Dynamic Regulation of Calcium Influx by G-Proteins, Action Potential Waveform, and Neuronal Firing Frequency

Homeostatic signaling stabilizes synaptic transmission at the neuromuscular junction (NMJ) of Drosophila, mice, and human. It is believed that homeostatic signaling at the NMJ is bi-directional and considerable progress has been made identifying mechanisms underlying the homeostatic potentiation of neurotransmitter release. However, very little is understood mechanistically about the opposing process, homeostatic depression, and how bi-directional plasticity is achieved. Here, we show that homeostatic potentiation and depression can be simultaneously induced, demonstrating true bi-directional plasticity. Next, we show that mutations that block homeostatic potentiation do not alter homeostatic depression, demonstrating that these are genetically separable processes. Finally, we show that homeostatic depression is achieved by decreased presynaptic calcium channel abundance and calcium influx, changes that are independent of the presynaptic action potential waveform. Thus, we identify a novel mechanism of homeostatic synaptic plasticity and propose a model that can account for the observed bi-directional, homeostatic control of presynaptic neurotransmitter release.

Download Full-text

A computational model for how the fast afterhyperpolarization paradoxically increases gain in regularly firing neurons

Journal of Neurophysiology ◽

10.1152/jn.00385.2017 ◽

2018 ◽

Vol 119 (4) ◽

pp. 1506-1520 ◽

Cited By ~ 5

Author(s):

David B. Jaffe ◽

Robert Brenner

Keyword(s):

Action Potential ◽

Computational Model ◽

Interspike Interval ◽

Computational Study ◽

Stimulus Frequency ◽

Bk Channels ◽

Neuronal Firing ◽

Inward Current ◽

Action Potential Waveform ◽

Potential Waveform

The gain of a neuron, the number and frequency of action potentials triggered in response to a given amount of depolarizing injection, is an important behavior underlying a neuron’s function. Variations in action potential waveform can influence neuronal discharges by the differential activation of voltage- and ion-gated channels long after the end of a spike. One component of the action potential waveform, the afterhyperpolarization (AHP), is generally considered an inhibitory mechanism for limiting firing rates. In dentate gyrus granule cells (DGCs) expressing fast-gated BK channels, large fast AHPs (fAHP) are paradoxically associated with increased gain. In this article, we describe a mechanism for this behavior using a computational model. Hyperpolarization provided by the fAHP enhances activation of a dendritic inward current (a T-type Ca2+ channel is suggested) that, in turn, boosts rebound depolarization at the soma. The model suggests that the fAHP may both reduce Ca2+ channel inactivation and, counterintuitively, enhance its activation. The magnitude of the rebound depolarization, in turn, determines the activation of a subsequent, slower inward current (a persistent Na+ current is suggested) limiting the interspike interval. Simulations also show that the effect of AHP on gain is also effective for physiologically relevant stimulation; varying AHP amplitude affects interspike interval across a range of “noisy” stimulus frequency and amplitudes. The mechanism proposed suggests that small fAHPs in DGCs may contribute to their limited excitability. NEW & NOTEWORTHY The afterhyperpolarization (AHP) is canonically viewed as a major factor underlying the refractory period, serving to limit neuronal firing rate. We recently reported that enhancing the amplitude of the fast AHP (fAHP) in a relatively slowly firing neuron (vs. fast spiking neurons) expressing fast-gated BK channels augments neuronal excitability. In this computational study, we present a novel, quantitative hypothesis for how varying the amplitude of the fAHP can, paradoxically, influence a subsequent spike tens of milliseconds later.

Download Full-text

Neuronal firing and waveform alterations through ictal recruitment in humans

10.1101/2020.01.11.902817 ◽

2020 ◽

Author(s):

Edward M. Merricks ◽

Elliot H. Smith ◽

Ronald G. Emerson ◽

Lisa M. Bateman ◽

Guy M. McKhann ◽

...

