Purkinje cells are the sole output from the cerebellar cortex, and so diseases that alter Purkinje cell develop and function have devastating effects on balance and coordination. My colleagues and I have demonstrated that the neurotrophin, BDNF, is necessary for normal Purkinje cell development, particularly for dendritic arborization. In the proposed research we will identify the cells that synthesize BDNF to regulate Purkinje cell development and determine whether the p75 receptor plays a role in this regulation. We will investigate further the nature of the biological effects of BDNF on Purkinje cells, to determine whether BDNF regulates Purkinje cell synapses.
Specific aim 1 is to test the hypothesis that BDNF synthesized and released by granule cell acts in an anterograde fashion to regulated Purkinje cell development; we will also examine the alternative possibilities that BDNF is instead involved in the interactions of climbing fiber or deep cerebellar nuclei neurons with Purkinje cells. We will use genetic or mechanical means to remove granule cells in vivo or remove afferent connections to the cerebellar cortex, and determine whether Purkinje still accumulate BDNF and undergo Trk phosphorylation. We will use organotypic and dissociated cell cultures to determine whether BDNF is required for granule cells to regulate Purkinje cell dendritic arborization.
Specific aim 2 is to test the hypothesis that both TrkB and the p75 receptor mediate the effects of BDNF in developing Purkinje cells. While our previous work has demonstrated that activation of the TrkB receptor is a critical component in the Purkinje cell response to BDNF, others have shown that antibodies to p75 perturb Purkinje cell dendritic growth and survival, suggesting that both receptors may participate in the BDNF response. We will analyze Purkinje cell morphology, cerebellar foliation, Trk phosphorylation and BDNF uptake in p75/BDNF compound mutant mice. These experiments will indicate signal transduction pathways critical for regulating Purkinje cell development.
Specific aim 3 is to test the hypothesis that BDNF is involve din the formation and maturation of granule cell-Purkinje cell synapses. We will use structural, biochemical and electrophysiologic approaches to compare parallel fiber: Purkinje cell synapses in wild type and BDNF-/- mice, and to evaluate acute and chronic effects of BDNF on Purkinje cell synapses. These studies will identify extracellular factors that regulate Purkinje cell development, and could provide the basis for therapeutic applications of neurotrophic factors on drugs in treating cerebellar diseases.
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