Chronic High-Inspired CO2 Decreases Excitability of Mouse Hippocampal Neurons

2007 ◽  
Vol 97 (2) ◽  
pp. 1833-1838 ◽  
Author(s):  
Xiang Q. Gu ◽  
Amjad Kanaan ◽  
Hang Yao ◽  
Gabriel G. Haddad
Keyword(s):  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Input Resistance ◽  
Resting Membrane Potential ◽  
Channel Current ◽  
Conductance Curve ◽  
Recovery From Inactivation ◽  
Channel Expression ◽  
Steady State Inactivation ◽  
And Function

To examine the effect of chronically elevated CO2 on excitability and function of neurons, we exposed mice to 8 and 12% CO2 for 4 wk (starting at 2 days of age), and examined the properties of freshly dissociated hippocampal neurons obtained from slices. Chronic CO2-treated neurons (CC) had a similar input resistance ( Rm) and resting membrane potential ( Vm) as control (CON). Although treatment with 8% CO2 did not change the rheobase (64 ± 11 pA, n = 9 vs. 47 ± 12 pA, n = 8 for CC 8% vs. CON; means ± SE), 12% CO2 treatment increased it significantly (73 ± 8 pA, n = 9, P = 0.05). Furthermore, the 12% CO2 but not the 8% CO2 treatment decreased the Na+ channel current density (244 ± 36 pA/pF, n = 17, vs. 436 ± 56 pA/pF, n = 18, for CC vs. CON, P = 0.005). Recovery from inactivation was also lowered by 12% but not 8% CO2. Other gating properties of Na+ current, such as voltage-conductance curve, steady-state inactivation, and time constant for deactivation, were not modified by either treatment. Western blot analysis showed that the expression of Na+ channel types I–III was not changed by 8% CO2 treatment, but their expression was significantly decreased by 20–30% ( P = 0.03) by the 12% treatment. We conclude from these data and others that neuronal excitability and Na+ channel expression depend on the duration and level of CO2 exposure and maturational changes occur in early life regarding neuronal responsiveness to CO2.

scholarly journals Decreased neuronal excitability in hippocampal neurons of mice exposed to cyclic hypoxia

2001 ◽  
Vol 91 (3) ◽  
pp. 1245-1250 ◽  
Author(s):  
Xiang Q. Gu ◽  
Gabriel G. Haddad
Keyword(s):  
Membrane Potential ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Resting Membrane Potential ◽  
Ca1 Neurons ◽  
Recovery From Inactivation ◽  
Channel Expression ◽  
Steady State Inactivation ◽  
And Function

To study the physiological effects of chronic intermittent hypoxia on neuronal excitability and function in mice, we exposed animals to cyclic hypoxia for 8 h daily (12 cycles/h) for ∼4 wk, starting at 2–3 days of age, and examined the properties of freshly dissociated hippocampal neurons in vitro. Compared with control (Con) hippocampal CA1 neurons, exposed (Cyc) neurons showed action potentials (AP) with a smaller amplitude and a longer duration and a more depolarized resting membrane potential. They also have a lower rate of spontaneous firing of AP and a higher rheobase. Furthermore, there was downregulation of the Na+ current density in Cyc compared with Con neurons (356.09 ± 54.03 pA/pF in Cyc neurons vs. 508.48 ± 67.30 pA/pF in Con, P < 0.04). Na+ channel characteristics, including activation, steady-state inactivation, and recovery from inactivation, were similar in both groups. The deactivation rate, however, was much larger in Cyc than in Con (at −100 mV, time constant for deactivation = 0.37 ± 0.04 ms in Cyc neurons and 0.18 ± 0.01 ms in Con neurons). We conclude that the decreased neuronal excitability in mice neurons treated with cyclic hypoxia is due, at least in part, to differences in passive properties (e.g., resting membrane potential) and in Na+ channel expression and/or regulation. We hypothesize that this decreased excitability is an adaptive response that attempts to decrease the energy expenditure that is used for adjusting disturbances in ionic homeostasis in low-O2conditions.

