2013 Theses Doctoral

Exploring the role of Rapgef6 in neuropsychiatric disorders

Levy, Rebecca Jeannette

Schizophrenia is highly heritable yet there are few confirmed, causal mutations. In human genetic studies, we discovered CNVs impacting RAPGEF6 and RAPGEF2. Behavioral analysis of a mouse modeling Rapgef6 deletion determined that amygdala function was the most impaired behavioral domain as measured by reduced fear conditioning and anxiolysis. More disseminated behavioral functions such as startle and prepulse inhibition were also reduced, while locomotion was increased. Hippocampal-dependent spatial memory was intact, as was prefrontal cortex function on a working memory task. Neural activation as measured by cFOS levels demonstrated a reduction in hippocampal and amygdala activation after fear conditioning. In vivo neural morphology assessment found CA3 spine density and primary dendrite number were reduced in knock out animals but additional hippocampal measurements were unaffected. Furthermore, amygdala spine density and prefrontal cortex dendrites were not changed. Considering all levels of analysis, the Rapgef6 mouse was most impaired in hippocampal and amygdala function, brain regions implicated in schizophrenia pathophysiology at a variety of levels. The exact cause of Rapgef6 pathology has not yet been determined, but the dysfunction appears to be due to subtle spine density changes as well as synaptic hypoactivity. Continued investigation may yield a deeper understanding of amygdala and hippocampal pathophysiology, particularly contributing to negative symptoms, as well as novel therapeutic targets in schizophrenia.