Title: MicroRNA Dysregulation in Neuropsychiatric Disorders and Cognitive Dysfunction
Description: MicroRNAs (miRNAs) are evolutionarily-conserved small non-coding RNAs that are important posttranscriptional regulators of gene expression. Genetic Variants may cause microRNA dysregulation and the concomitant aberrant target expression. The dysregulation of one or a few targets may in turn lead to functional consequences ranging from phenotypic variations to disease conditions. In this thesis, I present our studies of mouse models of two human genetic variants - a rare copy number variant (CNV), 22q11.2 microdeletions, and a common single nucleotide polymorphism (SNP), BDNF Val66Met. 22q11.2 microdeletions result in specific cognitive deficits and high risk to develop schizophrenia. Analysis of Df(16)A+/- mice, which model this microdeletion, revealed abnormalities in the formation of neuronal dendrites and spines as well as microRNA dysregulation in brain. We show a drastic reduction of miR- 185, which resides within the 22q11.2 locus, to levels more than expected by a hemizygous deletion and demonstrate that this reduction impairs dendritic and spine development. miR-185 targets and represses, through an evolutionary conserved target site, a previously unknown inhibitor of these processes that resides in the Golgi apparatus.

Sustained derepression of this inhibitor after birth represents the most robust transcriptional disturbance in the brains of Df(16)A+/- mice and could affect the formation and maintenance of neural circuits. Reduction of miR-185 also has milder effects on the expression of a group of Golgi-related genes. One the other hand, BNDF Val66Met results in impaired activity-dependent secretion of BDNF from neuronal terminals and affects episodic memory and affective behaviors. We found a modest reduction of miR-146b which causes derepression of mRNA and/or protein levels of a few targets. Our findings add to the growing evidence of the pivotal involvement of miRNAs in the development of neuropsychiatric disorders and cognitive dysfunction. In addition, the identification of key players in miRNA dysregulation has implications for both basic and translational research in psychiatric disorders and cognitive dysfunction.