scholarly journals Optogenetically Controlled Activity Pattern Determines Survival Rate of Developing Neocortical Neurons

2021 ◽  
Vol 22 (12) ◽  
pp. 6575
Author(s):  
I. Emeline Wong Fong Sang ◽  
Jonas Schroer ◽  
Lisa Halbhuber ◽  
Davide Warm ◽  
Jenq-Wei Yang ◽  
...  
Keyword(s):  
Cell Death ◽  
Action Potential ◽  
Cortical Neurons ◽  
Firing Pattern ◽  
Neuronal Survival ◽  
Temporal Structure ◽  
Burst Stimulation ◽  
Action Potential Firing ◽  
Death Rates ◽  
Potential Firing

A substantial proportion of neurons undergoes programmed cell death (apoptosis) during early development. This process is attenuated by increased levels of neuronal activity and enhanced by suppression of activity. To uncover whether the mere level of activity or also the temporal structure of electrical activity affects neuronal death rates, we optogenetically controlled spontaneous activity of synaptically-isolated neurons in developing cortical cultures. Our results demonstrate that action potential firing of primary cortical neurons promotes neuronal survival throughout development. Chronic patterned optogenetic stimulation allowed to effectively modulate the firing pattern of single neurons in the absence of synaptic inputs while maintaining stable overall activity levels. Replacing the burst firing pattern with a non-physiological, single pulse pattern significantly increased cell death rates as compared to physiological burst stimulation. Furthermore, physiological burst stimulation led to an elevated peak in intracellular calcium and an increase in the expression level of classical activity-dependent targets but also decreased Bax/BCL-2 expression ratio and reduced caspase 3/7 activity. In summary, these results demonstrate at the single-cell level that the temporal pattern of action potentials is critical for neuronal survival versus cell death fate during cortical development, besides the pro-survival effect of action potential firing per se.

scholarly journals Hyperexcitability precedes motoneuron loss in the Smn2B/− mouse model of spinal muscular atrophy

2019 ◽  
Vol 122 (4) ◽  
pp. 1297-1311 ◽  
Author(s):  
K. A. Quinlan ◽  
E. J. Reedich ◽  
W. D. Arnold ◽  
A. C. Puritz ◽  
C. F. Cavarsan ◽  
...  
Keyword(s):  
Cell Death ◽  
Mouse Model ◽  
Action Potential ◽  
Spinal Muscular Atrophy ◽  
Postnatal Development ◽  
Motor Unit ◽  
Muscular Atrophy ◽  
Action Potential Firing ◽  
Motor Unit Number Estimation ◽  
Potential Firing

Spinal motoneuron dysfunction and loss are pathological hallmarks of the neuromuscular disease spinal muscular atrophy (SMA). Changes in motoneuron physiological function precede cell death, but how these alterations vary with disease severity and motoneuron maturational state is unknown. To address this question, we assessed the electrophysiology and morphology of spinal motoneurons of presymptomatic Smn2B/− mice older than 1 wk of age and tracked the timing of motor unit loss in this model using motor unit number estimation (MUNE). In contrast to other commonly used SMA mouse models, Smn2B/− mice exhibit more typical postnatal development until postnatal day (P)11 or 12 and have longer survival (~3 wk of age). We demonstrate that Smn2B/− motoneuron hyperexcitability, marked by hyperpolarization of the threshold voltage for action potential firing, was present at P9–10 and preceded the loss of motor units. Using MUNE studies, we determined that motor unit loss in this mouse model occurred 2 wk after birth. Smn2B/− motoneurons were also larger in size, which may reflect compensatory changes taking place during postnatal development. This work suggests that motoneuron hyperexcitability, marked by a reduced threshold for action potential firing, is a pathological change preceding motoneuron loss that is common to multiple models of severe SMA with different motoneuron maturational states. Our results indicate voltage-gated sodium channel activity may be altered in the disease process. NEW & NOTEWORTHY Changes in spinal motoneuron physiologic function precede cell death in spinal muscular atrophy (SMA), but how they vary with maturational state and disease severity remains unknown. This study characterized motoneuron and neuromuscular electrophysiology from the Smn2B/− model of SMA. Motoneurons were hyperexcitable at postnatal day (P)9–10, and specific electrophysiological changes in Smn2B/− motoneurons preceded functional motor unit loss at P14, as determined by motor unit number estimation studies.