Maturation of neuronal excitability in hippocampal neurons of mice chronically exposed to cyclic hypoxia

2003 ◽  
Vol 284 (5) ◽  
pp. C1156-C1163 ◽  
Author(s):  
Xiang Q. Gu ◽  
Gabriel G. Haddad
Keyword(s):  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Postnatal Life ◽  
Inactivation Curve ◽  
Ca1 Neurons ◽  
Channel Characteristics ◽  
Hippocampal Ca1 ◽  
Channel Expression ◽  
Steady State Inactivation ◽  
And Function

To examine the effects of chronic cyclic hypoxia on neuronal excitability and function in mice, we exposed mice to cyclic hypoxia for 8 h daily (9 cycles/h) for ∼2 wk (starting at 2–3 days of age) and examined the properties of freshly dissociated hippocampal neurons obtained from slices. Compared with control (Con) hippocampal CA1 neurons, exposed neurons (CYC) had similar resting membrane potentials ( V m) and action potentials (AP). CYC neurons, however, had a lower rheobase than Con neurons. There was also an upregulation of the Na+current density (333 ± 84 pA/pF, n = 18) in CYC compared with that of Con neurons (193 ± 20 pA/pF, n = 27, P < 0.03). Na+channel characteristics were significantly altered by hypoxia. For example, the steady-state inactivation curve was significantly more positive in CYC than in Con (−60 ± 6 mV, n = 8, for CYC and −71 ± 3 mV, n = 14, for Con, P < 0.04). The time constant for deactivation (τd) was much shorter in CYC than in Con (at −100 mV, τd=0.83 ± 0.23 ms in CYC neurons and 2.29 ± 0.38 ms in Con neurons, P = 0.004). We conclude that the increased neuronal excitability in mice neurons treated with cyclic hypoxia is due to alterations in Na+ channel characteristics and/or Na+ channel expression. We hypothesize from these and previous data from our laboratory (Gu XQ and Haddad GG. J Appl Physiol 91: 1245–1250, 2001) that this increased excitability is a reflection of an enhanced central nervous system maturation when exposed to low O2 conditions in early postnatal life.

Effect of chronically elevated CO2 on CA1 neuronal excitability

2004 ◽  
Vol 287 (3) ◽  
pp. C691-C697 ◽  
Author(s):  
Xiang Q. Gu ◽  
Jin Xue ◽  
Gabriel G. Haddad
Keyword(s):  
Current Density ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Positive Direction ◽  
Inactivation Curve ◽  
Channel Characteristics ◽  
Channel Proteins ◽  
Voltage Curve ◽  
Steady State Inactivation ◽  
And Function

To study the effect of chronically elevated CO2 on the excitability and function of neurons, we exposed mice to 7.5–8% CO2 for ∼2 wk (starting at 2 days of age) and examined the properties of freshly dissociated hippocampal neurons. Neurons from control mice (CON) and from mice exposed to chronically elevated CO2 had similar resting membrane potentials and input resistances. CO2-exposed neurons, however, had a lower rheobase and a higher Na+ current density (580 ± 73 pA/pF; n = 27 neurons studied) than did CON neurons (280 ± 51 pA/pF, n = 34; P < 0.01). In addition, the conductance-voltage curve was shifted in a more negative direction in CO2-exposed than in CON neurons (midpoint of the curve was −46 ± 3 mV for CO2 exposed and −34 ± 3 mV for CON, P < 0.01), while the steady-state inactivation curve was shifted in a more positive direction in CO2-exposed than in CON neurons (midpoint of the curve was −59 ± 2 mV for CO2 exposed and −68 ± 3 mV for CON, P < 0.01). The time constant for deactivation at −100 mV was much smaller in CO2-exposed than in CON neurons (0.8 ± 0.1 ms for CO2 exposed and 1.9 ± 0.3 ms for CON, P < 0.01). Immunoblotting for Na+ channel proteins (subtypes I, II, and III) was performed on the hippocampus. Our data indicate that Na+ channel subtype I, rather than subtype II or III, was significantly increased (43%, n = 4; P < 0.05) in the hippocampi of CO2-exposed mice. We conclude that in mice exposed to elevated CO2, 1) increased neuronal excitability is due to alterations in Na+ current and Na+ channel characteristics, and 2) the upregulation of Na+ channel subtype I contributes, at least in part, to the increase in Na+ current density.

