MS, University of Cincinnati, 2020, Medicine: Biomedical Research Technology

A mutation in the Fragile X Mental Retardation 1 (FMR1) gene leads to the loss of a single protein, Fragile X Mental Retardation Protein (FMRP). The loss of FMRP causes Fragile X Syndrome (FXS), the most common monogenic cause of intellectual disability and autism spectrum disorders. FMRP regulates the stability, transport, and translation of hundreds of mRNAs. FMRP also regulates protein synthesis, interacts with ion channels, and is implicated in in neuronal plasticity and spine dynamics and DNA damage repair. The absence of FMRP therefore leads to complex disease mechanisms. Current drug interventions for FXS require repeat administration, focus on treatment of the behavioral symptoms instead of targeting a disease mechanism, and have not yet been proven effective. A strategy that permanently restores expression of functional FMRP in the brain is therefore currently the most promising approach to comprehensively alleviate behavioral and cognitive FXS-associated phenotypes. We have developed an adeno-associated virus (AAV) gene therapy approach to introduce the human FMR1 gene in a mouse model of FXS. The experimental strategies, including viral vectors, delivery, and outcome measures, were designed to be easily applied in humans to facilitate the transition of this potential novel therapy into clinical trials. We tested this approach in a pilot study where twelve wildtype (WT) mice were injected intracerebroventricularly with an AAV vector expressing eGFP, eleven WT mice with an AAV vector expressing human FMRP (hFMRP), and thirteen Fmr1 knockout (KO) mice each with either vector. Behavior testing started approximately one week post-injection and continued for approximately seven to eight weeks. Eight to ten weeks post-injection, mice were sacrificed, and brains were collected to investigate long-term potentiation (LTP), protein synthesis, and transgene expression. Results of the behavioral aspect of this pilot preclinical study indicate that AAV-mediated introdu (open full item for complete abstract)

Committee: Samantha Brugmann Ph.D. (Committee Chair); Christina Gross Ph.D. (Committee Member); Ernest Pedapati M.D. (Committee Member) Subjects: Neurology

Doctor of Philosophy, Miami University, 2019, Biology

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is the primary monogenetic cause of autism spectrum disorders. FXS is caused by a mutation in the regulatory region of the Fragile X Mental Retardation 1 (FMR1) gene, that ultimately leads to loss of the gene product Fragile X Mental Retardation Protein (FMRP). As FXS is a neurodevelopmental disorder, most studies have focused on the role of FMRP during development. However, a few studies have shown that the loss of FMRP during adulthood can impact learning, cognition, and behavior. The primary goal of this study was to decrease FMRP during adulthood and examine the impacts on immune function and social behavior using the cricket Acheta domesticus as a novel insect model. We examined immune function in males and females by assessing several important immune parameters including: the total number of circulating hemocytes in the hemolymph, the total hemolymph protein content, total phenoloxidase enzyme activity, and fat body lysozyme expression. We found that males and females exhibited similar changes in these immune parameters as a result of decreased Fmr1, but males were less likely to survive an immune challenge with an injection of lipopolysaccharide (LPS) from Serratia marcescens. This is the first study to demonstrate that decreased FMRP during adulthood causes sex-specific effects on the immune system. We also examined the effects of decreased Fmr1 on the agonistic behavior of adult male crickets. We observed that the average time to first physical contact during an agonistic interaction was significantly increased in fights between a control male and Fmr1 knockdown male and that Fmr1 knockdown males were less likely to initiate an aggressive interaction than control males. Despite initiating interactions less often, these males fought just as aggressively and won as often as controls. In this study, we also evaluated the parameters required to generate a successful parental R (open full item for complete abstract)

Committee: Kathleen Killian Dr. (Advisor) Subjects: Biology; Entomology; Genetics

PHD, Kent State University, 2017, College of Arts and Sciences / School of Biomedical Sciences

The ability to localize sound in space is an important task for communication and survival in complex acoustic environments for both humans and animals. For localizing sound in the horizontal plane, differences in sound information received by each ear generates binaural cues, such as the interaural level difference (ILD). Using whole-cell recordings in brain slices, this work focuses on the basic properties of synaptic inhibition in the avian ILD circuit, as well as the modulation of inhibition in the mammalian ILD circuit, both of which are critical for understanding the range of cellular sound localization coding solutions. In birds, the posterior portion of the dorsal nucleus of the lateral lemniscus (LLDp) encodes the ILD, but little is known about the mechanisms of synaptic inhibition underlying the ILD coding. Here, I provide the first evidence confirming a monosynaptic inhibition driven by direct electrical and chemical stimulation of the contralateral LLDp. Additionally, inhibition to LLDp neurons was largely GABAergic, although there is evidence for a glycinergic component, and the low internal chloride concentration suggests a hyperpolarizing action of inhibition in this circuit. In mammals, the medial nucleus of the trapezoid body (MNTB) provides synaptic inhibition to many auditory brainstem nuclei including the mammalian ILD encoding nucleus, and thus contributes to ILD coding. However, not much is understood of the synaptic inhibition the MNTB itself receives and it remains entirely unknown how this inhibition is regulated. Here, I investigated group I metabotropic glutamate receptor (mGluR I) modulation of the glycinergic and GABAergic inputs to MNTB neurons in both wildtype (WT) mice and a fragile X syndrome (FXS) mouse model, in which the fragile X mental retardation gene 1 is knocked out (Fmr1 KO). Loss of the FMR protein results in exaggerated activity of mGluR I, allowing for comparisons of mGluR I function under normal and disordered conditions (open full item for complete abstract)

Committee: Yong Lu Ph.D. (Advisor); Jeffrey Wenstrup Ph.D. (Committee Member); Merri Rosen Ph.D. (Committee Member); Christine Crish Ph.D. (Committee Chair); Sean Veney Ph.D. (Committee Chair) Subjects: Cellular Biology; Neurobiology; Neurosciences

MS, University of Cincinnati, 2004, Allied Health Sciences : Genetic Counseling

Recent research on cognitive behavioral profiles for specific genetic syndromes, such as fragile X syndrome, has generated information that special educators can incorporate into their teaching practices, though few studies have assessed their use of this information. This cross-sectional study surveyed special educators to characterize what fragile X specific information they had acquired, what they found most useful, and what information dissemination strategies they preferred. Approximately half of the 271 participants had some information related to fragile X syndrome and 80.8% expressed interest in incorporating fragile X syndrome information into their teaching. Over 50% perceived the topics of teaching strategies, behavioral interventions, and cognitive behavioral profiles as very useful. Teachers prefer to receive information through printed material, internet resources, professional workshops and other teachers.

Committee: Carol Christianson (Advisor) Subjects: