The emergence and plasticity of synapses at the axon initial segment

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

The axon initial segment (AIS) is a structure at the start of the axon with a high sodium and potassium channel density, defining the site of action potential generation. It is also the target of inhibitory synapses formed by a specific GABAergic interneuron, the Chandelier cell. Due to this strategic synaptic placement, Chandelier cells are thought to powerfully control network activity. Despite this, we know surprisingly little about this cell type. By visualising Chandelier cell interneurons and their boutons in somatosensory cortex at different developmental stages, we uncovered a critical temporal window of synapse formation at the AIS (P14-P16), which corresponds with the electrophysiological and morphological maturation of the Chandelier cell. Using a targeted chemogenetic approach, we showed that modulating the activity of either pyramidal cells or Chandelier cells themselves, resulted in a decrease in axo-axonic synapse number along the AIS. In parallel, we also observed a decrease in the length of the AIS and, as a consequence, a reduction in intrinsic excitability. Surprisingly, the same manipulation of neuronal activity in mature mice (P40-P46) showed the opposite
effect, an increase in axo-axonic synapse number. Since axo-axonic synapses change polarity from depolarising to hyperpolarising late in development, this form of plasticity likely constitutes a homeostatic mechanism that serves to keep network activity stable. To confirm this, I studied the functional impact of this synaptic plasticity using whole-cell electrophysiology as well as voltage imaging. In conclusion, my work on the activity-dependent development of Chandelier cells has uncovered a bidirectional plasticity of axo-axonic synapses in juvenile and adult mice. I propose that the AIS and its synapses are highly plastic and form an important hub for stabilising neuronal activity.
Date of Award1 Feb 2019
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorJuan Burrone (Supervisor)

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