Mechanism of the medium‐duration afterhyperpolarization in rat serotonergic neurons

Alix, Philippe; Venkatesan, Kumar; Scuvée‐Moreau, Jacqueline; Massotte, Laurent; Trung, Mai-Linh Nguyen; Cornil, Charlotte; Seutin, Vincent

doi:10.1111/ejn.12408

Cited by 11 publications

(7 citation statements)

References 49 publications

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“…A key characteristic of 5-HT neurons is their long-duration action potential followed by a medium duration AHP (Beck et al, 2003; Kirby et al, 2003; Rouchet et al, 2008; Alix et al, 2014). Since AHP modulation is closely linked to the alterations in the firing activity of 5-HT neurons (Rouchet et al, 2008; Crespi, 2009), we sought to determine whether the observed reduction in their activity is due to a more pronounced AHP.…”

Section: Resultsmentioning

confidence: 99%

Chronic social isolation reduces 5-HT neuronal activity via upregulated SK3 calcium-activated potassium channels

Sargin

Oliver

Lambe

2016

eLife

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The activity of serotonin (5-HT) neurons is critical for mood regulation. In a mouse model of chronic social isolation, a known risk factor for depressive illness, we show that 5-HT neurons in the dorsal raphe nucleus are less responsive to stimulation. Probing the responsible cellular mechanisms pinpoints a disturbance in the expression and function of small-conductance Ca2+-activated K+ (SK) channels and reveals an important role for both SK2 and SK3 channels in normal regulation of 5-HT neuronal excitability. Chronic social isolation renders 5-HT neurons insensitive to SK2 blockade, however inhibition of the upregulated SK3 channels restores normal excitability. In vivo, we demonstrate that inhibiting SK channels normalizes chronic social isolation-induced anxiety/depressive-like behaviors. Our experiments reveal a causal link for the first time between SK channel dysregulation and 5-HT neuron activity in a lifelong stress paradigm, suggesting these channels as targets for the development of novel therapies for mood disorders.DOI: http://dx.doi.org/10.7554/eLife.21416.001

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Section: Resultsmentioning

confidence: 99%

Chronic social isolation reduces 5-HT neuronal activity via upregulated SK3 calcium-activated potassium channels

Sargin

Oliver

Lambe

2016

eLife

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“…After breakthrough, a brief series of voltage protocols were delivered to ascertain the presence of A-type K + currents and/or T-type Ca 2+ currents for LDT and PPT cholinergic neurons ( 30 – 32 ) and a strong medium AHP current for DR serotonergic neurons [see Ref. ( 33 )]. Voltage clamp mode was used to record orexin currents in order to assess their spectral characteristics.…”

Section: Methodsmentioning

confidence: 99%

Orexin Receptor Activation Generates Gamma Band Input to Cholinergic and Serotonergic Arousal System Neurons and Drives an Intrinsic Ca2+-Dependent Resonance in LDT and PPT Cholinergic Neurons

et al. 2015

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A hallmark of the waking state is a shift in EEG power to higher frequencies with epochs of synchronized intracortical gamma activity (30–60 Hz) – a process associated with high-level cognitive functions. The ascending arousal system, including cholinergic laterodorsal (LDT) and pedunculopontine (PPT) tegmental neurons and serotonergic dorsal raphe (DR) neurons, promotes this state. Recently, this system has been proposed as a gamma wave generator, in part, because some neurons produce high-threshold, Ca2+-dependent oscillations at gamma frequencies. However, it is not known whether arousal-related inputs to these neurons generate such oscillations, or whether such oscillations are ever transmitted to neuronal targets. Since key arousal input arises from hypothalamic orexin (hypocretin) neurons, we investigated whether the unusually noisy, depolarizing orexin current could provide significant gamma input to cholinergic and serotonergic neurons, and whether such input could drive Ca2+-dependent oscillations. Whole-cell recordings in brain slices were obtained from mice expressing Cre-induced fluorescence in cholinergic LDT and PPT, and serotonergic DR neurons. After first quantifying reporter expression accuracy in cholinergic and serotonergic neurons, we found that the orexin current produced significant high frequency, including gamma, input to both cholinergic and serotonergic neurons. Then, by using a dynamic clamp, we found that adding a noisy orexin conductance to cholinergic neurons induced a Ca2+-dependent resonance that peaked in the theta and alpha frequency range (4–14 Hz) and extended up to 100 Hz. We propose that this orexin current noise and the Ca2+ dependent resonance work synergistically to boost the encoding of high-frequency synaptic inputs into action potentials and to help ensure cholinergic neurons fire during EEG activation. This activity could reinforce thalamocortical states supporting arousal, REM sleep, and intracortical gamma.

