Defense Date

2010

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Neuroscience

First Advisor

William Guido

Abstract

We study the activity-dependent refinement of sensory systems by using the mouse retinogeniculate system as a model. Spontaneous retinal waves lead to robust excitatory post-synaptic activity in developing relay cells in the dorsal lateral geniculate nucleus (dLGN) of the thalamus and are reportedly needed to help guide the segregation of retinal inputs into eye-specific domains as well as for the pruning of extraneous retinal inputs onto single dLGN relay cells. The composition of retinally evoked post-synaptic activity activated by these retinal waves in dLGN is largely unknown, but based on our in vitro recordings, such activity seems well suited to activate large, long-lasting, high-amplitude depolarizations mediated by L-type Ca2+ channel activation, plateau potentials. Plateau activity prevails early in life, at the peak of retinogeniculate refinement, however, little is known about the factors that contribute to the activation of these events, or the potential role of plateau potentials in mediating activity-dependent remodeling. In this thesis, we examined the factors and stimulus conditions that lead to the activation of plateau activity. We found that many aspects of developing retinogeniculatecircuitry (e.g., the high degree of retinal convergence, the temporal summation of excitatory post-synaptic potentials, and the lack of inhibitory connections) seem to favor their activation at early postnatal ages. We then tested whether such activity is necessary for the refinement of retinal projections, as well as their functional connections onto dLGN cells. To address this, we took a loss-of-function approach and made use of a transgenic mouse that lacks the β3 subunit of the L-type Ca2+ channel. These mutants have far fewer membrane-bound L-type Ca2+ channels and greatly attenuated L-type activity. In β3 nulls, L-type plateau potentials are rarely observed in the dLGN, even at young ages or when repetitive pulses of electrical stimulation are applied to the optic tract. Although these mice have normal stage II and III spontaneous retinal waves, the retinogeniculate projections of β3 null mice fail to segregate properly. In addition, the degree of retinal pruning is impaired. These results suggest that post-synaptic L-type Ca2+ channel activity is necessary to implement the activity-dependent refinement of the retinogeniculate pathway.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

12-2-2010

Included in

Neurosciences Commons

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