Targeted Disruption of the Deaf1 Gene in Mouse Brain and the Effects on Behavior and Gene Expression

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), <italic>DEAF1</italic> 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 <italic>Deaf1</italic> has been reported to alter 5-hydroxytryptamine (serotonin) receptor 1A (<italic>Htr1a</italic>) levels in the frontal cortex and dorsal raphe nucleus. We hypothesized that mice with targeted deletion of <italic>Deaf1</italic> in brain would produce behavior phenotypes analogous to human MDD and ID, and that changes in <italic>Deaf1</italic>-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 (<italic>Deaf1-flox</italic>). <italic>Deaf1-flox</italic> mice were bred to congenic status onto a C57BL/6 background, and were then bred to mice transgenic for the <italic>Nestin-Cre</italic> gene to produce embryonic knockout of <italic>Deaf1</italic> 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 <italic>Deaf1</italic> 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 <italic>Deaf1</italic> displayed severe deficits in fear conditioning tests. <italic>Eif4g3</italic> and <italic>Tmem80</italic> are target genes of Deaf1 and decreased mRNA levels were observed for <italic>Eif4g3</italic> and <italic>Tmem80</italic> throughout the brain of <italic>Deaf1</italic> knockout mice, with no change in <italic>Htr1a</italic> mRNA levels. Our results demonstrate that conditional knockout of <italic>Deaf1</italic> in neuronal precursors produces anxiety behavior and deficits in learning and memory in adult mice, potentially without changes in <italic>Htr1a</italic> mRNA levels, and that this mouse model may be useful in understanding the molecular mechanisms underlying MDD and ID in humans.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Campus Only Dissertation

Discipline thesis:degree_discipline

Molecular, Cellular, and Systemic Physiology

Year

2014

Author dc:creator

• Rajamanickam, Shivakumar

Contributors dc:contributor

• Collard, Michael

• DEAF1
• Gene Expression
• Intellectual Disorder
• Major Depressive Disorder
• Mouse Knockout
• Transcription Factor

Repository record dc:identifier

https://opensiuc.lib.siu.edu/dissertations/966

OAI identifier oai:identifier

oai:opensiuc.lib.siu.edu:dissertations-1970