Balancing the strength of excitatory and inhibitory elements within a network is essential for the proper function of the circuit. If excitatory systems dominate, spasticity or epileptiform activity could result. The period of circuit development is of crucial importance because it is then that the balance is first established. Insight to mechanisms that regulate excitatory and inhibitory synaptic strength during development would provide a critical step in our understanding of how networks arrive at this balance. A new form of synaptic plasticity has been identified in cultured neurons, which suggests that neurons homeostatically regulate their level of spiking activity by adjusting the strength of their synaptic inputs (synaptic scaling). The objective of this application is to determine the level of spiking activity in the postsynaptic neuron drives the maturation of synaptic strength during embryonic development of spinal motor networks. To this end we will block spiking activity in the motor network or in individual spinal neurons in ovo in the chick embryo. By comparing the strength of the synaptic inputs in activity-blocked and control neurons we will test the role of activity in the regulation of synaptic strength in an excitatory motoneuron (Specific Aim 1 & 2) and in an identified inhibitory GABAergic interneuron (Specific Aim 3 & 4). This is possible because we have recently characterized a class of interneuron that receives direct input from motoneurons. Using a combination of molecular, electrophysiological, optical, and immunocytochemical techniques we are proposing to begin a comprehensive study to understand the role of activity in the development of excitatory and inhibitory synaptic strength in excitatory and inhibitory spinal neurons. We are proposing that the level of activity regulates the strength of newly formed synaptic connections in the embryo. The results of the study will provide a better understanding of how a network achieves a balance between excitatory and inhibitory elements during development. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
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Chen, Daofen
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Emory University
Schools of Medicine
United States
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Wenner, Peter (2014) Homeostatic synaptic plasticity in developing spinal networks driven by excitatory GABAergic currents. Neuropharmacology 78:55-62
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
Wilhelm, Jennifer C; Rich, Mark M; Wenner, Peter (2009) Compensatory changes in cellular excitability, not synaptic scaling, contribute to homeostatic recovery of embryonic network activity. Proc Natl Acad Sci U S A 106:6760-5
Gonzalez-Islas, Carlos; Chub, Nikolai; Wenner, Peter (2009) NKCC1 and AE3 appear to accumulate chloride in embryonic motoneurons. J Neurophysiol 101:507-18
Wilhelm, Jennifer C; Wenner, Peter (2008) GABAA transmission is a critical step in the process of triggering homeostatic increases in quantal amplitude. Proc Natl Acad Sci U S A 105:11412-7
Xu, Huaying; Clement, Arthur; Wright, Terrence Michael et al. (2007) Developmental reorganization of the output of a GABAergic interneuronal circuit. J Neurophysiol 97:2769-79
Rich, Mark M; Wenner, Peter (2007) Sensing and expressing homeostatic synaptic plasticity. Trends Neurosci 30:119-25
Pallas, Sarah L; Wenner, Peter; Gonzalez-Islas, Carlos et al. (2006) Developmental plasticity of inhibitory circuitry. J Neurosci 26:10358-61
Gonzalez-Islas, Carlos; Wenner, Peter (2006) Spontaneous network activity in the embryonic spinal cord regulates AMPAergic and GABAergic synaptic strength. Neuron 49:563-75
Xu, Huaying; Whelan, Patrick J; Wenner, Peter (2005) Development of an inhibitory interneuronal circuit in the embryonic spinal cord. J Neurophysiol 93:2922-33