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TDP-43-dependent mis-splicing of KCNQ2 triggers intrinsic neuronal hyperexcitability in ALS/FTD

TDP-43 dysfunction in ALS/FTD causes faulty splicing of the KCNQ2 ion channel, leading to toxic protein buildup, neuron hyperactivity and a potential new biomarker and treatment target using RNA-based therapies.

Brian J. Joseph
Kelly A. Marshall
Evangelos Kiskinis
ResearchOpen Access31 Oct 2025
Nature Neuroscience

Volume: 28, P: 2476-2492
Presynaptic HCN1 channels regulate Ca_V3.2 activity and neurotransmission at select cortical synapses

The authors find that hyperpolarization-activated cyclic nucleotide–gated 1 (HCN1) channel subunits are localized to the active zone of asymmetric synaptic terminals targeting mouse entorhinal cortical layer III pyramidal neurons. The presynaptic HCN channels inhibit synaptic glutamate release by suppressing the activity of low-threshold voltage-gated T-type (Ca_V3.2) calcium channels.

Zhuo Huang
Rafael Lujan
Mala M Shah
Research27 Feb 2011
Nature Neuroscience

Volume: 14, P: 478-486
The subthreshold-active K_V7 current regulates neurotransmission by limiting spike-induced Ca²⁺ influx in hippocampal mossy fiber synaptic terminals

Martinello et al. show that the KV7 K⁺ channels, active at rest, diminish action potential-induced Ca²⁺ influx into hippocampal mossy fiber boutons. This reduction alters presynaptic spikes, reduces neurotransmitter release, and decreases short-term synaptic plasticity, highlighting a role for these channels in hippocampal CA3 neuronal excitability.

Katiuscia Martinello
Elisabetta Giacalone
Mala M. Shah
ResearchOpen Access26 Apr 2019
Communications Biology

Volume: 2, P: 1-12
HCN1 channels reduce the rate of exocytosis from a subset of cortical synaptic terminals

Zhuo Huang
Gengyu Li
Mala M. Shah
ResearchOpen Access10 Jan 2017
Scientific Reports

Volume: 7, P: 1-12

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TDP-43-dependent mis-splicing of KCNQ2 triggers intrinsic neuronal hyperexcitability in ALS/FTD

Presynaptic HCN1 channels regulate CaV3.2 activity and neurotransmission at select cortical synapses

The subthreshold-active KV7 current regulates neurotransmission by limiting spike-induced Ca2+ influx in hippocampal mossy fiber synaptic terminals

HCN1 channels reduce the rate of exocytosis from a subset of cortical synaptic terminals

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Presynaptic HCN1 channels regulate Ca_V3.2 activity and neurotransmission at select cortical synapses

The subthreshold-active K_V7 current regulates neurotransmission by limiting spike-induced Ca²⁺ influx in hippocampal mossy fiber synaptic terminals