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M-current inhibition rapidly induces a unique CK2-dependent plasticity of the axon initial segment

Lezmy, Jonathan; Lipinsky, Maya; Khrapunsky, Yana; Patrich, Eti; Shalom, Lia; Peretz, Asher; Fleidervish, Ilya A; (2017) M-current inhibition rapidly induces a unique CK2-dependent plasticity of the axon initial segment. Proceedings of the National Academy of Sciences , 114 (47) E10234-E10243. 10.1073/pnas.1708700114. Green open access

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Abstract

Alterations in synaptic input, persisting for hours to days, elicit homeostatic plastic changes in the axon initial segment (AIS), which is pivotal for spike generation. Here, in hippocampal pyramidal neurons of both primary cultures and slices, we triggered a unique form of AIS plasticity by selectively targeting M-type K+ channels, which predominantly localize to the AIS and are essential for tuning neuronal excitability. While acute M-current inhibition via cholinergic activation or direct channel block made neurons more excitable, minutes to hours of sustained M-current depression resulted in a gradual reduction in intrinsic excitability. Dual soma–axon patch-clamp recordings combined with axonal Na+ imaging and immunocytochemistry revealed that these compensatory alterations were associated with a distal shift of the spike trigger zone and distal relocation of FGF14, Na+, and Kv7 channels but not ankyrin G. The concomitant distal redistribution of FGF14 together with Nav and Kv7 segments along the AIS suggests that these channels relocate as a structural and functional unit. These fast homeostatic changes were independent of l-type Ca2+ channel activity but were contingent on the crucial AIS protein, protein kinase CK2. Using compartmental simulations, we examined the effects of varying the AIS position relative to the soma and found that AIS distal relocation of both Nav and Kv7 channels elicited a decrease in neuronal excitability. Thus, alterations in M-channel activity rapidly trigger unique AIS plasticity to stabilize network excitability.

Type: Article
Title: M-current inhibition rapidly induces a unique CK2-dependent plasticity of the axon initial segment
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1708700114
Publisher version: https://doi.org/10.1073/pnas.1708700114
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: homeostatic plasticity, axon initial segment, M-current, potassium channel, Kᵥ7
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10168516
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