Neurons of the central nervous system are organized into networks through a variety of synaptic interactions. Electrical synapses, formed by gap junctions between neurons, are a core component of this organization. Electrical synapses can synchronize activity of networks of the same neuron type and provide rapid, bi-directional electrical communication between neurons of different type. These properties are critical for many high-order network functions of the central nervous system. Electrical synapses are not static, but are tightly regulated. Changes in phosphorylation state of connexin 36 (Cx36) in some retinal neurons modify coupling quantitatively over more than an order of magnitude dynamic range. Such changes in coupling are a stereotyped element of retinal light adaptation, and many electrically coupled retinal networks are held in a very poorly coupled state during the daytime to optimize their function. The vast majority of electrical synapses throughout the central nervous system are composed of Cx36. ALL of these synapses are capable of the same scale of plasticity, but very little is known about the plasticity of most networks or their functional state. This project explores the hypothesis that optimal function of electrically coupled networks is often best served by weak coupling. To test this hypothesis we will develop conditional mutant mice in which the electrical synapses are locked in an open state by point mutations that mimic phosphorylation of Cx36. This should cause unusually high coupling in most networks affected. These animals will be used to determine the impact of strong coupling of neural networks in the retina in the daytime on visual functions and behavior. Further studies will examine specifically the necessity to use electrical synaptic plasticity to reconfigure rod visual pathways in the daytime to optimize ganglion cell responses in photopic light. This animal model will be useful to study plasticity of electrical coupling in most other circuits in the central nervous system. It will have further utility in studies of the role of gap junctional coupling in bystander cell death in brain injuries and diseases.
This project develops animal models to examine the roles of electrical synaptic plasticity within neural networks in the retina and throughout the central nervous system. Electrical synapses play important roles in neural network functions that affect light adaptation of visual functions, memory formation, and motor coordination. Recent studies indicate that the extent of electrical synapse function also correlates with pathological conditions including neural network hyperactivity in photoreceptor degenerative diseases and bystander neuron death in ischemic events, traumatic brain injury and seizures. The animal models developed in this project will provide insight into the fundamental requirement to control electrical synapse strength in the context of normal physiological function. They will also provide model systems to develop treatment strategies to mitigate bystander cell death in brain injuries and to correct the pathologies caused by aberrant regulation of electrical synapse strength.