Investigating Network Hyperexcitability in the Visual Cortex of Fmr1 KO Mice with in vivo Two-photon Calcium Imaging
Wierenga, Lauren A.
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Fragile X syndrome (FXS), the most common inherited form of autism, is caused by the transcriptional silencing of the Fmr1 gene, resulting in intellectual impairment and behavioral abnormalities in affected individuals. Studies in Fmr1 knockout (KO) mice have shed light on structural and functional features that may underlie this disorder, including the recent discovery of defects in γ-aminobutyric acid (GABA) receptors and signaling. The focus on these inhibitory defects has been at the molecular and cellular levels; however, they have yet to be investigated at the network level. Problems with GABA signaling may lead to inhibitory dysfunction of GABAergic interneurons and cause hyperexcitability in neural circuits, which may be an explanation for behavioral hypersensitivity and propensity to seizures observed in FXS individuals. In this study, we investigate whether presentation of a visual stimulus results in elevated neural activity in Fmr1 KO mice relative to wildtype (WT) mice. Using in vivo two-photon microscopy, we compare the spontaneous and evoked activity in the visual cortex (V1) of adult WT and Fmr1 KO mice expressing a genetically encoded calcium indicator, GCaMP5, in response to moving sinusoidal gratings. Our preliminary results suggest WT mice display a greater number of active cells during spontaneous (but not evoked) activity in lower L2/3 of V1 compared to Fmr1 KO mice. However, there was no significant difference in the number of active cells in upper L2/3 of V1 between WT and Fmr1 KO mice for spontaneous or evoked activity. Future experiments will be needed to confirm this finding and test desensitization and tuning properties of neurons within circuits of Fmr1 KO mice.