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. ? ?
