Advisory Committee Chair
Lori L McMahon
Advisory Committee Members
J David Sweatt
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Fragile X Syndrome (FX) is the most common inherited form of mental retarda-tion. Prominent characteristics of FX are mimicked in a mouse model with deleted fmr1 including hyperactivity, anxiety, developmental delay and social deficits. Additionally, FX mice display deficits in n-methyl-d-aspartate receptor (NMDAR) dependent long-term potentiation (LTP) at medial perforant path synapses onto dentate granule cells (MPP-DGC synapses). Because LTP is a cellular correlate of learning and memory, defi-cits in LTP at this synapse are thought to underlie impairments in pattern separation, a form of learning and memory dependent on proper DG function. Identifying the patho-logical mechanisms that cause impaired synaptic plasticity will aid in the development of novel therapeutic targets and treatments in FX. The activity of glycogen synthase kinase-3 (GSK3) is enhanced in hippocampus of FX mice. Accordingly, treatment with the GSK3 inhibitor lithium corrects several be-havioral phenotypes in FX mice. In order to investigate whether hyperactive GSK3 is causally related to the deficit in LTP at MPP-DGC synapses, we utilized FX mice and assessed the magnitude of LTP in the presence of lithium and CT99021, GSK3 inhibitors. We find that acute inhibition of GSK3 reverses deficits in LTP and steady-state depolari-zation (SSD) during high frequency stimulation but fails to rescue NMDAR hypofunction during SSD. Importantly, blockade of mGluRs, which rescues many of the phenotypes in FX mice, fails to rescue LTP at MPP-DGC. In order to identify whether HDAC3, a downstream target of GSK3, contributes to LTP deficits in FX mice we assessed the magnitude of LTP in the presence of a selective HDAC3 inhibitor. We find that HDAC3 inhibition fails to rescue LTP deficits in FX mice. However, non-selective HDAC inhibi-tion and selective HDAC3 inhibition enhance LTP at MPP-DGC synapses in WT mice. These results suggest that FMRP is required for enhanced LTP following HDAC inhibi-tion. Overall, these findings establish that synaptic deficits in FX can be reversed by in-terventions with GSK3 inhibitors, which may prove beneficial in the treatment of cogni-tive symptoms in FX. Furthermore, these findings identify a novel role for FMRP which may lead to a better understanding of disease pathology in FX.
Franklin, Aimee Vinson, "Elucidating the role of GSK3 in synaptic and cognitive deficits in Fragile X Syndrome" (2014). All ETDs from UAB. 1664.