Trans-synaptic regulation of neural connections : the role of neuronal activity and brain-derived neurotrophic factor (BDNF)

To determine how neural connections are formed and maintained, and how these connections adapt and respond to alterations in the nervous system, I have examined two aspects of morphological plasticity. First, I have examined the expression of the growth-associated molecule, Talpha1 alpha-tubulin, and its role in neuronal morphology in response to synaptic activity. Second, I have examined the role of one potential molecular extrinsic cue, the growth factor, brain-derived neurotrophic factor (BDNF), and its effects on synaptic input.First, I have investigated neuronal responses to elevated levels of trans-synaptic activity using an in vivo rat model of synaptically-induced hyperexcitability of hippocampal connections. In particular, intermittent stimulation for different time-periods induced the expression of Talpha1 alpha-tubulin in specific populations of mature hippocampal neurons. Because adult hippocampal neurons are known to sprout in response to high levels of excitatory input and because Talpha1 alpha-tubulin expression increases during sympathetic sprouting, the increase in Talpha1 alpha-tubulin mRNA in response to intermittent stimulation may reflect an ongoing activity-driven process of synaptic re-modeling in the hippocampus.One potential mechanism whereby activity may mediate some of its effects on morphological growth involves growth factors such as BDNF. To determine whether BDNF could directly regulate synaptogenesis, I focused my analysis on the spinal preganglionic neuron:sympathetic neuron synapse. To test the hypothesis that sympathetic neuron-derived BDNF regulates preganglionic afferent input, two types of mice were analyzed: (i) mice that overexpressed BDNF from the dopamine-beta-hydroxylase promoter (DBH:BDNF transgenic mice), and (ii) mice that lacked BDNF expression (BDNF knockout mice). I found that (i) preganglionic neurons express the full-length receptor TrkB, (ii) in DBH:BDNF mice, preganglionic neurons and axons hypertrophy and hyperinnervate their target, the SCG, (iii) there is no change in the number of preganglionic axons in the cervical sympathetic trunk (CST) in DBH:BDNF mice, and (iv) preganglionic innervation to the SCG is decreased in BDNF knockout mice. These results demonstrate that alterations in neuron-derived BDNF results in changes in synaptic innervation density from afferent input and suggest that a cascade of neurotrophin signalling may exist to establish and maintain the connectivity of neural pathways