Date of Award
Doctor of Philosophy (PhD)
Sheryl G. Beck
Anxiety disorders are the most prevalent class of mental illness, yet currently available treatments are often ineffective or inadequate, leaving many patients with lingering symptoms. The serotonin 1A receptor (1AR) has been implicated in the etiology of these disorders, which often show comorbidity with cognitive dysfunction. Mice with the 1AR genetically deleted or "knocked out" (1AKO) during a critical period in development (postnatal days 13-21) exhibit anxiety-like behavior and learning and memory deficits, and may therefore represent a useful genetic model in studying the neurobiological effects of this receptor. The hippocampus has been shown to highly express the 1AR and to be a key mediator in memory and the regulation of emotion. The experiments in this thesis focus on the structural and functional hippocampal changes in the 1AKO mouse compared to wild-type mice in order to elucidate the cellular mechanisms behind the alterations in behavior. Electrophysiology was used in the CA1 region of the hippocampus to show that pyramidal neurons in the 1AKO mouse receive less glutamatergic input than control mice during the critical period, resulting in decreased AMPA-mediated excitation and LTP in the adult. Interestingly, morphological analyses demonstrated a significant enhancement in proximal dendritic branching in both the juvenile and adult 1AKO mouse that may be the result of the developmental effects of increased serotonergic efflux. Additional experiments focused on the role of corticotropin-releasing factor (CRF) in the 1AKO mouse, based on the fact that peak hippocampal levels of this neuropeptide coincide in time with the critical period of development when 1AR deletion has pronounced effects. We found that adult 1AKO mice showed increased numbers of CRF-containing interneurons and that CRF1 receptor antagonism restored CA1 LTP to control levels. Taken together, these results reveal a complex interplay of decreased synaptogenesis and number of AMPA receptors, and excessive activation of CRF1 receptors that may underlie the cognitive deficits and anxiety-like behavior of the 1AKO mouse. The experiments support the continued research into the neurobiological mechanisms of human anxiety disorders.
Metzger, Kayla Lynn, "Hippocampal Circuitry Dysfunction in the 5-HT1A Knockout Mouse" (2012). Publicly Accessible Penn Dissertations. 549.