Final Report Summary - CEIDNFSTTAIS (Controlling excitability in developing neurons: from synapses to the axon initial segment)
Neurons in the brain are constantly changing the number of contacts they form with each other, as well as the strength of these connections. This is especially the case during development, as neurons wire up to form connections with each. Although these events are critical for the proper formation of the brain, so much change can also destabilise the system resulting in uncontrolled levels of activity in the brain that can be damaging to the organism. As a result, neurons in the brain employ a number of different strategies to remain stable whilst everything around them is changing. This fundamental process, generally referred to as homeostatic plasticity, serves to keep the overall activity levels of networks in the brain stable. Here we uncover novel forms of homeostatic plasticity in a number of different subcellular compartments within neurons, as well as network wide changes that control neuronal cell number. We find that chronic increases in activity can result in a structural form of plasticity at the site responsible for generating action potentials, the axon initial segment (AIS), which uncouples it from the inhibitory inputs it receives and decreases its overall excitability. In addition, we find that neuronal activity can also control the number of inhibitory interneurons in the brain, during a very early phase of development. We find that increased activity can rescue interneurons from dying, resulting in an increase in the total number of inhibitory neurons in the brain. We propose that this novel form of modulation will serve to stabilise the brain during the initial period of circuit wiring. But neurons use a number of different approaches to remain stable that also include the synapse. For example, we find that homeostatic plasticity can also alter the ultrastructure of synapses. Specifically, we describe how the small domains responsible for the release of neurotransmitter at the synapse can change, thereby modulating the amount of neurotransmitter they release. By changing the clustering state of the proteins found at these domains, they can control the access of vesicles that contain neurotransmitter and therefore the likelihood that they will release their contents. Finally, and somewhat surprisingly, we found that activity appears to play no role in the distribution of synapses along the vast dendrites of neurons. However, this study did uncover a novel distribution of synapses with distance along dendrites that may help explain how neurons integrate synaptic signals in the brain. We found that synapses became smaller with distance along a dendrite resulting in a graded change in the way neurotransmitter signals are read out. Together our research has shown that neurons employ multiple strategies for controlling their overall levels of activity in the brain with goal of remaining stable in the midst of a constantly changing environment.