The role of brain-derived neurotrophic factor in the regulation of dendritic arbor morphology, neuronal network activity, and neuroprotection

The dendritic architecture of a neuron determines how it receives inputs, and thus, changes in dendrite morphology will affect connectivity among neurons. Aberrant changes in the development of the arbor, or after the arbor has formed, can disrupt the functioning of neural circuits, causing severe brain dysfunction and leading to pathologies seen in cognitive disorders, neurological diseases, and trauma. Brain-derived neurotrophic factor (BDNF) is one of the most well-studied regulators of dendritic and synaptic plasticity. It is also known to be a pro-survival factor and is overexpressed in neurons that survive injuries, such as ischemia. This dissertation explores how BDNF shapes the dendritic arbor of single hippocampal neurons and the dynamics of in vitro hippocampal networks. Previous work in our laboratory has shown that BDNF significantly increases proximal dendrite branching in hippocampal neurons after 72 hours of bath application. Building on this work, we show that local application of BDNF via microbeads increases both proximal and distal dendrite branching in a shorter time than does bath application. We also show that overexpression of BDNF shapes the dendritic arbor differently depending on the intracellular targeting of BDNF transcripts. To understand how BDNF affects the development of hippocampal neuronal networks, we use microelectrode arrays (MEAs) to record the spontaneous activity of these networks before and after bath application of BDNF. Our results suggest a role for BDNF in the long-term development of neuronal network dynamics, as changes in network parameters were only observed at one week after treatment. Finally, we explore whether BDNF exerts neuroprotective effects following excitotoxic injury. Global activity parameters decrease following injury with excess glutamate with no benefit from BDNF treatment, but BDNF does protect connections with distinct baseline synchronizations from injury-induced decreases. Taken together, our results indicate that BDNF is involved in the development of the dendritic arbor, the maturation of neuronal networks, and the protection of distinct connections after excitotoxic injury.Ph.D.Includes bibliographical referencesby Kate M. O’Neil