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

Martinello, Katiuscia; Giacalone, E.; Migliore, Michele; Brown, David A.; Shah, Maulik

doi:10.1038/s42003-019-0408-4

Cited by 20 publications

(29 citation statements)

References 78 publications

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“…The apparent resting membrane potential of the recorded MF axon was −75.2 mV, close to the resting membrane potential previously reported for the somata and axons of granule cells (~ −80 mV (Brunner & Szabadics, 2016; Martinello, Giacalone, Migliore, Brown, & Shah, 2019; Ruiz, Campanac, Scott, Rusakov, & Kullmann, 2010; Schmidt-Hieber, Jonas, & Bischofberger, 2004; Staley, Otis, & Mody, 1992)). This moderate shift, caused by the leak through the seal, suggests orders of magnitude larger R seal compared to the axonal input resistance.…”

Section: Methodssupporting

confidence: 87%

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Small size of recorded neuronal structures confines the accuracy in direct axonal voltage measurements

aacuteh

Tarcsay

Brunner

2021

Preprint

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Patch-clamp instruments including amplifier circuits and pipettes affect the recorded voltage signals. We hypothesized that realistic and complete in silico representation of recording instruments together with detailed morphology and biophysics of small recorded structures will precisely reveal signal distortions and provides a tool that predicts native signals from distorted voltage recordings. Therefore, we built a model that was verified by small axonal recordings. The model accurately recreated actual action potential measurements with typical recording artefacts and predicted the native electrical behavior. The simulations verified that recording instruments substantially filter voltage recordings. Moreover, we revealed that instrumentation directly interferes with local signal generation depending on the size of the recorded structures, which complicates the interpretation of recordings from smaller structures, such as axons. However, our model offers a straightforward approach that predicts the native waveforms of fast voltage signals and the underlying conductances even from the smallest neuronal structures.

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Section: Methodssupporting

confidence: 87%

“…The actual APs were weighted eight-fold, starting 0.5 ms before the peak. The optimization ended 1.5 ms following the AP peak to avoid the contamination of the parameter estimation with afterdepolarization related mechanisms not implicated in the model (Martinello et al, 2019; Ohura & Kamiya, 2018).…”

Section: Methodsmentioning

confidence: 99%

Small size of recorded neuronal structures confines the accuracy in direct axonal voltage measurements

aacuteh

Tarcsay

Brunner

2021

Preprint

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“…Furthermore, K v 7 inhibition with linopirdine and XE991 treatment also increases neurotransmitter release ( Nickolson et al, 1990 ; Martire et al, 2004 ; Peretz et al, 2007 ). While K v 7 current restrains AP-evoked Ca 2+ influx into the presynaptic terminal and decreases the paired pulse ratio of evoked EPSCs at the mossy fiber–CA3 synapses ( Martinello et al, 2019 ), paired pulse facilitation of EPSP is higher at CA1–CA3 synapses in XE991-treated mice ( Fontan-Lozano et al, 2011 ), suggesting differential roles of K v 7 channels in short-term plasticity at two different synapses.…”

Section: Role Of K V 7 Channels In Synaptic Transmmentioning

confidence: 99%

The Role of Kv7 Channels in Neural Plasticity and Behavior

2020

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Activity-dependent persistent changes in neuronal intrinsic excitability and synaptic strength are widely thought to underlie learning and memory. Voltage-gated KCNQ/K v 7 potassium channels have been of great interest as the potential targets for memory disorders due to the beneficial effects of their antagonists in cognition. Importantly, de novo dominant mutations in their neuronal subunits KCNQ2/K v 7.2 and KCNQ3/K v 7.3 are associated with epilepsy and neurodevelopmental disorder characterized by developmental delay and intellectual disability. The role of K v 7 channels in neuronal excitability and epilepsy has been extensively studied. However, their functional significance in neural plasticity, learning, and memory remains largely unknown. Here, we review recent studies that support the emerging roles of K v 7 channels in intrinsic and synaptic plasticity, and their contributions to cognition and behavior.

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“…These subunits are abundant at axon initial segment (AIS), nodes of Ranvier, coclustered with Nav channels, and synaptic terminals. There are less expressed at the soma but they are absent in dendrites of cortical pyramidal cells while in cortical interneurons these channels are detected in these subcellular regions ( Devaux et al 2004;Lawrence et al , 2006;Battefeld et al, 2014;Huang and Trussell , 2011;Martinello et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Time-limited alterations in cortical activity of a Knock-in mice model ofKCNQ2-related Developmental and Epileptic Encephalopathy

Biba

Kurz

Villard

et al. 2020

Preprint

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De novo variants in the KCNQ2 gene encoding the Kv7.2 subunit of the voltage-gated potassium Kv7/M channel are the main cause of Early Onset Epileptic Encephalopathy (EOEE) with suppression burst suggesting that this channel plays an important role for proper brain development. Functional analysis of these variants in heterologous cells has shown that most of them are loss of function leading to a reduction of M current. However the cellular mechanism of the neuronal network dysfunctionning is still not known. Here we characterized the electrophysiological properties of developing pyramidal cells of the layer II/III and V and analyzed spontaneous synaptic activity in these layers in motor cortical slices obtained from a recently generated heterozygous knock-in mouse harboring the loss-of-function pathogenic p.T274M variant. Experiments were performed on animals aged one week, three weeks and four-five weeks, and the results were compared with those of pyramidal cells recorded in slices from wild-type mice untreated or treated with the Kv7 channel blocker XE-991. We showed that the variant led to a hyperexcitability of pyramidal cells of layer II/III in cortical slices from animal aged 1 week and 3 weeks and to a level that was similar to the effect of XE-911. In layer V the impact of the variant was observed in slices from animal aged 3 weeks but not earlier and to a level that was lower to the effect of XE-991. However, in cortical slices from animal aged 4-5 weeks electrophysiological properties of pyramidal cells of layers II/III and V were no more affected by the variant but still sensitive to XE-991. The recovery of the electrophysiological responses in knock-in animals was associated with a slight but significant distal shift of the axonal initial segment (AIS) from the soma of pyramidal cells of layer II/III and V. Recordings of spontaneous synaptic activity in these layers revealed the presence of recurrent GABAergic network activities (RGNA) that were mainly observed during the three first postnatal weeks of life and which occurrence and frequency were increased in pyramidal cells of the layer II/III but not of the layer V of the knock-in mouse. There were no significant differences in synaptic activities mediated by GABA and glutamate receptors in cortical slices from animal aged 4-5 weeks. Together our data provided evidences that the heterozygous p.T274M variant impacts the activity of pyramidal cells and probably of Gabaergic interneurons during a limited period of development. Our data also indicated that neurons of the layer II/III are more sensitive to the variant than those located in the layer V in terms of age of onset, neuronal firing and spontaneous synaptic activities. Moreover our data suggest that a compensatory mechanism might take place in the knock-in mice aged 4-5 weeks allowing the recovery of control activity at cellular and network levels and which is associated with a slight displacement of the AIS. Thus, the effect of the variant on neuronal activity is developmentally regulated a...

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

Cited by 20 publications

References 78 publications

Small size of recorded neuronal structures confines the accuracy in direct axonal voltage measurements

Small size of recorded neuronal structures confines the accuracy in direct axonal voltage measurements

The Role of Kv7 Channels in Neural Plasticity and Behavior

Time-limited alterations in cortical activity of a Knock-in mice model ofKCNQ2-related Developmental and Epileptic Encephalopathy

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