Defense Date

2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Neuroscience

First Advisor

Michael Fox

Abstract

Visual system development requires the formation of precise circuitry in the dorsal lateral geniculate nucleus (dLGN) of the thalamus. Although much work has examined the molecular mechanisms by which retinal axons target and form synapses in dLGN, much less is known about the mechanisms that coordinate the formation of non-retinal inputs in dLGN. These non-retinal inputs represent ~90% of the terminals that form in dLGN. Interestingly, recently reports show that the targeting and formation of retinal and non-retinal inputs are temporally orchestrated. dLGN relay neurons are first innervated by retinal axons, and it is only after retinogeniculate synapses form that axons from cortical layer VI neurons are permitted to enter and arborize in dLGN. The molecular mechanisms governing the spatiotemporal regulation of corticogeniculate innervation are unknown. Here we screened for potential cues in the perinatal dLGN that might repel the premature invasion of corticogeniculate axons prior to the establishment of retinogeniculate circuitry. We discovered aggrecan, an inhibitory chondroitin sulfate proteoglycan (CSPG), was highly enriched in the perinatal dLGN, and aggrecan protein levels dropped dramatically at ages corresponding to the entry of corticogeniculate axons into the dLGN. In vitro assays demonstrated that aggrecan is sufficient to repel axons from layer VI cortical neurons, and early degradation of aggrecan, with chondroitinase ABC (chABC), promoted advanced corticogeniculate innervation in vivo. These results support the notion that aggrecan is necessary for preventing premature innervation of the dLGN by corticogeniculate axons. To understand the mechanisms that control aggrecan distribution, we identified a family of extracellular enzymes (the a disintegrin and metalloproteinase with thromobospondin motifs [ADAMTS] family) expressed in postnatal dLGN that are known to contain aggrecan-degrading activity. Importantly, ADAMTS family members are upregulated in dLGN after retinogeniculate synapses form, and intrathalamic injection of ADAMTS4 (also known as aggrecanase-1) resulted in premature invasion of dLGN by corticogeniculate axons. Taken together these results implicate aggrecan and ADAMTSs in the spatial and temporal regulation of non-retinal inputs to the dLGN.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

November 2013

Included in

Neurosciences Commons

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