Keyword(s):

Action Potential ◽

Template Matching ◽

Animal Studies ◽

Microelectrode Array ◽

Focal Epilepsy ◽

Neuronal Firing ◽

Single Neurons ◽

Action Potential Waveform ◽

Concentration Changes ◽

Potential Waveform

AbstractClinical analyses of neuronal activity during seizures, invariably using extracellular recordings, is greatly hindered by various phenomena that are well established in animal studies: changes in local ionic concentration, changes in ionic conductance, and intense, hypersynchronous firing. The first two alter the action potential waveform, whereas the third increases the “noise”; all three factors confound attempts to detect and classify single neurons (units). To address these analytical difficulties, we developed a novel template-matching based spike sorting method, which enabled identification of 1,239 single units in 27 patients with intractable focal epilepsy, that were tracked throughout multiple seizures. These new analyses showed continued neuronal firing through the ictal transition, which was defined as a transient period of intense tonic firing consistent with previous descriptions of the ictal wavefront. After the ictal transition, neurons displayed increased spike duration (p < 0.001) and reduced spike amplitude (p < 0.001), in keeping with prior animal studies; units in non-recruited territories, by contrast, showed more stable waveforms. All units returned to their pre-ictal waveforms after seizure termination. Waveshape changes were stereotyped across seizures within patients. Our analyses of single neuron firing patterns, at the ictal wavefront, showed widespread intense activation, and commonly involving marked waveshape alteration. We conclude that the distinction between tissue that has been recruited to the seizure versus non-recruited territories is evident at the level of single neurons, and that increased waveform duration and decreased waveform amplitude are hallmarks of seizure invasion that could be used as defining characteristics of local recruitment.Significance StatementAnimal studies consistently show marked changes in action potential waveform during epileptic discharges, but acquiring similar evidence in humans has proved difficult. Assessing neuronal involvement in ictal events is pivotal to understanding seizure dynamics and in defining clinical localization of epileptic pathology. Using a novel method to track neuronal firing, we analyzed microelectrode array recordings of spontaneously occurring human seizures, and here report two dichotomous activity patterns. In cortex that is recruited to the seizure, neuronal firing rates increase and waveforms become longer in duration and shorter in amplitude, while penumbral tissue shows stable action potentials, in keeping with the “dual territory” model of seizure dynamics.

Download Full-text

KCNQ channels enable reliable presynaptic spiking and synaptic transmission at high-frequency

10.1101/2019.12.26.888875 ◽

2019 ◽

Author(s):

Yihui Zhang ◽

Dainan Li ◽

Youad Darwish ◽

Laurence O. Trussell ◽

Hai Huang

Keyword(s):

Action Potential ◽

Synaptic Transmission ◽

High Frequency ◽

Calcium Influx ◽

List Type ◽

Kcnq Channels ◽

Axon Terminals ◽

Presynaptic Action ◽

Action Potential Waveform ◽

Potential Waveform

SUMMARYThe presynaptic action potential (AP) results in calcium influx which triggers neurotransmitter release. For this reason, the AP waveform is crucial in determining the timing and strength of synaptic transmission. The calyx of Held nerve terminals of rat show minimum changes in AP waveform during high-frequency AP firing. We found that the stability of the calyceal AP waveform requires KCNQ K+ channel activated during high-frequency spiking activity. High-frequency presynaptic spikes gradually led to accumulation of KCNQ channels in open states which kept interspike membrane potential sufficiently negative to maintain Na+ channel availability. Accordingly, blocking KCNQ channels during stimulus trains led to inactivation of presynaptic Na+, and to a lesser extent KV1 channels, thereby reducing the AP height and broadening AP duration. Thus, while KCNQ channels are generally thought to prevent hyperactivity of neurons, we find that in axon terminals these channels function to facilitate high-frequency firing needed for sensory coding.HIGHLIGHTSKCNQ channels are activated during high-frequency firingThe activity of KCNQ channels helps the recovery of Na+ and KV1 channels from inactivation and maintains action potential waveformReliable presynaptic action potential waveform preserves stable Ca2+ influx and reliable synaptic signaling

Download Full-text

Increased excitability and altered action potential waveform in cerebellar granule neurons of the Ts65Dn mouse model of Down syndrome

Brain Research ◽

10.1016/j.brainres.2012.05.027 ◽

2012 ◽

Vol 1465 ◽

pp. 10-17 ◽

Cited By ~ 8

Author(s):

