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.

Public Health Relevance

Spontaneous network activity in embryonic neural circuits is maintained through changes in homeostatic plasticity mechanisms. We are studying these mechanisms as they drive changes that will define the maturation of network excitability and will help us understand the hyperexcitability that is associated with several neurodevelopmental disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS065992-09
Application #
9974093
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Churn, Severn Borden
Project Start
2010-09-17
Project End
2025-03-31
Budget Start
2020-06-15
Budget End
2021-03-31
Support Year
9
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Emory University
Department
Physiology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Lindsly, Casie; Gonzalez-Islas, Carlos; Wenner, Peter (2017) Elevated intracellular Na+ concentrations in developing spinal neurons. J Neurochem 140:755-765
Gonzalez-Islas, Carlos; Garcia-Bereguiain, Miguel Angel; O'Flaherty, Brendan et al. (2016) Tonic nicotinic transmission enhances spinal GABAergic presynaptic release and the frequency of spontaneous network activity. Dev Neurobiol 76:298-312
Fong, Ming-fai; Newman, Jonathan P; Potter, Steve M et al. (2015) Upward synaptic scaling is dependent on neurotransmission rather than spiking. Nat Commun 6:6339
Lindsly, Casie; Gonzalez-Islas, Carlos; Wenner, Peter (2014) Activity blockade and GABAA receptor blockade produce synaptic scaling through chloride accumulation in embryonic spinal motoneurons and interneurons. PLoS One 9:e94559
Wenner, Peter (2014) Homeostatic synaptic plasticity in developing spinal networks driven by excitatory GABAergic currents. Neuropharmacology 78:55-62
Garcia-Bereguiain, Miguel Angel; Gonzalez-Islas, Carlos; Lindsly, Casie et al. (2013) In vivo synaptic scaling is mediated by GluA2-lacking AMPA receptors in the embryonic spinal cord. J Neurosci 33:6791-9
Gonzalez-Islas, Carlos; Garcia-Bereguiain, Miguel Angel; Wenner, Peter (2012) Tonic and transient endocannabinoid regulation of AMPAergic miniature postsynaptic currents and homeostatic plasticity in embryonic motor networks. J Neurosci 32:13597-607
Gonzalez-Islas, Carlos; Chub, Nikolai; Garcia-Bereguiain, Miguel Angel et al. (2010) GABAergic synaptic scaling in embryonic motoneurons is mediated by a shift in the chloride reversal potential. J Neurosci 30:13016-20