A pivotal event in the developing nervous system is formation of proper synaptic connections, a process governed by intrinsic cellular guidance cues and by extrinsic, """"""""activity-dependent"""""""", information obtained from the environment. External stimuli have their greatest impact during critical periods in which connections between nerve cells are highly plastic and susceptible to modification. At the molecular level, two of the key regulators of activity-dependence are the NMDA subtype of glutamate receptor, and brain-derived neurotrophic factor (BDNF). With the use of selective antagonists, each has been shown independently to affect the ability of growing nerve fibers to compete for postsynaptic targets and even influence the duration of critical periods during development. The central goal of this proposal is to elucidate interactions between these two molecules, thus providing insights into how they work together to refine synaptic connectivity into early adulthood.To accomplish this task, we will build upon previous work from my laboratory showing that BDNF can modify the activity of NMDA receptors in hippocampal neurons, particularly those containing the NR2B subunit. Expression levels of NR2B are highly correlated with critical period duration, and may play an obligatory role in synaptic plasticity during ontogeny. Therefore, we will determine whether BDNF modulation of NMDA receptors is prominent during early development, whether it targets synaptic or extrasynaptic NR2B-containing NMDA receptors, and whether it is hippocampus-specific or found in other brain regions as well. We will also capitalize on our new finding that modulation of NMDA receptors by BNDF is activity-dependent, an essential requirement for involvement in synaptic competition. We will use this information to determine whether BDNF modulation is synapse- or cell-specific, whether it involves neuronal release of BDNF, and whether, like many forms of synaptic plasticity, it is triggered by calcium influx through NMDA receptors.Addressing these questions will increase our knowledge of how neural circuits are constructed during development, and perhaps even help us determine how to rebuild these pathways after brain trauma.
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