Sensory renal innervation: a kidney-specific firing activity due to a unique expression pattern of voltage-gated sodium channels?

2013 ◽  
Vol 304 (5) ◽  
pp. F491-F497 ◽  
Author(s):  
Wolfgang Freisinger ◽  
Johannes Schatz ◽  
Tilmann Ditting ◽  
Angelika Lampert ◽  
Sonja Heinlein ◽  
...  
Keyword(s):  
Action Potential ◽  
Sodium Channels ◽  
Sensory Neurons ◽  
Firing Pattern ◽  
Drg Neurons ◽  
Action Potential Firing ◽  
Tonic Firing ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Potential Firing

Sensory neurons with afferent axons from the kidney are extraordinary in their response to electrical stimulation. More than 50% exhibit a tonic firing pattern, i.e., sustained action potential firing throughout depolarizing, pointing to an increased excitability, whereas nonrenal neurons show mainly a phasic response, i.e., less than five action potentials. Here we investigated whether these peculiar firing characteristics of renal afferent neurons are due to differences in the expression of voltage-gated sodium channels (Navs). Dorsal root ganglion (DRG) neurons from rats (Th11-L2) were recorded by the current-clamp technique and distinguished as “tonic” or “phasic.” In voltage-clamp recordings, Navs were characterized by their tetrodotoxoxin (TTX) sensitivity, and their molecular identity was revealed by RT-PCR. The firing pattern of 66 DRG neurons (41 renal and 25 nonrenal) was investigated. Renal neurons exhibited more often a tonic firing pattern (56.1 vs. 12%). Tonic neurons showed a more positive threshold (−21.75 ± 1.43 vs.−29.33 ± 1.63 mV; P < 0.05), a higher overshoot (56.74 [53.6–60.96] vs. 46.79 mV [38.63–54.75]; P < 0.05) and longer action potential duration (4.61 [4.15–5.85] vs. 3.35 ms [2.12–5.67]; P < 0.05). These findings point to an increased presence of the TTX-resistant Navs 1.8 and 1.9. Furthermore, tonic neurons exhibited a relatively higher portion of TTX-resistant sodium currents. Interestingly, mRNA expression of TTX-resistant sodium channels was significantly increased in renal, predominantly tonic, DRG neurons. Hence, under physiological conditions, renal sensory neurons exhibit predominantly a firing pattern associated with higher excitability. Our findings support that this is due to an increased expression and activation of TTX-resistant Navs.

scholarly journals Zinc Enhances the Inhibitory Effects of Strychnine-Sensitive Glycine Receptors in Mouse Hippocampal Neurons

2007 ◽  
Vol 98 (6) ◽  
pp. 3666-3676 ◽  
Author(s):  
Hai Xia Zhang ◽  
Liu Lin Thio
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Hippocampal Slices ◽  
Glycine Receptors ◽  
Inhibitory Effects ◽  
Action Potential Firing ◽  
Embryonic Mouse ◽  
Potential Firing

