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Exploring the Role of Rapgef6 in Neuropsychiatric Disorders

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Exploring the Role of Rapgef6 in Neuropsychiatric Disorders Exploring the Role of Rapgef6 in Neuropsychiatric Disorders Rebecca Jeannette Levy Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2013 © 2012 Rebecca Jeannette Levy All rights reserved ABSTRACT Exploring the role of Rapgef6 in neuropsychiatric disorders Rebecca Jeannette Levy 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. Table of Contents Chapter 1: Introduction ................................................................................................................... 1 1.1 Clinical introduction to schizophrenia .................................................................................. 1 1.2 Schizophrenia etiology .......................................................................................................... 5 1.2.1 Neurotransmitter theories of schizophrenia .................................................................... 5 1.2.2 Environmental factors in schizophrenia ......................................................................... 7 1.3 Genetics of schizophrenia ..................................................................................................... 9 1.3.1 Common vs. rare variants (adapted from (Levy et al. 2012)) ........................................ 9 1.3.2 Copy number variant results in schizophrenia (adapted from (Levy et al. 2012)) ....... 12 1.3.3 Sequencing results in schizophrenia ............................................................................. 19 1.3.4 Interactions among rare and common variants ............................................................. 21 1.3.5 Rare variants affect circuitry ........................................................................................ 22 1.4 Comorbidity and coheritability of schizophrenia with affective and anxiety disorders ..... 23 1.5 Animal modeling of neuropsychiatric disease .................................................................... 25 1.5.1 Animal model validity .................................................................................................. 25 1.5.2 Rare mutation models of schizophrenia ....................................................................... 26 1.6 Statement of hypothesis ...................................................................................................... 29 1.7 In the next chapter ............................................................................................................... 29 Chapter 2: RAPGEF6 Genetic Findings ....................................................................................... 31 2.0 My role ................................................................................................................................ 31 i 2.1 Introduction: 5q genetic results in schizophrenia ................................................................ 31 2.2 Methods ............................................................................................................................... 33 2.2.1 Patient collection (adapted from (Xu et al. 2008)) ....................................................... 33 2.2.2 Copy number variant scan (adapted from (Xu et al. 2008; Xu et al. 2009)) ................ 34 2.2.3 CNV validation by qPCR and MLPA (adapted from (Xu et al. 2008; Xu et al. 2009)) ............................................................................................................................................... 36 2.2.4 Whole exome sequencing (adapted from (Xu et al. 2012)) .......................................... 37 2.3 Results ................................................................................................................................. 39 2.3.1 Copy number variant scan ............................................................................................ 39 2.3.2 Clinical history of patients ............................................................................................ 40 2.3.3 Whole exome sequencing ............................................................................................. 42 2.4 Summary of findings ........................................................................................................... 43 2.5 Discussion ........................................................................................................................... 43 2.5.1 Role of Rapgef6 in cell adhesion .................................................................................. 43 2.5.2 Neural role of Rapgef family members ........................................................................ 47 2.5.3 Neural role of Rap family members ............................................................................. 50 2.5.4 Rare genetic models...................................................................................................... 52 2.6 Future directions .................................................................................................................. 53 2.6.1 Genetics ........................................................................................................................ 53 2.6.2 In the next chapter ........................................................................................................ 53 ii Chapter 3: Animal Behavior ......................................................................................................... 54 3.0 My Role ............................................................................................................................... 54 3.1 Introduction ......................................................................................................................... 54 3.1.1 Validity and utility of rodent modeling ........................................................................ 54 3.1.2 Endophenotypes of schizophrenia amenable to modeling ........................................... 55 3.1.3 Rodent behavior domains explored .............................................................................. 57 3.1.4 Role of Rapgef and Rap proteins in behavior ............................................................... 59 3.2 Methods ............................................................................................................................... 61 3.2.1 Animal model generation and housing ......................................................................... 61 3.2.2 Open field ..................................................................................................................... 62 3.2.3 Novel object recognition .............................................................................................. 63 3.2.4 Morris water maze ........................................................................................................ 63 3.2.5 T maze .......................................................................................................................... 64 3.2.6 Prepulse inhibition ........................................................................................................ 66 3.2.7 Auditory testing ............................................................................................................ 66 3.2.8 Fear conditioning .......................................................................................................... 68 3.2.9 cFOS activation after fear conditioning........................................................................ 69 3.2.10 Data analysis ............................................................................................................... 69 3.3 Results ................................................................................................................................. 70 3.3.1 Generation of mouse model .......................................................................................... 70 iii 3.3.2 Open field ....................................................................................................................
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