scholarly journals Increased neuronal excitability and seizures in the Na+/H+ exchanger null mutant mouse

2001 ◽  
Vol 281 (2) ◽  
pp. C496-C503 ◽  
Author(s):  
Xiang Q. Gu ◽  
Hang Yao ◽  
Gabriel G. Haddad
Keyword(s):  
Neuronal Excitability ◽  
Neurological Diseases ◽  
Seizure Disorder ◽  
Motor Deficits ◽  
Wild Type ◽  
Ca1 Neurons ◽  
Recovery From Inactivation ◽  
Hippocampal Ca1 ◽  
Channel Expression ◽  
Steady State Inactivation

Mice lacking the Na+/H+ exchanger isoform 1 (NHE1) manifest neurological diseases that include ataxia, motor deficits, and a seizure disorder. The molecular basis for the phenotype has not been clear, and it has not been determined how the lack of NHE1 leads, in particular, to the seizure disorder. We have shown in this work that hippocampal CA1 neurons in mutant mice have a much higher excitability than in wild-type mice. This higher excitability is partly based on an upregulation of the Na+ current density (608.2 ± 123.2 pA/pF in NHE1 mutant vs. 334.7 ± 63.7 pA/pF in wild type in HCO[Formula: see text]/CO2). Alterations in Na+channel characteristics, including steady-state inactivation (shift of 18 mV in the depolarization direction in the mutant), recovery from inactivation (τh = 5.22 ± 0.49 ms in wild-type neurons and 2.20 ± 0.20 ms in mutant neurons), and deactivation (at −100 mV, τd = 1.75 ± 0.53 ms in mutant and 0.21 ± 0.05 ms in wild-type neurons) further enhance the differences in excitability between mutant and wild-type mice. Our investigation demonstrates the existence of an important functional interaction between the NHE1 protein and the voltage-sensitive Na+ channel. We hypothesize that the increased neuronal excitability and possibly the seizure disorder in mice lacking the NHE1 is due, at least in part, to changes in Na+ channel expression and/or regulation.

scholarly journals The NALCN Channel Regulator UNC-80 Functions in a Subset of Interneurons To Regulate Caenorhabditis elegans Reversal Behavior

2019 ◽  
Vol 10 (1) ◽  
pp. 199-210 ◽  
Author(s):  
Chuanman Zhou ◽  
Jintao Luo ◽  
Xiaohui He ◽  
Qian Zhou ◽  
Yunxia He ◽  
...  
Keyword(s):  
Plant Hormone ◽  
Neuronal Excitability ◽  
Resting Membrane Potential ◽  
Loss Of Function ◽  
Wild Type ◽  
C Elegans ◽  
Link Type ◽  
Complex Functions ◽  
And Function ◽  
Multiple Loss

