Avwenagha, Ovokeloye; (2000) Neurotrophins in the developing and adult rat visual system: In vivo and in vitro studies. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In vivo anatomical studies were performed with the aim of clarifying the cellular and subcellular distribution and the developmental pattern of expression of brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4), neurotrophin-3 (NT-3) and their receptors, trkB and trkC in the rat visual pathway. BDNF and trkB proteins were expressed in developmentally regulated patterns in most visual centres including the lateral geniculate nucleus (LGN), superior colliculus (SC), and the visual cortex. With some exceptions, BDNF and trkB mRNA expression patterns in visual centres were similar to those of their proteins; however in some visual centres, BDNF mRNA expression was not detected, but BDNF protein was restricted to neuropil. The expression of NT-4, NT-3 and trkC mRNAs was limited to neurons in the SC and visual cortex. By pre-embedding electron microscopy, BDNF was predominantly located in retinal terminals and trkB at the apposing postsynaptic densities and associated with axonal and dendrite microtubules. BDNF and trkB proteins, their mRNAs and NT-4 mRNA (but not NT-3 or trkC) were present in developing and adult retinal ganglion cells (RGCs). Retinal explant cultures were used to study the effects of neurotrophins on developing and regenerating RGC axons. BDNF and NT-4, but not NT-3 protein, significantly increased the outgrowth (number and length) of regenerating RGC axons and RGC axons at El5, and to a lesser extent at later embryonic stages. BDNF and NT- 4, but not NT-3 protein, increased the intensity of -III tubulin, F-actin and GAP-43 immunoreaction product in RGC axons and growth cones. Treatment with TrkB-IgG arrested RGC axon outgrowth, induced growth cone collapse and resulted in the loss of F-actin in the P-domain of RGC axonal growth cones. The expression pattern of trkB and BDNF mRNAs during development and in adulthood and the effects of BDNF in vitro suggest that BDNF plays important roles in visual system maturation and maintenance. The lack of neurotrophin expression in some retinorecipient centres but the localisation of BDNF protein in retinal terminals suggests that BDNF anterogradely transported from RGCs may exert important effects on their central targets.

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