Project 2: Network mechanisms of neurophysiology and behavior in mouse models of Fragile X Syndrome. Translational biomarkers for Fragile X Syndrome (FXS) were suggested from the findings of our research team that sensory circuits are hyperexcitable in both FXS patients and Fmr1 KO mice, as measured with electroencephalogram (EEG) in mice and humans and in in vitro brain slices. Our team of investigators, working closely together within an NIH Collaborative Center for Fragile X Research, has discovered multiple neurophysiological signatures of FXS, both in the resting state and with sound-evoked EEG, that are remarkably conserved between FXS patients and Fmr1 KO mice. Recently, we have employed multi-electrode array (MEA) EEG in awake, behaving mice and discovered enhanced resting state gamma power and impaired auditory chirp- induced cortical synchronization in Fmr1 KO mice, similar to findings in FXS patients. In the current group of studies, we propose to: (1) identify network level deficits that might underlie sensory and cognitive dysfunction in FXS using MEA EEG recordings and analyzing interactions across spectral bands and brain regions in developing (P21-23) and adult WT vs. Fmr1 KO mice; and (2) test the effects of GABAergic and glutamatergic drugs on EEG and behavior in Fmr1 KO mice. Both (1) and (2) will be done in coordination with clinicians in Project 1 to test identical drugs and EEG outcome measures across species. (3) Implement multichannel depth electrodes in Fmr1 KO mice to evaluate layer-specific cortical physiological abnormalities. (4) Test the effects of endocannabinoid drugs and selective deletion of CB1Rs in inhibitory neurons on EEG and behavior in Fmr1 KO mice. Both (3) and (4) will be done in coordination with Project 3 researchers working on in vitro slice preparations to identify synaptic and cellular deficits. Thus, Project 2 will be a critical hub of the center by translating cellular and molecular level analyses to clinical approaches using network and layer-specific MEA EEG analysis and behavior in Fmr1 KO mice. We anticipate identification of novel biomarker-based drug targets for treatment of FXS.