NALCN (Na+leak channel, non-selective) is a conserved, voltage-insensitive cation channel that regulates resting membrane potential and neuronal excitability. UNC79 and UNC80 are key regulators of the channel function. However, the behavioral effects of the channel complex are not entirely clear and the neurons in which the channel functions remain to be identified. In a forward genetic screen for C. elegans mutants with defective avoidance response to the plant hormone methyl salicylate (MeSa), we isolated multiple loss-of-function mutations in unc-80 and unc-79. C. elegans NALCN mutants exhibited similarly defective MeSa avoidance. Interestingly, NALCN, unc-80 and unc-79 mutants all showed wild type-like responses to other attractive or repelling odorants, suggesting that NALCN does not broadly affect odor detection or related forward and reversal behaviors. To understand in which neurons the channel functions, we determined the identities of a subset of unc-80-expressing neurons. We found that unc-79 and unc-80 are expressed and function in overlapping neurons, which verified previous assumptions. Neuron-specific transgene rescue and knockdown experiments suggest that the command interneurons AVA and AVE and the anterior guidepost neuron AVG can play a sufficient role in mediating unc-80 regulation of the MeSa avoidance. Though primarily based on genetic analyses, our results further imply that MeSa might activate NALCN by direct or indirect actions. Altogether, we provide an initial look into the key neurons in which the NALCN channel complex functions and identify a novel function of the channel in regulating C. elegans reversal behavior through command interneurons.

Contribution of Nav1.8 Sodium Channels to Action Potential Electrogenesis in DRG Neurons

2001 ◽  
Vol 86 (2) ◽  
pp. 629-640 ◽  
Author(s):  
Muthukrishnan Renganathan ◽  
Theodore R. Cummins ◽  
Stephen G. Waxman
Keyword(s):  
Action Potential ◽  
Sodium Channels ◽  
Action Potentials ◽  
Input Resistance ◽  
Resting Membrane Potential ◽  
Drg Neurons ◽  
Significant Difference ◽  
Steady State Inactivation ◽  
Current Threshold

C-type dorsal root ganglion (DRG) neurons can generate tetrodotoxin-resistant (TTX-R) sodium-dependent action potentials. However, multiple sodium channels are expressed in these neurons, and the molecular identity of the TTX-R sodium channels that contribute to action potential production in these neurons has not been established. In this study, we used current-clamp recordings to compare action potential electrogenesis in Nav1.8 (+/+) and (−/−) small DRG neurons maintained for 2–8 h in vitro to examine the role of sodium channel Nav1.8 (α-SNS) in action potential electrogenesis. Although there was no significant difference in resting membrane potential, input resistance, current threshold, or voltage threshold in Nav1.8 (+/+) and (−/−) DRG neurons, there were significant differences in action potential electrogenesis. Most Nav1.8 (+/+) neurons generate all-or-none action potentials, whereas most of Nav1.8 (−/−) neurons produce smaller graded responses. The peak of the response was significantly reduced in Nav1.8 (−/−) neurons [31.5 ± 2.2 (SE) mV] compared with Nav1.8 (+/+) neurons (55.0 ± 4.3 mV). The maximum rise slope was 84.7 ± 11.2 mV/ms in Nav1.8 (+/+) neurons, significantly faster than in Nav1.8 (−/−) neurons where it was 47.2 ± 1.3 mV/ms. Calculations based on the action potential overshoot in Nav1.8 (+/+) and (−/−) neurons, following blockade of Ca2+ currents, indicate that Nav1.8 contributes a substantial fraction (80–90%) of the inward membrane current that flows during the rising phase of the action potential. We found that fast TTX-sensitive Na+ channels can produce all-or-none action potentials in some Nav1.8 (−/−) neurons but, presumably as a result of steady-state inactivation of these channels, electrogenesis in Nav1.8 (−/−) neurons is more sensitive to membrane depolarization than in Nav1.8 (+/+) neurons, and, in the absence of Nav1.8, is attenuated with even modest depolarization. These observations indicate that Nav1.8 contributes substantially to action potential electrogenesis in C-type DRG neurons.

scholarly journals Melatonin Reduces Excitability in Dorsal Root Ganglia Neurons with Inflection on the Repolarization Phase of the Action Potential

