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. Therefore, it is not surprising that the incidence of network hyperexcitability is higher in the neonatal period than in any other age group. 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. Recently, an exciting new field has emerged that provides critical insights to understanding the rules that networks follow in order to achieve appropriate levels of activity. Many studies have now shown that networks homeostatically maintain activity levels within an appropriate range by adjusting synaptic strength (homeostatic synaptic plasticity). The vast majority of these studies have blocked network activity in vitro (culture systems) for days, and changes in synaptic strength are in a compensatory direction. 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. We have found that changes in cellular excitability mediate the initial homeostatic recovery of perturbed activity levels in the embryonic spinal cord. The objective of this application is to better understand the role and mechanisms underlying homeostatic changes in cellular excitability and synaptic strength in the developing circuit. We are proposing to perturb network activity in a more realistic manner in the living embryo, allow for the homeostatic recovery of activity, and then carry out a comprehensive assessment of the proteins that mediate the initiation, signaling, and expression of compensatory changes in excitability and synaptic strength. The project will provide a more extensive, realistic understanding of homeostatic plasticity, and define its role in the maturation of network excitability. Further, the study will identify proteins underlying each form of homeostatic plasticity, and therefore provide therapeutic targets for conditions of hyperexcitability. Our approach introduces a new method into the homeostatic field that will elucidate a molecular network that will identify genes that associate with human disease, and help us better understand the function of homeostatic plasticity.

Public Health Relevance

We are testing the possibility that a spontaneous network activity that is expressed in embryonic neural circuits regulates the intrinsic cellular excitability in the embryonic spinal cord. In this way, we are studying the maturation of embryonic network excitability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065992-07
Application #
9462901
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Churn, Severn Borden
Project Start
2010-09-17
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
7
Fiscal Year
2018
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
Gonzalez-Islas, Carlos; Bülow, Pernille; Wenner, Peter (2018) Regulation of synaptic scaling by action potential-independent miniature neurotransmission. J Neurosci Res 96:348-353
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