Neuronal plasticity in the dentate gyrus of a mouse model of Fragile X syndrome

Fragile-X syndrome (FXS) is the most common form of inherited intellectual disability (ID), representing a considerable burden of health in our society. FXS is caused by repression of the transcription of one gene, Fmr1. Normally, expression of the Fmr1 gene leads to the production of one type of protein, the Fragile-X Mental Retardation Protein (FMRP). At the cellular level, FXS is caused by a lack of FMRP. The fact that mice and humans possess a nearly identical Fmr1 gene has permitted the generation of a mouse model of FXS using modern transgenesis techniques (Fmr1 knockout (KO) mice). The study of the behavior of Fmr1 KO mice was expected to quickly reveal ID with subsequent elucidation of the syndrome’s neurobiological underpinnings. Unfortunately, the manifestation of presumed ID (defined as significant impairments in intellectual and adaptive functioning) at the behavioral and neurobiological levels in Fmr1 KO mice has been surprisingly elusive. How repression of Fmr1 gene expression affects the human brain to produce ID is unclear. The dentate gyrus (DG) subfield of the hippocampus is a region of the brain that is associated with learning and emotion, exhibits marked structural and functional plasticity, and was unexplored in Fmr1 KO mice prior to the work presented in this thesis. Our overarching hypothesis is that lack of expression of the Fmr1 gene deleteriously alters structural and functional plasticity in the mammalian DG, and impairs aspects of learning and emotion associated with this brain region. Chapter 1 introduces topics such as FXS, the hippocampus, plasticity and the mouse model of FXS. Specific hypotheses are listed at the end of chapter 1. Chapters 2 and 3 are manuscripts written for publication in peer-reviewed journals. The bulk of the data relating to the testing of the specific hypotheses are presented in these chapters. Chapter 4 is a general discussion that seeks to place the results presented in the thesis into context within the literature, and also identifies important future directions. The thesis concludes with a new model posited for the pathophysiology of FXS.Medicine, Faculty ofGraduat