Maria M. Usowicz ◽

Claire L.P. Garden

Keyword(s):

Down Syndrome ◽

Mouse Model ◽

Action Potential ◽

Cerebellar Granule Neurons ◽

Granule Neurons ◽

Ts65dn Mouse ◽

Cerebellar Granule ◽

Action Potential Waveform ◽

Potential Waveform

Download Full-text

Action Potential Waveform Variability Limits Multi-Unit Separation in Freely Behaving Rats

PLoS ONE ◽

10.1371/journal.pone.0038482 ◽

2012 ◽

Vol 7 (6) ◽

pp. e38482 ◽

Cited By ~ 19

Author(s):

Peter Stratton ◽

Allen Cheung ◽

Janet Wiles ◽

Eugene Kiyatkin ◽

Pankaj Sah ◽

...

Keyword(s):

Action Potential ◽

Action Potential Waveform ◽

Freely Behaving ◽

Potential Waveform

Download Full-text

Altered action potential waveform and shorter axonal initial segment in hiPSC-derived motor neurons with mutations in VRK1

Neurobiology of Disease ◽

10.1016/j.nbd.2021.105609 ◽

2022 ◽

pp. 105609

Author(s):

Rémi Bos ◽

Khalil Rihan ◽

Patrice Quintana ◽

Lara El-Bazzal ◽

Nathalie Bernard-Marissal ◽

...

Keyword(s):

Action Potential ◽

Motor Neurons ◽

Initial Segment ◽

Axonal Initial Segment ◽

Action Potential Waveform ◽

Potential Waveform

Download Full-text

Preterm Birth Impedes Structural and Functional Development of Cerebellar Purkinje Cells in the Developing Baboon Cerebellum

Brain Sciences ◽

10.3390/brainsci10120897 ◽

2020 ◽

Vol 10 (12) ◽

pp. 897

Author(s):

Tara Barron ◽

Jun Hee Kim

Keyword(s):

Preterm Birth ◽

Action Potential ◽

Purkinje Cell ◽

Purkinje Cells ◽

Late Gestation ◽

Cerebellar Development ◽

Layer Width ◽

Action Potential Waveform ◽

Developmental Features ◽

Potential Waveform

Human cerebellar development occurs late in gestation and is hindered by preterm birth. The fetal development of Purkinje cells, the primary output cells of the cerebellar cortex, is crucial for the structure and function of the cerebellum. However, morphological and electrophysiological features in Purkinje cells at different gestational ages, and the effects of neonatal intensive care unit (NICU) experience on cerebellar development are unexplored. Utilizing the non-human primate baboon cerebellum, we investigated Purkinje cell development during the last trimester of pregnancy and the effect of NICU experience following premature birth on developmental features of Purkinje cells. Immunostaining and whole-cell patch clamp recordings of Purkinje cells in the baboon cerebellum at different gestational ages revealed that molecular layer width, driven by Purkinje dendrite extension, drastically increased and refinement of action potential waveform properties occurred throughout the last trimester of pregnancy. Preterm birth followed by NICU experience for 2 weeks impeded development of Purkinje cells, including action potential waveform properties, synaptic input, and dendrite extension compared with age-matched controls. In addition, these alterations impact Purkinje cell output, reducing the spontaneous firing frequency in deep cerebellar nucleus (DCN) neurons. Taken together, the primate cerebellum undergoes developmental refinements during late gestation, and NICU experience following extreme preterm birth influences morphological and physiological features in the cerebellum that can lead to functional deficits.

Download Full-text

Effects of ACh and adenosine mediated by Kir3.1 and Kir3.4 on ferret ventricular cells

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00130.2002 ◽

2002 ◽

Vol 283 (2) ◽

pp. H615-H630 ◽

Cited By ~ 17

Author(s):

H. Dobrzynski ◽

N. C. Janvier ◽

R. Leach ◽

J. B. C. Findlay ◽

M. R. Boyett

Keyword(s):

