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

ABSTRACT: Little is known about the properties and function of ion channels that affect synaptic terminal-resting properties. One particular subthreshold-active ion channel, the Kv7 potassium channel, is highly localized to axons, but its role in regulating synaptic terminal intrinsic excitability and release is largely unexplored. Using electrophysiological recordings together with computational modeling, we found that the K_V7 current was active at rest in adult hippocampal mossy fiber synaptic terminals and enhanced their membrane conductance. The current also restrained action potential-induced Ca²⁺ influx via N- and P/Q-type Ca²⁺ channels in boutons. This was associated with a substantial reduction in the spike half-width and afterdepolarization following presynaptic spikes. Further, by constraining spike-induced Ca²⁺ influx, the presynaptic K_V7 current decreased neurotransmission onto CA3 pyramidal neurons and short-term synaptic plasticity at the mossy fiber-CA3 synapse. This is a distinctive mechanism by which K_V7 channels influence hippocampal neuronal excitability and synaptic plasticity.

SUBMITTER: Martinello K

PROVIDER: S-EPMC6486593 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Martinello Katiuscia K Giacalone Elisabetta E Migliore Michele M Brown David A DA Shah Mala M MM

Communications biology 20190426

Little is known about the properties and function of ion channels that affect synaptic terminal-resting properties. One particular subthreshold-active ion channel, the Kv7 potassium channel, is highly localized to axons, but its role in regulating synaptic terminal intrinsic excitability and release is largely unexplored. Using electrophysiological recordings together with computational modeling, we found that the KV7 current was active at rest in adult hippocampal mossy fiber synapti ...[more]

PMID: 31044170

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Project description:Membrane excitability in the axonal growth cones of embryonic neurons influences axon growth. Voltage-gated K+ (Kv) channels are key factors in controlling membrane excitability, but whether they regulate axon growth remains unclear. Here, we report that Kv3.4 is expressed in the axonal growth cones of embryonic spinal commissural neurons, motoneurons, dorsal root ganglion neurons, retinal ganglion cells, and callosal projection neurons during axon growth. Our in vitro (cultured dorsal spinal neurons of chick embryos) and in vivo (developing chick spinal commissural axons and rat callosal axons) findings demonstrate that knockdown of Kv3.4 by a specific shRNA impedes axon initiation, elongation, pathfinding, and fasciculation. In cultured dorsal spinal neurons, blockade of Kv3.4 by blood depressing substance II suppresses axon growth via an increase in the amplitude and frequency of Ca2+ influx through T-type and L-type Ca2+ channels. Electrophysiological results show that Kv3.4, the major Kv channel in the axonal growth cones of embryonic dorsal spinal neurons, is activated at more hyperpolarized potentials and inactivated more slowly than it is in postnatal and adult neurons. The opening of Kv3.4 channels effectively reduces growth cone membrane excitability, thereby limiting excessive Ca2+ influx at subthreshold potentials or during Ca2+-dependent action potentials. Furthermore, excessive Ca2+ influx induced by an optogenetic approach also inhibits axon growth. Our findings suggest that Kv3.4 reduces growth cone membrane excitability and maintains [Ca2+]i at an optimal concentration for normal axon growth.SIGNIFICANCE STATEMENT Accumulating evidence supports the idea that impairments in axon growth contribute to many clinical disorders, such as autism spectrum disorders, corpus callosum agenesis, Joubert syndrome, Kallmann syndrome, and horizontal gaze palsy with progressive scoliosis. Membrane excitability in the growth cone, which is mainly controlled by voltage-gated Ca2+ (Cav) and K+ (Kv) channels, modulates axon growth. The role of Cav channels during axon growth is well understood, but it is unclear whether Kv channels control axon outgrowth by regulating Ca2+ influx. This report shows that Kv3.4, which is transiently expressed in the axonal growth cones of many types of embryonic neurons, acts to reduce excessive Ca2+ influx through Cav channels and thus permits normal axon outgrowth.

Dataset Information

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

Publications

The subthreshold-active K<sub>V</sub>7 current regulates neurotransmission by limiting spike-induced Ca<sup>2+</sup> influx in hippocampal mossy fiber synaptic terminals.

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