2019 ◽  
Vol 20 (11) ◽  
pp. 2611 ◽  
Author(s):  
Klausen Oliveira-Abreu ◽  
Nathalia Silva-dos-Santos ◽  
Andrelina Coelho-de-Souza ◽  
Francisco Ferreira-da-Silva ◽  
Kerly Silva-Alves ◽  
...  
Keyword(s):  
Action Potential ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Neuronal Excitability ◽  
Input Resistance ◽  
Cell Types ◽  
Neuronal Population ◽  
Resting Membrane Potential ◽  
Electrophysiological Properties ◽  
Repolarization Phase

Melatonin is a neurohormone produced and secreted at night by pineal gland. Many effects of melatonin have already been described, for example: Activation of potassium channels in the suprachiasmatic nucleus and inhibition of excitability of a sub-population of neurons of the dorsal root ganglia (DRG). The DRG is described as a structure with several neuronal populations. One classification, based on the repolarizing phase of the action potential (AP), divides DRG neurons into two types: Without (N0) and with (Ninf) inflection on the repolarization phase of the action potential. We have previously demonstrated that melatonin inhibits excitability in N0 neurons, and in the present work, we aimed to investigate the melatonin effects on the other neurons (Ninf) of the DRG neuronal population. This investigation was done using sharp microelectrode technique in the current clamp mode. Melatonin (0.01–1000.0 nM) showed inhibitory activity on neuronal excitability, which can be observed by the blockade of the AP and by the increase in rheobase. However, we observed that, while some neurons were sensitive to melatonin effect on excitability (excitability melatonin sensitive—EMS), other neurons were not sensitive to melatonin effect on excitability (excitability melatonin not sensitive—EMNS). Concerning the passive electrophysiological properties of the neurons, melatonin caused a hyperpolarization of the resting membrane potential in both cell types. Regarding the input resistance (Rin), melatonin did not change this parameter in the EMS cells, but increased its values in the EMNS cells. Melatonin also altered several AP parameters in EMS cells, the most conspicuously changed was the (dV/dt)max of AP depolarization, which is in coherence with melatonin effects on excitability. Otherwise, in EMNS cells, melatonin (0.1–1000.0 nM) induced no alteration of (dV/dt)max of AP depolarization. Thus, taking these data together, and the data of previous publication on melatonin effect on N0 neurons shows that this substance has a greater pharmacological potency on Ninf neurons. We suggest that melatonin has important physiological function related to Ninf neurons and this is likely to bear a potential relevant therapeutic use, since Ninf neurons are related to nociception.

scholarly journals Slc7a5 alters Kvβ-mediated regulation of Kv1.2

2020 ◽  
Vol 152 (7) ◽  
Author(s):  
Shawn M. Lamothe ◽  
Harley T. Kurata
Keyword(s):  
Neuronal Excitability ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Extrinsic Factors ◽  
Neutral Amino Acid Transporter ◽  
Recovery From Inactivation ◽  
Steady State Inactivation ◽  
Accessory Subunit ◽  
Delayed Recovery ◽  
Hyperpolarizing Shift

The voltage-gated potassium channel Kv1.2 plays a pivotal role in neuronal excitability and is regulated by a variety of known and unknown extrinsic factors. The canonical accessory subunit of Kv1.2, Kvβ, promotes N-type inactivation and cell surface expression of the channel. We recently reported that a neutral amino acid transporter, Slc7a5, alters the function and expression of Kv1.2. In the current study, we investigated the effects of Slc7a5 on Kv1.2 in the presence of Kvβ1.2 subunits. We observed that Slc7a5-induced suppression of Kv1.2 current and protein expression was attenuated with cotransfection of Kvβ1.2. However, gating effects mediated by Slc7a5, including disinhibition and a hyperpolarizing shift in channel activation, were observed together with Kvβ-mediated inactivation, indicating convergent regulation of Kv1.2 by both regulatory proteins. Slc7a5 influenced several properties of Kvβ-induced inactivation of Kv1.2, including accelerated inactivation, a hyperpolarizing shift and greater extent of steady-state inactivation, and delayed recovery from inactivation. These modified inactivation properties were also apparent in altered deactivation of the Kv1.2/Kvβ/Slc7a5 channel complex. Taken together, these findings illustrate a functional interaction arising from simultaneous regulation of Kv1.2 by Kvβ and Slc7a5, leading to powerful effects on Kv1.2 expression, gating, and overall channel function.

