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 (e.g. cells increase in size). Therefore it is not surprising that the incidence of seizure activity is higher in the neonatal period than in any other age group. Neonatal seizures are often the first indication of neurological dysfunction, and are strong predictors of long-term cognitive and developmental impairment. Understanding the rules and mechanisms that underlie the maturation of network excitability are therefore essential. In the last decade 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) for days, and although activity doesn't homeostatically recover, changes in synaptic strength are in a compensatory direction. Therefore, it is assumed, although untested, that these changes would normally act to recover activity levels following perturbations in vivo. 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 are faster and likely more important in the initial recovery of normal activity levels. The objective of this application is to better understand the role of cellular excitability in the process of homeostatically recovering and maintaining network activity in developing networks. We are proposing to perturb network activity in the living embryo, allow for the homeostatic recovery of activity and assess how changes in cellular excitability contribute to this recovery. This will provide a more realistic, comprehensive understanding of the homeostatic regulation of cellular excitability and its role in maintaining appropriate activity levels and maturing network excitability.

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 motor and interneurons. 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 #
3R01NS065992-03S1
Application #
8607620
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
2010-09-17
Project End
2014-08-31
Budget Start
2013-01-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$85,343
Indirect Cost
$30,636
Name
Emory University
Department
Physiology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
Wenner, Peter (2014) Homeostatic synaptic plasticity in developing spinal networks driven by excitatory GABAergic currents. Neuropharmacology 78:55-62
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
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