The emergence and plasticity of a balance between excitation and inhibition along dendrites

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A single neuron in the brain can receive signals from thousands of other neurons. Each signal arrives at specialised sites, known as synapses that are distributed across a tree-like structure known as the dendrite. Every neuron must then decide, based on these incoming signals, whether or not to generate an output signal of its own. The integration of input signals by a neuron is therefore crucial for determining how information flows through the brain. Recent evidence has shown than not all synapses are alike however. The strength of a synapse, i.e. its ability to influence the generation of an output signal, can vary according to position on the dendrite. What's more remarkable though is that neurons receive two types of input: excitatory signals that promote output, and inhibitory signals that prevent it. The behaviour of a neuron is therefore precisely regulated by how these two opposing forces interact with one another in space and time. The importance of developing and maintaining a correct balance between excitation and inhibition is underscored by the fact that an incorrect balance may underlie many neurological disorders such as epilepsy, autism and schizophrenia. However, we know very little about precisely how excitatory and inhibitory synapses are distributed across neurons in the mature brain or how the interaction between them influences neuronal output. We know even less about how the spatial relationship of excitatory and inhibitory synapses is established as the neurons in the brain wire up during development nor how they are adjusted the sensory experience the animal is subjected to as they grow. This is particularly important given that many neurological disorders arise as a consequence of abnormal brain development. In this proposal we will engineer neurons in the mouse brain to express fluorescent markers of different colours to label excitatory and inhibitory synapses. This will allow us to visualize, in a single neuron, how both types of synapse are distributed and how this distribution develops during the wiring of the brain. We will also examine how the distribution of excitatory and inhibitory inputs changes in response to chronic changes in experience (in this case visual input) that results in changes in the activity of neurons. These fluorescent markers will also serve as a guide that will allow us to selectively activate identified synapses and ask specific questions - how does stimulation of single excitatory synapse influence the activity of a neuron and how does this change when neighbouring or distant inhibitory synapses are also active? These studies will provide important insight into how neurons and circuits develop and how excitatory and inhibitory signals are integrated in the healthy brain. This, in-turn, will lay the foundations for studying these processes in models of neurological disorders.