Although extracellular Zn2+ is an endogenous biphasic modulator of strychnine-sensitive glycine receptors (GlyRs), the physiological significance of this modulation remains poorly understood. Zn2+ modulation of GlyR may be especially important in the hippocampus where presynaptic Zn2+ is abundant. Using cultured embryonic mouse hippocampal neurons, we examined whether 1 μM Zn2+, a potentiating concentration, enhances the inhibitory effects of GlyRs activated by sustained glycine applications. Sustained 20 μM glycine (EC25) applications alone did not decrease the number of action potentials evoked by depolarizing steps, but they did in 1 μM Zn2+. At least part of this effect resulted from Zn2+ enhancing the GlyR-induced decrease in input resistance. Sustained 20 μM glycine applications alone did not alter neuronal bursting, a form of hyperexcitability induced by omitting extracellular Mg2+. However, sustained 20 μM glycine applications depressed neuronal bursting in 1 μM Zn2+. Zn2+ did not enhance the inhibitory effects of sustained 60 μM glycine (EC70) applications in these paradigms. These results suggest that tonic GlyR activation could decrease neuronal excitability. To test this possibility, we examined the effect of the GlyR antagonist strychnine and the Zn2+ chelator tricine on action potential firing by CA1 pyramidal neurons in mouse hippocampal slices. Co-applying strychnine and tricine slightly but significantly increased the number of action potentials fired during a depolarizing current step and decreased the rheobase for action potential firing. Thus Zn2+ may modulate neuronal excitability normally and in pathological conditions such as seizures by potentiating GlyRs tonically activated by low agonist concentrations.

scholarly journals The thalamic low-threshold Ca 2+ potential: a key determinant of the local and global dynamics of the slow (<1 Hz) sleep oscillation in thalamocortical networks

2011 ◽  
Vol 369 (1952) ◽  
pp. 3820-3839 ◽  
Author(s):  
Vincenzo Crunelli ◽  
Adam C. Errington ◽  
Stuart W. Hughes ◽  
Tibor I. Tóth
Keyword(s):  
Action Potential ◽  
Slow Oscillation ◽  
Global Dynamics ◽  
Action Potential Firing ◽  
Local And Global Dynamics ◽  
Up States ◽  
Potential Firing ◽  
Low Threshold

During non-rapid eye movement sleep and certain types of anaesthesia, neurons in the neocortex and thalamus exhibit a distinctive slow (<1 Hz) oscillation that consists of alternating UP and DOWN membrane potential states and which correlates with a pronounced slow (<1 Hz) rhythm in the electroencephalogram. While several studies have claimed that the slow oscillation is generated exclusively in neocortical networks and then transmitted to other brain areas, substantial evidence exists to suggest that the full expression of the slow oscillation in an intact thalamocortical (TC) network requires the balanced interaction of oscillator systems in both the neocortex and thalamus. Within such a scenario, we have previously argued that the powerful low-threshold Ca 2+ potential (LTCP)-mediated burst of action potentials that initiates the UP states in individual TC neurons may be a vital signal for instigating UP states in related cortical areas. To investigate these issues we constructed a computational model of the TC network which encompasses the important known aspects of the slow oscillation that have been garnered from earlier in vivo and in vitro experiments. Using this model we confirm that the overall expression of the slow oscillation is intricately reliant on intact connections between the thalamus and the cortex. In particular, we demonstrate that UP state-related LTCP-mediated bursts in TC neurons are proficient in triggering synchronous UP states in cortical networks, thereby bringing about a synchronous slow oscillation in the whole network. The importance of LTCP-mediated action potential bursts in the slow oscillation is also underlined by the observation that their associated dendritic Ca 2+ signals are the only ones that inform corticothalamic synapses of the TC neuron output, since they, but not those elicited by tonic action potential firing, reach the distal dendritic sites where these synapses are located.

scholarly journals pigkMutation underliesmachobehavior and affects Rohon-Beard cell excitability

2015 ◽  
Vol 114 (2) ◽  
pp. 1146-1157 ◽  
Author(s):  
V. Carmean ◽  
M. A. Yonkers ◽  
M. B. Tellez ◽  
J. R. Willer ◽  
G. B. Willer ◽  
...  
Keyword(s):  
Action Potential ◽  
Sensory Neurons ◽  
Sodium Current ◽  
Genetic Defect ◽  
Sensory Cells ◽  
Loss Of Function ◽  
Wild Type ◽  
Action Potential Firing ◽  
Potential Firing ◽  
Touch Response

