MicroRNAs (miRNAs) are a class of small non-coding regulatory RNAs. Abnormalities in miRNA expression and miRNA-mediated gene regulation have been observed in a variety of human diseases, including psychiatric and neurodevelopmental disorders. In most cases, miRNAs appear to be components of both the genetic architecture of these complex phenotypes and integral parts of the biological pathways that mediate the effects of the primary genetic deficits and could serve as novel therapeutic targets. Some of the strongest evidence for a direct pathogenic link between psychiatric disorders, cognitive dysfunction and miRNAs is provided by studies on the mouse model of a well- established genetic risk factor, the 22q11.2 microdeletion (Df(16)A+/- mice). Analysis of this mouse model provided compelling evidence that the 22q11.2 microdeletion results in abnormal processing of brain miRNAs. Our recent work has identified two major components of the 22q11.2-associated miRNA dysregulation, as well as a major downstream target of the miRNA dysregulation. Despite substantial progress, the extent to which miRNA dysregulation contributes to the cellular, synaptic and behavioral phenotypes associated with the 22q11.2 microdeletion in vivo remains to be determined and additional key downstream targets remain to be identified. This is the focus of this grant proposal. Understanding how miRNA-dependent gene regulation disrupted by a structural mutation with unequivocal causal links to schizophrenia and cognitive dysfunction contributes to the emergence of the psychiatric and cognitive phenotypes associated with this genomic imbalance will provide important mechanistic insights and can guide analysis of miRNA contribution to other psychiatric, neurodevelopmental and cognitive disorders.

Public Health Relevance

This proposal is inherently translational in nature, aimed at elucidating the neurobiological substrates of psychiatric disease. It is aimed at identifying specific patterns of abnormal gene expression caused by loci predisposing to schizophrenia and cognitive dysfunction and link them to the cellular, synaptic and cognitive processes they impact. Identifying such patterns would set the stage for a novel approach to therapies aimed at reversing the underlying pathophysiology and restoring normal function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH097879-03
Application #
8658851
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2012-06-15
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Physiology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
Choi, Se Joon; Mukai, Jun; Kvajo, Mirna et al. (2017) A Schizophrenia-Related Deletion Leads to KCNQ2-Dependent Abnormal Dopaminergic Modulation of Prefrontal Cortical Interneuron Activity. Cereb Cortex :1-17
Zaremba, Jeffrey D; Diamantopoulou, Anastasia; Danielson, Nathan B et al. (2017) Impaired hippocampal place cell dynamics in a mouse model of the 22q11.2 deletion. Nat Neurosci 20:1612-1623
Diamantopoulou, Anastasia; Sun, Ziyi; Mukai, Jun et al. (2017) Loss-of-function mutation in Mirta22/Emc10 rescues specific schizophrenia-related phenotypes in a mouse model of the 22q11.2 deletion. Proc Natl Acad Sci U S A 114:E6127-E6136
Piskorowski, Rebecca A; Nasrallah, Kaoutsar; Diamantopoulou, Anastasia et al. (2016) Age-Dependent Specific Changes in Area CA2 of the Hippocampus and Social Memory Deficit in a Mouse Model of the 22q11.2 Deletion Syndrome. Neuron 89:163-76
Takata, Atsushi; Ionita-Laza, Iuliana; Gogos, Joseph A et al. (2016) De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia. Neuron 89:940-7
Hsu, Pei-Ken; Xu, Bin; Mukai, Jun et al. (2015) The BDNF Val66Met variant affects gene expression through miR-146b. Neurobiol Dis 77:228-37
Barr, Ian; Weitz, Sara H; Atkin, Talia et al. (2015) Cobalt(III) Protoporphyrin Activates the DGCR8 Protein and Can Compensate microRNA Processing Deficiency. Chem Biol 22:793-802
Mukai, Jun; Tamura, Makoto; FĂ©nelon, Karine et al. (2015) Molecular substrates of altered axonal growth and brain connectivity in a mouse model of schizophrenia. Neuron 86:680-95
Takata, Atsushi; Xu, Bin; Ionita-Laza, Iuliana et al. (2014) Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene. Neuron 82:773-80
Ellegood, J; Markx, S; Lerch, J P et al. (2014) Neuroanatomical phenotypes in a mouse model of the 22q11.2 microdeletion. Mol Psychiatry 19:99-107

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