Friday, May 10, 2024
5/10/2024
Project Summary CDKL5 Deficiency Disorder (CDD) is an X-linked genetic disorder caused by mutations in the cdkl5 (cyclin-dependent kinase-like 5) gene. Patients with CDD exhibit many features common to Autism Spectrum Disorder, but also frequently suffer from cortical visual impairment. Specifically, patients with CDD display deficits in visually-evoked potentials, an indirect measure of visually evoked thalamocortical input. Emerging evidence suggests that loss of CDKL5 is also associated with neuronal hyperexcitability. Together, this suggests that loss of CDKL5 may shift the balance between thalamocortical and intracortical processing. Mice lacking CDKL5 recapitulate many aspects of human CDD patients, including visual impairment, and also exhibit changes in arousal. Work from our lab and others has demonstrated that arousal states reflect distinct underlying physiological processes that influence spontaneous and sensory-evoked neural activity. However, the relative impact of behavioral state dysregulation on thalamocortical dynamics and the contribution of a shift from feedforward inputs to intracortical network control on visual processing remains unknown. Leveraging a recently developed technique from our lab, we can simultaneously monitor spontaneous and visually-evoked thalamic axon activity in the primary visual cortex and cortical activity across the dorsal neocortex in the awake, behaving mouse. Using this approach, we have begun to characterize the functional consequences of CDKL5 deficiency on state-dependent thalamocortical dynamics and visual processing. Our preliminary data demonstrates that CDKL5 deficient mice display altered arousal states and cortical activity in a sex-dependent manner, along with increased intracortical functional connectivity. Initial experiments suggest that CDKL5 deficient mice also exhibit reduced visual response magnitudes in in primary visual cortex. We will therefore test the following hypotheses: 1) dysregulation of behavioral state in CDKL5 deficiency also disrupts thalamocortical network activity; 2) loss of CDKL5 results in an increase in intracortical connectivity and a decrease in thalamocortical connectivity; 3) CDKL5 deficiency leads to reduced thalamocortical visual sensitivity; and 4) CDKL5 deficiency decreases feedforward transformation of sensory information. Together, our results will provide unprecedented insight into the functional consequences of CDKL5 deficiency for state-dependent thalamocortical networks and visual processing in a mouse model of CDD.
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