Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Zhaolan Zhou

Second Advisor

Douglas A. Coulter

Abstract

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a severe neurodevelopmental disorder named CDKL5 deficiency disorder (CDD). In humans, CDD is characterized by early-onset epilepsy, severe intellectual disability, autistic features, and various comorbidities. Mice lacking functional CDKL5 protein show a constellation of behavioral deficits, including impaired learning and memory, reduced sociability, and increased stereotypy, that are reminiscent of human symptoms. Despite its simple genetic etiology, how the loss of CDKL5 leads to the unique symptomatology of CDD is not well understood. Using genetically modified mouse models of CDD, we dissect the cellular origins of behavioral, circuit, and synaptic phenotypes in CDD. We find that impaired learning and memory primarily originates from CDKL5 loss in forebrain glutamatergic neurons, whereas autistic-like features primarily originate from CDKL5 loss in forebrain GABAergic neurons. At the cellular and circuit level, loss of CDKL5 in glutamatergic neurons leads to altered pyramidal neuron morphology and concomitant changes in excitatory and inhibitory synaptic transmission, resulting in disrupted spatiotemporal dynamics of microcircuits. In contrast, loss of CDKL5 in GABAergic neurons leads to a non-cell autonomous change in excitatory synaptic transmission and circuit hyperexcitability. Consistent with this finding, acute pharmacologic reduction of glutamatergic synaptic signaling rescues selective phenotypes of CDD in mice. Taken together, our results suggest that CDKL5 plays distinct roles in forebrain glutamatergic and GABAergic neurons to regulate cellular morphology, synaptic function, and circuit excitability, and that modulation of synaptic transmission provides a novel therapeutic avenue to treat CDD.

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