scholarly journals Mechanisms of atrial-selective block of Na+ channels by ranolazine: I. Experimental analysis of the use-dependent block

2011 ◽  
Vol 301 (4) ◽  
pp. H1606-H1614 ◽  
Author(s):  
Andrew C. Zygmunt ◽  
Vladislav V. Nesterenko ◽  
Sridharan Rajamani ◽  
Dan Hu ◽  
Hector Barajas-Martinez ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Selective Inhibition ◽  
Resting Membrane Potential ◽  
Inactivation Curve ◽  
Hek 293 ◽  
Hek 293 Cells ◽  
Channel Current ◽  
Ventricular Cells ◽  
293 Cells ◽  
Steady State Inactivation

Atrial-selective inhibition of cardiac Na+ channel current ( INa) and INa-dependent parameters has been shown to contribute to the safe and effective management of atrial fibrillation. The present study examined the basis for the atrial-selective actions of ranolazine. Whole cell INa was recorded at 15°C in canine atrial and ventricular myocytes and in human embryonic kidney (HEK)-293 cells expressing SCN5A. Tonic block was negligible at holding potentials from −140 to −100 mV, suggesting minimal drug interactions with the closed state. Trains of 40 pulses were elicited over a range of holding potentials to determine use-dependent block. Guarded receptor formalism was used to analyze the development of block during pulse trains. Use-dependent block by ranolazine increased at more depolarized holding potentials, consistent with an interaction of the drug with either preopen or inactivated states, but was unaffected by longer pulse durations between 5 and 200 ms, suggesting a weak interaction with the inactivated state. Block was significantly increased at shorter diastolic intervals between 20 and 200 ms. Responses in atrial and ventricular myocytes and in HEK-293 cells displayed a similar pattern. Ranolazine is an open state blocker that unbinds from closed Na+ channels unusually fast but is trapped in the inactivated state. Kinetic rates of ranolazine interactions with different states of atrial and ventricular Na+ channels were similar. Our data suggest that the atrial selectivity of ranolazine is due to a more negative steady-state inactivation curve, less negative resting membrane potential, and shorter diastolic intervals in atrial cells compared with ventricular cells at rapid rates.

scholarly journals Genetic expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy

2021 ◽  
Author(s):  
Lena H Nguyen ◽  
Youfen Xu ◽  
Travorn Mahadeo ◽  
Longbo Zhang ◽  
Tiffany V Lin ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Firing Pattern ◽  
Intractable Epilepsy ◽  
Structure And Function ◽  
Resting Membrane Potential ◽  
Neuronal Dysfunction ◽  
Translational Repressor ◽  
Malformation Of Cortical Development ◽  
Channel Expression ◽  
And Function

Hyperactivation of mTOR signaling during fetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development (FMCD) and intractable epilepsy. Recent evidence suggests increased cap-dependent translation downstream of mTOR contributes to FMCD formation and seizures. However, whether reducing overactive translation once the developmental pathologies are established reverses neuronal abnormalities and seizures is unknown. Here, we found that the translational repressor 4E-BP1, which is inactivated by mTOR-mediated phosphorylation, is hyperphosphorylated in patient FMCD tissue and in a mouse model of FMCD. Expressing constitutive active 4E-BP1 to repress aberrant translation in juvenile mice with FMCD reduced neuronal cytomegaly and corrected several electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern, and aberrant HCN4 channel expression. This was accompanied by improved cortical spectral activity and decreased seizures. Although mTOR controls multiple pathways, our study shows that targeting 4E-BP1-mediated translation alone is sufficient to alleviate neuronal dysfunction and ongoing epilepsy.

Sign in / Sign up

Export Citation Format

Share Document