Differential Control of Axonal and Somatic Resting Potential by Voltage-Dependent Conductances in Cortical Layer 5 Pyramidal Neurons

Hu, Wenqin; Bean, Bruce P.

doi:10.1016/j.neuron.2018.08.042

Cited by 36 publications

(35 citation statements)

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“…We also find that action potentials are initiated from spike thresholds that are 14.3 mV more hyperpolarized than somatic spikes. Furthermore, the average non-spike voltage recorded in both the main axon and striatal axon is 6.7 mV and 8.8 mV more negative than values reported for the soma, respectively, which also fits with data from cortical layer five pyramidal neurons ( Hu and Bean, 2018 ).…”

Section: Discussionsupporting

confidence: 87%

Axonal mechanisms mediating γ-aminobutyric acid receptor type A (GABA-A) inhibition of striatal dopamine release

Kramer

Twedell

Shin

et al. 2020

eLife

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Axons of dopaminergic neurons innervate the striatum where they contribute to movement and reinforcement learning. Past work has shown that striatal GABA tonically inhibits dopamine release, but whether GABA-A receptors directly modulate transmission or act indirectly through circuit elements is unresolved. Here, we use whole-cell and perforated-patch recordings to test for GABA-A receptors on the main dopaminergic neuron axons and branching processes within the striatum of adult mice. Application of GABA depolarized axons, but also decreased the amplitude of axonal spikes, limited propagation and reduced striatal dopamine release. The mechanism of inhibition involved sodium channel inactivation and shunting. Lastly, we show the positive allosteric modulator diazepam enhanced GABA-A currents on dopaminergic axons and directly inhibited release, but also likely acts by reducing excitation from cholinergic interneurons. Thus, we reveal the mechanisms of GABA-A receptor modulation of dopamine release and provide new insights into the actions of benzodiazepines within the striatum.

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Section: Discussionsupporting

confidence: 87%

Axonal mechanisms mediating γ-aminobutyric acid receptor type A (GABA-A) inhibition of striatal dopamine release

Kramer

Twedell

Shin

et al. 2020

eLife

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“…Activation of HCN channels creates a depolarizing influence that brings the RMP closer to the AP threshold, but the same HCN channels also generate a shunting conductance that reduces the input resistance and neuronal excitability 40 . Furthermore, the depolarization produced by HCN channels modulates functional states of Na + , K + , and Ca 2+ channels that are critical for AP signaling 37,[41][42][43][44] . These multiple actions of HCN channels make it challenging to predict the net effect of HCN channels on neuronal excitability in a cell type-specific manner.…”

Section: Discussionmentioning

confidence: 99%

An axon-specific expression of HCN channels catalyzes fast action potential signaling in GABAergic interneurons

Roth

2020

Nat Commun

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During high-frequency network activities, fast-spiking, parvalbumin-expressing basket cells (PV +-BCs) generate barrages of fast synaptic inhibition to control the probability and precise timing of action potential (AP) initiation in principal neurons. Here we describe a subcellular specialization that contributes to the high speed of synaptic inhibition mediated by PV +-BCs. Mapping of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel distribution in rat hippocampal PV +-BCs with subcellular patch-clamp methods revealed that functional HCN channels are exclusively expressed in axons and completely absent from somata and dendrites. HCN channels not only enhance AP initiation during sustained high-frequency firing but also speed up the propagation of AP trains in PV +-BC axons by dynamically opposing the hyperpolarization produced by Na +-K + ATPases. Since axonal AP signaling determines the timing of synaptic communication, the axon-specific expression of HCN channels represents a specialization for PV +-BCs to operate at high speed.

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“…While rheobase was reduced, interestingly we detected a higher voltage threshold, reduced AP amplitude, elevated fast after-hyperpolarization (fAHP), and increased half-width values in MSNs from Scn2a gtKO/gtKO mice ( Figure 1H-L ). Voltage-dependent conductance can affect neuronal RMP ( 25 ), and RMP is known to influence neuronal excitability ( 26 ). We thus performed recordings at a fixed membrane potential (MP) to understand whether the altered RMP is a major factor for this observed hyperexcitability of MSNs.…”

Section: Resultsmentioning

confidence: 99%

Severe deficiency of voltage-gated sodium channel Na_V1.2 elevates neuronal excitability in adult mice

Zhang

Chen

Eaton

et al. 2021

Preprint

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Scn2a encodes voltage-gated sodium channel NaV1.2, which mediates neuronal firing. The current paradigm suggests that NaV1.2 gain-of-function variants enhance neuronal excitability resulting in epilepsy, whereas NaV1.2 deficiency impairs neuronal excitability contributing to autism. In this paradigm, however, why about a third of patients with NaV1.2 deficiency still develop seizures remains a mystery. Here we challenge the conventional wisdom, reporting that neuronal excitability is increased with severe NaV1.2 deficiency. Using a unique gene-trap knockout mouse model of Scn2a, we found enhanced intrinsic excitabilities of principal neurons in the cortico-striatal circuit, known to be involved in Scn2a-related seizures. This increased excitability is autonomous, and is reversible by genetic restoration of Scn2a expression in adult mice. Mechanistic investigation reveals a compensatory downregulation of potassium channels including KV1.1, which could be targeted to alleviate neuronal hyperexcitability. Our unexpected findings may explain NaV1.2 deficiency-related epileptic seizures in humans and provide molecular targets for potential interventions.

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Differential Control of Axonal and Somatic Resting Potential by Voltage-Dependent Conductances in Cortical Layer 5 Pyramidal Neurons

Cited by 36 publications

References 0 publications

Axonal mechanisms mediating γ-aminobutyric acid receptor type A (GABA-A) inhibition of striatal dopamine release

Axonal mechanisms mediating γ-aminobutyric acid receptor type A (GABA-A) inhibition of striatal dopamine release

An axon-specific expression of HCN channels catalyzes fast action potential signaling in GABAergic interneurons

Severe deficiency of voltage-gated sodium channel Na_V1.2 elevates neuronal excitability in adult mice

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Differential Control of Axonal and Somatic Resting Potential by Voltage-Dependent Conductances in Cortical Layer 5 Pyramidal Neurons

Cited by 36 publications

References 0 publications

Axonal mechanisms mediating γ-aminobutyric acid receptor type A (GABA-A) inhibition of striatal dopamine release

Axonal mechanisms mediating γ-aminobutyric acid receptor type A (GABA-A) inhibition of striatal dopamine release

An axon-specific expression of HCN channels catalyzes fast action potential signaling in GABAergic interneurons

Severe deficiency of voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice

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Severe deficiency of voltage-gated sodium channel Na_V1.2 elevates neuronal excitability in adult mice