Action Potential ◽

Outward Current ◽

Current Clamp ◽

Inotropic Effects ◽

Clamp Technique ◽

Action Potential Clamp ◽

Ventricular Cells ◽

Action Potential Waveform ◽

Potential Waveform ◽

Action Potential Shortening

The inotropic effects of ACh and adenosine on ferret ventricular cells were investigated with the action potential-clamp technique. Under current clamp, both agonists resulted in action potential shortening and a decrease in contraction. Under action potential clamp, both agonists failed to decrease contraction substantially. In the absence of agonist, application of the short action potential waveform (recorded previously in the presence of agonist) also resulted in a decrease in contraction. Under action potential clamp, application of ACh resulted in a Ba2+-sensitive outward current with the characteristics of muscarinic K+ current ( I K,ACh); the presence of the muscarinic K+ channel was confirmed by PCR and immunocytochemistry. In the absence of agonist, on application of the short ACh action potential waveform, the decrease in contraction was accompanied by loss of the inward Na+/Ca2+exchange current ( I NaCa). ACh also inhibited the background inward K+ current ( I K,1). It is concluded that ACh activates I K,ACh, inhibits I K,1, and indirectly inhibits I NaCa; this results in action potential shortening, decrease in contraction, and, as a result of the inhibition of I K,1, minimum decrease in excitability.

Download Full-text

Multiple potassium conductances and their role in action potential repolarization and repetitive firing behavior of neonatal rat hypoglossal motoneurons

Journal of Neurophysiology ◽

10.1152/jn.1993.69.6.2150 ◽

1993 ◽

Vol 69 (6) ◽

pp. 2150-2163 ◽

Cited By ~ 175

Author(s):

F. Viana ◽

D. A. Bayliss ◽

A. J. Berger

Keyword(s):

Action Potential ◽

Calcium Influx ◽

Potassium Conductance ◽

Firing Frequency ◽

Neonatal Rat ◽

Repetitive Firing ◽

Firing Behavior ◽

Hypoglossal Motoneurons ◽

Potassium Conductances ◽

Action Potential Repolarization

1. The role of multiple potassium conductances in action potential repolarization and repetitive firing behavior of hypoglossal motoneurons was investigated using intracellular recording techniques in a brain stem slice preparation of the neonatal rat (0-15 days old). 2. The action potential was followed by two distinct afterhyperpolarizations (AHPs). The early one was of short duration and is termed the fAHP; the later AHP was of longer duration and is termed the mAHP. The amplitudes of both AHPs were enhanced by membrane potential depolarization (further from EK). In addition, their amplitudes were reduced by high extracellular K+ concentration, suggesting that activation of potassium conductances underlies both phases of the AHP. 3. Prolongation of the action potential and blockade of the fAHP were observed after application of 1) tetraethylammonium (TEA) (1-10 mM) and 2) 4-aminopyridine (4-AP) (0.1-0.5 mM). Calcium channel blockers had little or no effect on the fAHP or action potential duration. 4. The size of the mAHP was diminished by 1) manganese, 2) lowering external Ca2+, 3) apamin, and 4) intracellular injection of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) suggesting that influx of calcium activates the potassium conductance that underlies the mAHP. 5. The mAHP was unaffected by nifedipine (20 microM), but was strongly reduced by focal application of omega-conotoxin GVIA, suggesting that N-type calcium channels represent the major calcium influx pathway for activation of the calcium-dependent K+ conductance underlying the mAHP. 6. Repetitive firing properties were investigated by injecting long-duration depolarizing current pulses. Steady-state firing rose linearly with injected current amplitude. The slope of the firing frequency-current (f-I) relationship averaged approximately 30 Hz/nA in control conditions. Blockade of the conductance underlying the mAHP caused a marked increase in the minimal repetitive firing frequency and in the slope of the f-I plot, indicating a prominent role for the conductance underlying the mAHP in controlling repetitive firing behavior. 7. We conclude that action potential repolarization and AHPs are due to activation of pharmacologically distinct potassium conductances. Whereas repolarization of the action potential and the fAHP involves primarily a voltage-dependent, calcium-independent potassium conductance that is TEA- and 4-AP-sensitive, the mAHP requires the influx of extracellular calcium and is apamin sensitive. Activation of the calcium-activated potassium conductance greatly influences the normal repetitive firing of neonatal hypoglossal motoneurons.

Download Full-text