Date of Award

12-1-2014

Degree Name

Doctor of Philosophy

Department

Molecular, Cellular, and Systemic Physiology

First Advisor

Collard, Michael

Abstract

DEAF1 is a transcription factor linked to suicide and depression and is recurrently mutated in non-syndromic intellectual disorder (ID). In humans with major depressive disorder (MDD), DEAF1 is reported to have altered expression in the prefrontal cortex and the dorsal raphe nucleus of females but not males, and therefore may function in sex-specific depression. Standard (whole body) knockout of Deaf1 has been reported to alter 5-hydroxytryptamine (serotonin) receptor 1A (Htr1a) levels in the frontal cortex and dorsal raphe nucleus. We hypothesized that mice with targeted deletion of Deaf1 in brain would produce behavior phenotypes analogous to human MDD and ID, and that changes in Deaf1-target gene expression would be associated with behavior changes. To test this hypothesis, we produced a mouse line to allow conditional gene targeting of exons 2-5 (Deaf1-flox). Deaf1-flox mice were bred to congenic status onto a C57BL/6 background, and were then bred to mice transgenic for the Nestin-Cre gene to produce embryonic knockout of Deaf1 in neuronal precursor cells. Adult mice were tested for anxiety behavior using the Elevated Plus Maze and Open Field Exploration tests, and were tested for depression-like behavior using the Porsolt forced swim and sucrose preference tests. Relative to control mice, both male and female mice with homozygous deletion of Deaf1 in brain displayed increased anxiety measured by the anxiety tests, and no differences were measured in tests for depression-like behavior. Rotarod testing showed no deficits in motor skills of male mice. Learning and memory in mice were tested using Morris Water Maze (MWM) and fear conditioning. No change in long-term memory in male mice was observed in MWM, but both male and female mice lacking Deaf1 displayed severe deficits in fear conditioning tests. Eif4g3 and Tmem80 are target genes of Deaf1 and decreased mRNA levels were observed for Eif4g3 and Tmem80 throughout the brain of Deaf1 knockout mice, with no change in Htr1a mRNA levels. Our results demonstrate that conditional knockout of Deaf1 in neuronal precursors produces anxiety behavior and deficits in learning and memory in adult mice, potentially without changes in Htr1a mRNA levels, and that this mouse model may be useful in understanding the molecular mechanisms underlying MDD and ID in humans.

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