Date on Master's Thesis/Doctoral Dissertation

12-2018

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Anatomical Sciences and Neurobiology

Degree Program

Anatomical Sciences and Neurobiology, PhD

Committee Chair

Guido, William

Committee Co-Chair (if applicable)

Bickford, Martha

Committee Member

Bickford, Martha

Committee Member

Krimm, Robin

Committee Member

McGee, Aaron

Committee Member

Fox, Michael

Author's Keywords

thalamus; dorsal lateral geniculate nucleus; vision; interneurons; development; mouse

Abstract

The dorsal lateral geniculate nucleus (dLGN) of the mouse is a model system to study the development of thalamic circuitry. While most studies focus on relay neurons of dLGN, little is known about the factors regulating the development of the other principal cell type, intrinsic interneurons. To date, the targeting and migratory path of dLGN interneurons as well as their morphological development remains unclear. Here we examined whether the migration, structure, and function of interneurons relies on retinal signaling. We took a loss-of-function approach and crossed GAD67-GFP mice, which express green fluorescent protein (GFP) in dLGN interneurons, with math5 nulls (math5-/-), mutants that lack retinofugal projections. Tracing studies with BDA show that interneurons migrate from the third ventricle, and arrive in dLGN at early postnatal ages. By P4, neurons complete the first phase of a multi-staged developmental process, as interneuron number and distribution reaches an adult-like state. In-vitro recordings and 3-D reconstructions of biocytin-filled interneurons at different ages showed that remodeling begins during the second week, and includes a period of exuberant branching, where arbors grow in number, complexity, and field size. Such growth is followed by pruning and stabilization, as interneurons adopt their adult-like bipolar architecture and form functional connections with relay cells. However, the absence of retinal signaling disrupts these processes. Fewer interneurons occupy dLGN, and cells fail to disperse. Estimates of interneuron number in thalamic nuclei along the migratory path in math5-/- mice suggest that the absence of retinal input causes misrouting of dLGN interneurons into the ventrobasal complex (VB). In fact, studies in Fibroblast growth factor 15 null (Fgf15-/-) mice, a neurotrophic factor responsible for GABAergic differentiation, show Fgf15 regulates interneuron targeting to dLGN. Arbor remodeling is also disrupted in the absence of retinal signaling, as interneurons maintained a sparse architecture at all ages. DHPG experiments in math5-/- mice, the metabotropic glutamate receptor 1,5 (mGluR1,5) agonist that targets F2 terminals on interneuron processes, revealed interneurons exhibited fewer/and or weaker synapses with relay neurons in dLGN. Taken together, these data suggest that retinal signaling is needed to support the targeting, arbor elaboration, and synaptic connectivity of dLGN interneurons.

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