Keeping the balance: Molecular mechanisms controlling axon initial segment plasticity

On behalf of Molecular Mechanisms of Neuronal Connectivity: From Membranes to Synapses' Group, Amélie Freal from UMC Amsterdam will give a talk titled "Keeping the balance: Molecular mechanisms controlling axon initial segment plasticity" as part of the ongoing Student/Postdoc-Run Speaker Series (SPRSS).

Abstract:

Activity-dependent plasticity of the axon initial segment (AIS) allows neurons to adapt action potential output to changes in network activity and is emerging as a crucial regulator of network activity homeostasis. The initiation of action potentials at the AIS highly depends on the local density and distribution of voltage-gated ion channels, but the molecular mechanisms regulating their plasticity remain largely unknown.

Here, we developed genetic tools to label endogenous sodium channels and their scaffolding protein Ankyrin-G, to reveal their nanoscale organization and longitudinally image AIS plasticity in hippocampal neurons both in slices and primary cultures.

During short-term plasticity, we found that NMDA receptor activation causes long-term synaptic depression as well as rapid shortening of the AIS. During this shortening, Nav1.2 channels are endocytosed from the distal AIS, and this correlates with an increase in the threshold for action potential generation. During long-term silencing of neuronal network, we found that while excitatory neurons strongly upregulate Nav1.6 channels at their AIS, the expression of this channel is downregulated in inhibitory neurons. We are now investigating the transcriptional regulation and the membrane trafficking of the Nav1.6 channel to get insight into the molecular mechanisms allowing neurons to adjust their intrinsic excitability and balance excitation/inhibition homeostasis in neuronal networks.