archives@tulane.edu / Autism spectrum disorders (ASD) are commonly characterized by abnormal social behaviors. Fragile X syndrome (FXS) is the most common inherited intellectual disability in humans and the most common single-gene cause of ASD symptoms. FXS is caused by the loss or malfunction of the fragile X mental retardation protein (FMRP), an mRNA-binding protein that regulates numerous synaptic proteins, both translationally and through direct protein-protein interactions. One direct-binding target is the large-conductance potassium (BK) channel. BK channels have been shown to be hypoactive in FXS, and represent possible targets for treatment in both general ASD and in FXS specifically. Also, two members of the KCNQ class of voltage-activated potassium channels, KV7.2 and KV7.3, have been identified as FMRP translation targets. Finally, a commonly observed abnormality in the ASD brain is an imbalance in the ratio of excitatory to inhibitory signaling (E/I balance) causing general hyperexcitability in numerous brain areas. One area in which altered E/I balance is often observed is the medial prefrontal cortex (mPFC), which is involved with the processing of social information. Therefore, the goal of this dissertation was to determine if stimulating potassium channel function in the mPFC of Fmr1 KO mice would correct abnormal social behavior. In addition, the possible mechanistic determinants and effects on E/I balance were investigated in WT and Fmr1 KO mice.
Infusion of the potassium channel activator, BMS-204352, into the mPFC of KO mice had no effect on social approach behavior, but corrected social novelty impairments as measured by a 3-Chamber Test. Whole-cell patch clamp recordings of pyramidal neurons in layer V of the mPFC revealed no differences in mEPSCs between KO and WT mice, but did reveal higher frequency of mIPSCs in KO mice. Treatment with BMS-204352 resulted in a decrease in mEPSC amplitude in both genotypes, which was blocked by the BK channel antagonist, paxilline. Effects of BMS-204352 treatment on mIPSCs revealed two possible populations of cell types. One population of exhibited a decrease in frequency of mIPSCs, an effect seen in both genotypes. The other population exhibited a slight increase in frequency of mIPSCs, but this was seen only in KO cells. Treatment with paxilline caused a decrease in mIPSC frequency in both genotypes, which was not altered with subsequent BMS-204352 treatment. Pretreatment with the KV7 channel antagonist XE 991 prevented BMS-204352-induced cross-genotype decrease in mIPSC frequency, but did not prevent BMS-204352-induced frequency increase in KO cells. Western blot analyses revealed no changes between genotypes in BK channel expression, but a trend to increased KV7.3 expression in the PFC of KOs compared to WTs. With these data, it was concluded that aberrant activity of potassium channels in the mPFC of KOs mediates some of the social abnormalities observed in the phenotype, that KOs may exhibit increased KV7.3 expression as a potential compensatory mechanism for BK channel dysfunction, and that potassium channels are a promising potential target for future treatment of ASD symptoms / 1 / Ted Sawyer
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_120452 |
| Date | January 2020 |
| Contributors | Sawyer, Edward (author), Schrader, Laura (Thesis advisor), School of Science & Engineering Neuroscience (Degree granting institution) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Type | Text |
| Format | electronic, pages: 142 |
| Rights | No embargo, Copyright is in accordance with U.S. Copyright law. |
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