The role of intrinsic cellular excitability in homeostatic plasticity of developing circuits

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Abstract It is an extraordinary accomplishment that most developing neuronal networks achieve an appropriate level of excitability, during a dynamic period of embryonic development when there are several challenges to a network's excitability. Errors in such a complicated process can lead to alterations in the excitability of neonatal spinal circuit, which can be observed behaviorally as myoclonus, hypertonia, recurrent tremor, and spasticity. Understanding the rules and mechanisms that underlie the maturation of network excitability are therefore essential. An exciting new field has emerged, which provides critical insights to understanding the rules that networks follow in order to achieve appropriate levels of activity. Many studies have now shown that perturbations to network activity trigger changes in synaptic strength which are thought to homeostatically recover and maintain activity levels within an appropriate range. Compensatory changes in intrinsic cellular excitability (cell's responsiveness to synaptic input) also likely contribute to the homeostatic process, although these changes have received far less attention than synaptic compensations. By taking advantage of the accessibility of the chick embryo we have been able to follow an actual homeostatic recovery of activity (embryonic movements). Because of this, we have been able to identify a critical and previously unrecognized homeostatic mechanism where changes in resting membrane potential mediate the initial homeostatic recovery of perturbed activity levels in the living embryonic spinal cord. We will identify the mechanism underlying this compensation in the first aim of the grant. Based on a recent study and our proteomic analysis from our previous grant period, we are proposing to examine an unexpected critical relationship between mitochondrial function and homeostatic plasticity in aim 2. Finally in aim 3 we will carry out this work in the genetically advantageous mouse model system. Our study will identify the mechanisms of homeostatic plasticity in the living system and will begin to elucidate the calcium triggers for these forms of plasticity. The work can instruct pharmacological interventions that ameliorate hyperexcitability associated with neurodevelopmental disorders, and help us better understand the function of homeostatic plasticity.