Activity-dependent changes in neuronal architecture : dendrites, axon and the axon initial segment

• Main Author: Mukanowa, Janina
• Other Authors: Burrone, Juan
• Published: King's College London (University of London) 2014
• Subjects: 612.8
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.650797

The assembly of the brain during embryonic development was thought to be largely independent of its electrical activity. It was believed that activity, broadly defined as spontaneous or evoked changes in membrane potential, is important only in later stages of development, after a basic template of the nervous system has already been established. Recent data, however, suggests that activity plays a crucial role in all stages of neural development, from cell proliferation and migration to establishment and maturation of synaptic connections. In this thesis, I explore the role of activity on early development of axons, dendrites and the axon initial segments of hippocampal neurons in vitro. Activity was modulated by either elevated levels of KCl or optogenetic stimulation of ChR2-expressing neurons. Elevated activity had only a modest effect on the morphology of dendritic and axonal compartments, however it strongly affected the structure of the axon initial segment (AIS). Chronic depolarisation of developing hippocampal neurons led to reversible, cell-death independent, AIS disassembly in a subset of susceptible neurons. This effect required Ca2+ influx though L-type voltage-gated Ca2+ channels and was observed mostly in young (4-7 DIV) neurons, suggesting the existence of a developmental window for this type of activity-induced change. Electrophysiological recordings and Ca2+ imaging experiments showed that cells without an AIS have markedly decreased Na+ currents and are unable to initiate repetitive firing. The AISs that were not disassembled in response to elevated activity had significantly altered structural properties, in terms of their length and position along the axon. The exact nature of these changes depended on the specific developmental stage at which the neurons were depolarised. The susceptibility of the AIS to alterations in neuronal activity may suggest the existence of a novel form of plasticity in immature neurons, which may be important for stabilisation of neuronal activity in developing hippocampal circuits.