Innovations In Clinical Neuroscience

JAN-FEB 2017

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

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[ 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 ] Innovations in CLINICAL NEUROSCIENCE 55 location. Another notable similarity b etween miR-219 and miR-132 is that they both have been shown to influence genes important to circadian clock entrainment, 13 which is of potential relevance to schizophrenia, given the o bserved deficits in circadian synchronization. 14,15 CONCLUSION Neural miRNAs are responsive to environmental, synaptic, and pathological changes and are actively secreted by cells as exosomes from brain into blood. While serum miRs cannot cross the blood brain barrier (BBB), naturally occurring exosomes are capable of crossing the BBB. These exosomes bear cell-type specific surface markers. Using a neural- specific surface marker, neural-derived exosomes can be successfully isolated and can be used as diagnostic markers for many psychiatric conditions. For example, brain-derived exosomes are fused with neuron-specific RVG peptide (rabies virus glycoprotein, a peptide known to selectively target the nicotinic acetylcholine receptor in neurons) and are loaded with MiRNA by electroporation. These intravenously injected exosomes can cross the BBB and deliver MiRNA specifically to neurons, microglia, and oligodendrocytes in the brain, resulting in a specific gene knockdown. However, to realize the therapeutic potential of MiRNAs in greater depth, efficient, tissue-specific, and nonimmunogenic delivery of exosomes must be developed. RVG exosomes are capable of delivering MiRNAs specifically and safely after systemic administration and, therefore, represent a promising vehicle for gene therapies targeting psychiatric disorders. More research on the mechanisms of the development of n europsychiatric diseases must be conducted to generate more successful therapeutic strategies. The exact nature and extent of dysregulation of microRNAs in psychiatric disorders is yet to be d etermined. Current studies are heterogeneous, and even studies of same source material have delivered disparate findings. Considerable obstacles remain before microRNAs can be used as therapeutic targets in psychiatric disorders. REFERENCES 1. Pascual-Leone A, Amedi A, Fregni F, Merabet LB. The plastic human brain cortex. Annu Rev Neurosci. 2005;28:377–401. 2. Schouten M, Aschrafi A, Bielefeld P, Doxakis E, Fitzsimons C. microRNAs and the regulation of neuronal plasticity under stress conditions. Neuroscience. 2013;241:188–205. 3. Wang X, Wang X. Systematic identification of microRNA functions by combining target prediction and expression profiling. Nucleic Acids Res. 2006;34(5):1646–1652. 4. Lee Y, Ahn C, Han J, et al. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003;425(6956):415–419. 5. Yi R, Qin Y, Macara IG, Cullen BR. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 2003;17(24):3011– 3016. 6. Schwarz DS, Hutvágner G, Du T, Xu Z, Aronin N, Zamore PD. Asymmetry in the assembly of the RNAi enzyme complex. Cell. 2003;115(2):199–208. 7. Baudry A, Mouillet-Richard S, Schneider B, Launay J-M, Kellermann O. miR-16 targets the serotonin transporter: a new facet for adaptive responses to antidepressants. Science. 2010;329(5998):1537–1541. 8. Schratt GM, Tuebing F, Nigh EA, et al. A brain-specific microRNA regulates dendritic spine development. Nature. 2006;439(7074):283–289. 9. Rong H, Liu TB, Yang KJ, et al. MicroRNA-134 plasma levels before and after treatment for bipolar mania. J Psychiatr Res. 2011;45(1):92–95. 10. Tabares-Seisdedos R, Rubenstein J. Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer. Mol Psychiatry. 2009;14(6):563–589. 11. Fénelon K, Mukai J, Xu B, et al. Deficiency of Dgcr8, a gene disrupted by the 22q11. 2 microdeletion, results in altered short-term plasticity in the prefrontal cortex. Proc Natl Acad Sci. 2011;108(11):4447–4452. 12. Kocerha J, Faghihi MA, Lopez-Toledano MA, et al. MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proc Natl Acad Sci. 2009;106(9):3507–3512. 13. Cheng H-YM, Papp JW, Varlamova O, et al. microRNA modulation of circadian- clock period and entrainment. Neuron. 2007;54(5):813–829. 14. Boivin DB. Circadian rhythms and clock genes in psychotic disorders. Isr J Psychiatry Relat Sci. 2010;47(1):27. 15. Lamont EW, Legault-Coutu D, Cermakian N, Boivin DB. The role of circadian clock genes in mental disorders. Dialogues Clin Neurosci. 2007;9(3):333.

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