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“…One important class of K + channels are the calcium-activated potassium channels (CAKC). CAKCs regulate membrane potential (Gui et al, 2012;Alix et al, 2014;Rohmann et al, 2015;Yang, 2016), cell volume regulation and renal K + excretion (Latorre et al, 2017;Sforna et al, 2018) among other cellular functions.…”

Section: Introductionmentioning

confidence: 99%

A Novel Calcium-Activated Potassium Channel Controls Membrane Potential and Intracellular pH in Trypanosoma cruzi

Barrera

Skorka

Boktor

et al. 2020

Front. Cell. Infect. Microbiol.

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Trypanosoma cruzi develops in environments where nutrient availability, osmolarity, ionic concentrations, and pH undergo significant changes. The ability to adapt and respond to such conditions determines the survival and successful transmission of T. cruzi. Ion channels play fundamental roles in controlling physiological parameters that ensure cell homeostasis by rapidly triggering compensatory mechanisms. Combining molecular, cellular and electrophysiological approaches we have identified and characterized the expression and function of a novel calcium-activated potassium channel (TcCAKC). This channel resides in the plasma membrane of all 3 life stages of T. cruzi and shares structural features with other potassium channels. We expressed TcCAKC in Xenopus laevis oocytes and established its biophysical properties by two-electrode voltage clamp. Oocytes expressing TcCAKC showed a significant increase in inward currents after addition of calcium ionophore ionomycin or thapsigargin. These responses were abolished by EGTA suggesting that TcCAKC activation is dependent of extracellular calcium. This activation causes an increase in current and a negative shift in reversal potential that is blocked by barium. As predicted, a single point mutation in the selectivity filter (Y313A) completely abolished the activity of the channels, confirming its potassium selective nature. We have generated knockout parasites deleting one or both alleles of TcCAKC. These parasite strains showed impaired growth, decreased production of trypomastigotes and slower intracellular replication, pointing to an important role of TcCAKC in regulating infectivity. To understand the cellular mechanisms underlying these phenotypic defects, we used fluorescent probes to evaluate intracellular membrane potential, pH, and intracellular calcium. Epimastigotes lacking the channel had significantly lower cytosolic calcium, hyperpolarization, changes in intracellular pH, and increased rate of proton extrusion. These results are in agreement with previous reports indicating that, in trypanosomatids, membrane potential and intracellular pH maintenance are linked. Our work shows TcCAKC is a novel potassium channel that contributes to homeostatic regulation of important physiological processes in T. cruzi and provides new avenues to explore the potential of ion channels as targets for drug development against protozoan parasites.

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Mechanism of the medium‐duration afterhyperpolarization in rat serotonergic neurons

Cited by 11 publications

References 49 publications

Chronic social isolation reduces 5-HT neuronal activity via upregulated SK3 calcium-activated potassium channels

Chronic social isolation reduces 5-HT neuronal activity via upregulated SK3 calcium-activated potassium channels

Orexin Receptor Activation Generates Gamma Band Input to Cholinergic and Serotonergic Arousal System Neurons and Drives an Intrinsic Ca2+-Dependent Resonance in LDT and PPT Cholinergic Neurons

A Novel Calcium-Activated Potassium Channel Controls Membrane Potential and Intracellular pH in Trypanosoma cruzi

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