University of Cambridge > > MRC LMB Seminar Series > Neuronal plasticity: from synapses to the axon initial segment

Neuronal plasticity: from synapses to the axon initial segment

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We are interested in understanding how neurons wire up to form a stable network. Specifically, we would like to know how synaptic contacts between neurons form and mature during development. The transfer of information at mature synaptic contacts arises from the release of neurotransmitter from synaptic vesicles into the small confines of the synaptic cleft and subsequent activation of post-synaptic receptors. However, we know very little about the mechanisms of transmitter release during development, nor indeed when it is that synaptic transmission begins. We use cultured hippocampal neurons to study how axons and dendrites contact each other to form synapses and subsequently follow how these connections mature. A number of different genetically-encoded probes were implemented to assess the gradual maturation of both presynaptic and postsynaptic compartments. Our results show that axons from young neurons (before synapses have formed) display initially high levels of spontaneous vesicle cycling that are progressively down-regulated during synapse formation, with a concomitant increase in activity-dependent cycling as development proceeds. Interestingly, this early, spontaneous release of neurotransmitter is sensed by distant postsynaptic receptors, resulting in spatially broad calcium signals along a dendrite driven by NMDA receptors. We find that over 80% of these dendritic response sites did not co-localise with an axonal presynaptic terminal suggesting that during neuronal development, synaptic transmission can occur before contact is initiated. We are currently exploring the possible role that spontaneous release may have on driving local interactions between neurons as connections are established.

We are also particularly interested in understanding how network activity remains stable during development, a period that is highly plastic and characterised by rapid and large scale changes in connectivity. For this purpose, neurons use homeostatic forms of plasticity to control their excitability. Here, we used an optotgenetic approach to precisely control the activity of individual neurons in a network and study homeostatic plasticity at two crucial sites for neuronal information processing and integration: the synapse and the axon initial segment (AIS). We find that chronic changes in the activity of a single neuron results in compensatory, cell-wide changes in synaptic gain. In parallel to this synaptic phenotype we find that the intrinsic properties of neurons are also modulated: chronic increases in neuronal or network activity also cause a dramatic distal shift in AIS position along an axon. Since the AIS represents the site of action potential initiation, we propose that movement of the AIS distally or proximally along the axon may therefore represent a novel mechanism for controlling the intrinsic excitability of a neuron.

This talk is part of the MRC LMB Seminar Series series.

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