Translatable EEG biomarkers of Intellectual Disability in Pre-Clinical Mouse Models of Fragile X syndrome and Tuberous Sclerosis Complex (360G-Wellcome-207727_Z_17_Z)

This project will introduce new electroencephalogram biomarkers of known neuronal events, including synaptic plasticity, activity of two different GABAergic inhibitory neuronal subclasses and burst firing, which can be experimentally constrained in primary visual cortex by habituation to simple visual stimuli and presentation of novelty. The immediate primary goal of the project is to show that cortical dysfunction is severe enough to be evident in these biomarkers in pre-clinical mouse models of two highly penetrant, single gene causes of neurodevelopmental psychiatric disorders, Fragile X Syndrome and Tuberous Sclerosis Complex, both of which have known synaptic plasticity and excitatory/inhibitory balance phenotypes. In each case, efficacious drug treatments exist, although neither is considered an ideal candidate for human use, motivating a secondary goal to demonstrate that altered biomarkers can be remedied. The overall goal of this application is to provide a seed for three complementary future projects: First, to take advantage of genetic and invasive experimental tools in mice to deeply understand processes of learning (habituation) and memory (novelty detection). Second, to understand their dysfunction in genetically defined neurodevelopmental psychiatric disorders and, third, to translate the use of these biomarkers into human subjects for patient stratification and assessment of response to treatment.