The study of touch-evoked behavior allows investigation of both the cells and circuits that generate a response to tactile stimulation. We investigate a touch-insensitive zebrafish mutant, macho (maco), previously shown to have reduced sodium current amplitude and lack of action potential firing in sensory neurons. In the genomes of mutant but not wild-type embryos, we identify a mutation in the pigk gene. The encoded protein, PigK, functions in attachment of glycophosphatidylinositol anchors to precursor proteins. In wild-type embryos, pigk mRNA is present at times when mutant embryos display behavioral phenotypes. Consistent with the predicted loss of function induced by the mutation, knock-down of PigK phenocopies maco touch insensitivity and leads to reduced sodium current (INa) amplitudes in sensory neurons. We further test whether the genetic defect in pigk underlies the maco phenotype by overexpressing wild-type pigk in mutant embryos. We find that ubiquitous expression of wild-type pigk rescues the touch response in maco mutants. In addition, for maco mutants, expression of wild-type pigk restricted to sensory neurons rescues sodium current amplitudes and action potential firing in sensory neurons. However, expression of wild-type pigk limited to sensory cells of mutant embryos does not allow rescue of the behavioral touch response. Our results demonstrate an essential role for pigk in generation of the touch response beyond that required for maintenance of proper INa density and action potential firing in sensory neurons.

scholarly journals The input-output relation of primary nociceptive neurons is determined by the morphology of the peripheral nociceptive terminals

2020 ◽  
Author(s):  
Omer Barkai ◽  
Rachely Butterman ◽  
Ben Katz ◽  
Shaya Lev ◽  
Alexander M. Binshtok
Keyword(s):  
Action Potential ◽  
Input Output ◽  
Pain Sensation ◽  
Action Potential Firing ◽  
Nociceptive Neurons ◽  
Pathological Conditions ◽  
Potential Firing ◽  
Noxious Stimuli ◽  
The Individual ◽  
Neuronal Output

AbstractThe output from the peripheral terminals of primary nociceptive neurons, which detect and encode the information regarding noxious stimuli, is crucial in determining pain sensation. The nociceptive terminal endings are morphologically complex structures assembled from multiple branches of different geometry, which converge in a variety of forms to create the terminal tree. The output of a single terminal is defined by the properties of the transducer channels producing the generation potentials and voltage-gated channels, translating the generation potentials into action potential firing. However, in the majority of cases, noxious stimuli activate multiple terminals; thus, the output of the nociceptive neuron is defined by the integration and computation of the inputs of the individual terminals. Here we used a computational model of nociceptive terminal tree to study how the architecture of the terminal tree affects input-output relation of the primary nociceptive neurons. We show that the input-output properties of the nociceptive neurons depend on the length, the axial resistance, and location of individual terminals. Moreover, we show that activation of multiple terminals by capsaicin-like current allows summation of the responses from individual terminals, thus leading to increased nociceptive output. Stimulation of terminals in simulated models of inflammatory or nociceptive hyperexcitability led to a change in the temporal pattern of action potential firing, emphasizing the role of temporal code in conveying key information about changes in nociceptive output in pathological conditions, leading to pain hypersensitivity.Significance statementNoxious stimuli are detected by terminal endings of the primary nociceptive neurons, which are organized into morphologically complex terminal trees. The information from multiple terminals is integrated along the terminal tree, computing the neuronal output, which propagates towards the CNS, thus shaping the pain sensation. Here we revealed that the structure of the nociceptive terminal tree determines the output of the nociceptive neurons. We show that the integration of noxious information depends on the morphology of the terminal trees and how this integration and, consequently, the neuronal output change under pathological conditions. Our findings help to predict how nociceptive neurons encode noxious stimuli and how this encoding changes in pathological conditions, leading to pain.

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