We propose to investigate the physiological consequences of two recently identified dendritic channelopathies in hippocampal pyramidal neurons from the fmr1-/y mouse model of Fragile X syndrome (FXS). Despite their critical importance in the regulation of neuronal function, there have been surprisingly few physiological investigations of ion channel function in FXS. This is particularly noteworthy, because FMRP, the protein that is missing in FXS, binds to more than twenty mRNAs encoding a number of ion channel proteins, including the putative A-type K+ channel subunit KV4.2 and the h-channel subunit HCN2, and modulates ion channel function via protein-protein interactions. A-type K+ channels and h-channels have a strong influence over the integrative properties of hippocampal dendrites in part because of their very high dendritic expression and specific biophysical properties. We propose to use whole-cell and cell-attached electrophysiological recording in combination with single cell calcium imaging to investigate how changes in Ih and IKA alter the integrative properties of the distal dendrites of CA1 pyramidal neurons in the fmr1-/y mouse. We will also use electrophysiology in combination with immunohistochemistry and western blotting to investigate whether these two channelopathies persist across the dorsal-ventral axis of the hippocampus. Lastly, we will investigate whether regional restoration of FMRP expression in adult mice can rescue the cellular and behavioral abnormalities that occur in FXS. This project will provide the first physiological investigation of the impact of channelopathies on dendritic function in Fragile X syndrome.
Fragile X Syndrome is the most common form of inherited mental impairment with symptoms including an IQ below 70 (90-109 is considered average), epilepsy, hyperactivity, impaired working memory, attention deficits and autistic behavior. The exact neurological cause of Fragile X Syndrome remains unknown. To further understand the changes caused by this complex disorder, it is important to develop a better understanding of the basic neurobiology associated with Fragile X Syndrome.
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