Innovations In Clinical Neuroscience

JAN-FEB 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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Page 53 of 63

Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 4 , N U M B E R 1 – 2 , J A N U A R Y – F E B R U A R Y 2 0 1 7 ] 54 MiRNAs are ~22 nucleotide (nt)-long, s mall, non-coding RNA molecules. MiRNA biogenesis is initiated via transcription by RNA polymerase II, generating primary transcripts known as pri-miRs. Pri-miRs are cropped by r ibonuclease III Drosha and its cofactor, DiGeorge syndrome critical region gene 8 (DGCR8), to generate approximately 65nt-long, hairpin-shaped precursors known as pre-miRs. 4 Drosha and DGCR8 form a protein complex called a microprocessor, crucial for initial miR biogenesis. Pre-miRs are then exported by the nuclear transport factor exportin-5 (Exp5) to the cytoplasm where pre-miRNAs are processed by Dicer to a duplex of 22nt, double-stranded, mature miRNAs. 5 One strand (antisense) of the mature miRNA is assembled into an RNA-induced silencing complex (RISC), while the other strand of the duplex is degraded. 6 One or both strands of a duplex have the potential to recognize cognate binding sites, miRNA recognition elements (MREs), in the three prime untranslated region (3' UTR) of protein coding mRNAs. Mature miRNAs silence gene expression by promoting translational repression and/or mRNA degradation. A single miRNA has the potential to target hundreds of distinct mRNA molecules. Limbic area components, including hippocampi, amygdale, and ventromedial prefrontal cortices, are sensitive to stress-induced changes in neuronal plasticity; however, the hippocampi are the most sensitive among these. Elevation in glucocorticoids associated with activation of the HPA axis seems to be a central mechanism for regulation of neurogenesis by stress. The glucocorticoid receptor (GR) is a key regulator of structural plasticity and neurogenesis in the hippocampus. The highest density of glucocorticoid receptors (GRs) is present in these limbic structures, suggesting they are the primary targets of glucocorticoids in the brain in an acute stress response. Target genes of these miRNAs include those encoding for brain-derived neurotrophic factor (BDNF), which is widely expressed throughout the brain to promote neuronal survival and maturation, synaptic plasticity and synaptic function; cAMP response element-binding protein (CREB), a transcription factor involved in s ynaptic plasticity and memory formation; and LIM domain kinase-1 (LimK-1), an enzyme that regulates dendrite size. MiRNA suppression of LimK-1 can be reversed by BDNF. MicroRNAs AS MARKERS IN DEPRESSION Due to the broad phenotype of major depressive disorder (MDD), it is likely impossible to identify a single, effective, diagnostic biomarker reflecting the activity of a pathway (or pathways) involved in depressive symptoms. MiR-16 was identified as a posttranscriptional repressor of the serotonin transporter (SERT), a pharmacological target of today's selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs). MiR-16 was identified as a negative regulator of SERT through computer analysis. The role of miRNAs in depression was initially ascertained from an in-vivo study of the raphe nuclei in mice; the investigators showed that fluoxetine increased levels of miR-16, which led to decreased SERT levels and increased serotonin signaling at the synapse. Hence, miR-16 acts as a central regulator of SERT expression. Furthermore, it also behaves as the mediator of the adaptive response of serotonergic and noradrenergic neurons to fluoxetine treatment. 7 MiRNAs provide a mechanism for adaptive changes in SERT expression in monoaminergic neurons, which can differentiate into either serotonergic (1C115-HT) or noradrenergic (1C11NE neuroectodermal cell line) neuronal cells. MicroRNAs IN BIPOLAR DISORDER MiRNA-134 represses the translation of the Limk1-mRNA, a protein kinase that influences dendritic spine development. The miRNA-mediated repression of translation occurs by exogenous stimuli like BDNF, which has emerged as a key mediator for synaptic efficacy, neuronal connectivity ,and neuroplasticity. 8 In a study of 21 drug-free bipolar type 1 individuals with mania and 21 controls, 9 miR-134 levels in bipolar patients were inversely correlated with severity of manic symptoms, and their levels increased f ollowing treatment. Although numbers were low, and treatment was open-label, this study suggests that miRNAs have the potential to serve as both therapeutic targets and biomarkers for bipolar d isorder. MicroRNAs IN SCHIZOPHRENIA Chromosome 8p, from which at least seven miRNAs are transcribed, is an important area for neurodevelopmental disorders, such as autism and schizophrenia. 10 Patients with DiGeorge 22q11.2 deletion have a deficiency in DGCR8 (a key miRNA-processing gene) expression, resulting in decreased miR biosynthesis, imposing a 30-fold increased risk of schizophrenia. 11 The functional targets of these miRNAs include a number of genes that have been implicated in schizophrenia, such as BDNF, the dopamine receptor DRD1, the synaptic protein neuregulin 1 (NRG1) and early growth response gene 3 (EGR3). Hypo-functional NMDA-receptor signaling in dorsolateral prefrontal cortex and superior temporal gyrus is consistent with cognitive and behavioral disturbances of schizophrenia, autism, and attention deficit hyperactivity disorder (ADHD). MiR- 219 negatively regulates the function of NMDA receptors, serving as an integral component of the NMDA-R signaling cascade. MiR-219 may directly modulate NMDA-R signaling by regulating the expression of components in this cascade. Over-expression of miR-219 in cortical cells may inhibit Ca 2+ influx through NMDA-R signaling transduction upon receptor activation in vitro. MiR-219 targets the calcium/calmodulin-dependent protein kinase II gamma subunit (CaMKIIγ), a component of the NMDA receptor signaling cascade. 12 This microRNA responds rapidly to alterations in NMDA-R signaling, exerts translational control of CaMKII expression, and contributes to altered behavioral manifestations. Manipulating the expression or activity of miR-219 may, therefore, provide a potential therapeutic tool for the treatment of schizophrenia. The most well-studied miRNA family is that of miR-132/miR-212. These miRNAs share sequence similarities and are expressed from the same genomic

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