Date of Graduation

2017

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Neurology

Committee Chair

Eric S Tucker

Committee Co-Chair

Ariel Agmon

Committee Member

Peter Mathers

Committee Member

Scott Weed

Committee Member

Shuo Wei

Abstract

The cerebral cortex, responsible for higher order functions, is a layered structure that relies on the precise wiring of two main types of neurons, excitatory neurons and inhibitory interneurons. In order to maintain a critical balance of excitation and inhibition in the cortex, a smaller, yet very diverse, population of cortical interneurons provides inhibition to a much larger cohort of excitatory neurons. This makes interneurons a vulnerable population where the slightest perturbations to their location and wiring with excitatory neurons can contribute to the acquisition of neurological disorders like autism, schizophrenia and epilepsy.;During development, cortical interneurons migrate tangentially from the medial and caudal ganglionic eminences in the ventral forebrain to the cortex. Unlike cortical excitatory neurons that are born in the ventricular zone of the dorsal forebrain and migrate radially on radial glial scaffolding, cortical interneurons are born in the ventral forebrain and migrate tangentially, primarily using molecular guidance cues in the extracellular environment to enter, navigate, and form streams in the nascent cerebral cortex. As development proceeds, interneurons depart from migratory streams on diagonal or radial trajectories in order to populate the cortical plate, where they eventually segregate into layers and make synaptic connections with other cortical neurons. Signaling pathways allow interneurons to express the correct complement of cell surface guidance receptors, transduce signals associated with the activation of those receptors, and facilitate the rearrangement of their cytoskeleton in order to aid in their travel. These processes are essential for the proper entrance of cortical interneurons into the cerebral cortex, their exit from migratory streams, and ultimately their layering in the cortical plate. Yet, how intracellular signaling pathways govern these processes remains largely unknown.;The c-Jun N-terminal kinase (JNK) signaling pathway, primarily known for its role in cell death, plays a large role in cell migration by activating downstream targets that modify the cytoskeleton and cell architecture. However, its importance in cortical interneuron migration has not been established. This work, organized into four main chapters including two main data chapters and an appendix, provides the first evidence that cortical interneurons use JNK signaling to enter and navigate in the developing cerebral cortex. In the first data chapter, we establish that Jnk is present within cortical interneurons and Jnk1 is required for their entry into the cerebral cortex between embryonic day (E) E12.5 and E13.5 of mouse development. The second data chapter provides evidence that JNK signaling is important for maintaining migratory streams and that pharmacological inhibition or genetic ablation of Jnk from interneurons incites their exit from migratory streams and subsequent entry into the cortical plate between E14.5 and E15.5. Further, the work provided in the Appendix indicates disruption to the localization of Jnk-phosphorylated doublecortin, a microtubule associating protein important for branching of the leading processes of the migrating interneurons. Together, this work suggests that JNK signaling plays a critical role during cortical interneuron migration and may provide insight into how neurodevelopmental disorders like epilepsy, autism and schizophrenia could arise.

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