizophrenia, a seven-miRNA signature (hsamiR-34a, hsa-miR-449a, hsa-miR-564, hsa-miR-432, hsa-miR548d, hsa-miR-572 and hsa-miR-652) was identified in mononuclear leukocytes, which were found to be correlated with patients' negative symptoms, neurocognitive performance scores, and event-related potentials [48]. From a disease etiology point of view, functional role of hsa-miRNA-219 was illustrated by evidence that it modulated NMDA receptor-mediated neurobehavioral dysfunction by targeting CaMKIIgamma, a component of the NMDA receptor signaling cascade in the pre frontal cortex (PFC) of mice [49]. In Alzheimer's, miRNA profiling experiments have resulted in identification of disease-specific miRNAs that have been validated in two or more independent studies [50].…”