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.

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.

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.

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 Thyroid Hormone (T3)-Induced Up-Regulation of Voltage-Activated Sodium Current in Cultured Postnatal Hippocampal Neurons Requires Secretion of Soluble Factors from Glial Cells

2009 ◽  
Vol 23 (9) ◽  
pp. 1494-1504 ◽  
Author(s):  
Vanessa Niederkinkhaus ◽  
Romy Marx ◽  
Gerd Hoffmann ◽  
Irmgard D. Dietzel
Keyword(s):  
Thyroid Hormone ◽  
Glial Cells ◽  
Current Density ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Sodium Current ◽  
Na Current ◽  
Soluble Factors ◽  
Voltage Gated ◽  
Postnatal Rats

Abstract We have previously shown that treatment with the thyroid hormone T3 increases the voltage-gated Na+current density (Nav-D) in hippocampal neurons from postnatal rats, leading to accelerated action potential upstrokes and increased firing frequencies. Here we show that the Na+ current regulation depends on the presence of glial cells, which secrete a heat-instable soluble factor upon stimulation with T3. The effect of conditioned medium from T3-treated glial cells was mimicked by basic fibroblast growth factor (bFGF), known to be released from cerebellar glial cells after T3 treatment. Neutralization assays of astrocyte-conditioned media with anti-bFGF antibody inhibited the regulation of the Nav-D by T3. This suggests that the up-regulation of the neuronal sodium current density by T3 is not a direct effect but involves bFGF release and satellite cells. Thus glial cells can modulate neuronal excitability via secretion of paracrinely acting factors.

scholarly journals The Specific Effects of OD-1, a Peptide Activator, on Voltage-Gated Sodium Current and Seizure Susceptibility

2020 ◽  
Vol 21 (21) ◽  
pp. 8254
Author(s):  
Ming-Chi Lai ◽  
Sheng-Nan Wu ◽  
Chin-Wei Huang
Keyword(s):  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Sodium Current ◽  
Hippocampal Slices ◽  
Inactivation Curve ◽  
Voltage Gated ◽  
Epileptiform Discharges ◽  
State Dependent ◽  
Na Currents

OD-1, a scorpion toxin, has been previously recognized as an activator of voltage-gated Na+ currents. To what extent this agent can alter hippocampal neuronal Na+ currents and network excitability and how it can be applied to neuronal hyperexcitability research remains unclear. With the aid of patch-clamp technology, it was revealed that, in mHippoE-14 hippocampal neurons, OD-1 produced a concentration-, time-, and state-dependent rise in the peak amplitude of INa. It shifted the INa inactivation curve to a less negative potential and increased the frequency of spontaneous action currents. Further characterization of neuronal excitability revealed higher excitability in the hippocampal slices treated with OD-1 as compared with the control slices. A stereotaxic intrahippocampal injection of OD-1 generated a significantly higher frequency of spontaneous seizures and epileptiform discharges compared with intraperitoneal injection of lithium-pilocarpine- or kainic acid-induced epilepsy, with comparable pathological changes. Carbamazepine significantly attenuated OD-1 induced seizures and epileptiform discharges. The OD-1-mediated modifications of INa altered the electrical activity of neurons in vivo and OD-1 could potentially serve as a novel seizure and excitotoxicity model.

Posttranscriptional modulation of KCNQ2 gene expression by the miR-106b microRNA family

2021 ◽  
Vol 118 (47) ◽  
pp. e2110200118
Author(s):  
Kwon-Woo Kim ◽  
Keetae Kim ◽  
Hee-Jin Kim ◽  
Byeol-I Kim ◽  
Myungin Baek ◽  
...  
Keyword(s):  
Current Density ◽  
Messenger Rna ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Family Members ◽  
Firing Frequency ◽  
Early Postnatal Development ◽  
Protein Levels ◽  
Channel Expression ◽  
Stable Forms

MicroRNAs (miRNAs) have recently emerged as important regulators of ion channel expression. We show here that select miR-106b family members repress the expression of the KCNQ2 K+ channel protein by binding to the 3′-untranslated region of KCNQ2 messenger RNA. During the first few weeks after birth, the expression of miR-106b family members rapidly decreases, whereas KCNQ2 protein level inversely increases. Overexpression of miR-106b mimics resulted in a reduction in KCNQ2 protein levels. Conversely, KCNQ2 levels were up-regulated in neurons transfected with antisense miRNA inhibitors. By constructing more specific and stable forms of miR-106b controlling systems, we further confirmed that overexpression of precursor-miR-106b-5p led to a decrease in KCNQ current density and an increase in firing frequency of hippocampal neurons, while tough decoy miR-106b-5p dramatically increased current density and decreased neuronal excitability. These results unmask a regulatory mechanism of KCNQ2 channel expression in early postnatal development and hint at a role for miR-106b up-regulation in the pathophysiology of epilepsy.

scholarly journals Regulation of neuronal excitability by release of proteins from glial cells

2015 ◽  
Vol 370 (1672) ◽  
pp. 20140194 ◽  
Author(s):  
Birte A. Igelhorst ◽  
Vanessa Niederkinkhaus ◽  
Claudia Karus ◽  
Maren D. Lange ◽  
Irmgard D. Dietzel
Keyword(s):  
Thyroid Hormone ◽  
Glial Cells ◽  
Current Density ◽  
Hippocampal Neurons ◽  
Time Course ◽  
Neuronal Excitability ◽  
Neurotrophin 3 ◽  
Hippocampal Cultures ◽  
Hormone Influence ◽  
Factor Α

Effects of glial cells on electrical isolation and shaping of synaptic transmission between neurons have been extensively studied. Here we present evidence that the release of proteins from astrocytes as well as microglia may regulate voltage-activated Na + currents in neurons, thereby increasing excitability and speed of transmission in neurons kept at distance from each other by specialized glial cells. As a first example, we show that basic fibroblast growth factor and neurotrophin-3 , which are released from astrocytes by exposure to thyroid hormone, influence each other to enhance Na + current density in cultured hippocampal neurons. As a second example, we show that the presence of microglia in hippocampal cultures can upregulate Na + current density. The effect can be boosted by lipopolysaccharides, bacterial membrane-derived stimulators of microglial activation. Comparable effects are induced by the exposure of neuron-enriched hippocampal cultures to tumour necrosis factor-α , which is released from stimulated microglia. Taken together, our findings suggest that release of proteins from various types of glial cells can alter neuronal excitability over a time course of several days. This explains changes in neuronal excitability occurring in states of thyroid hormone imbalance and possibly also in seizures triggered by infectious diseases.

Simulated ischemia enhances L-type calcium current in pacemaker cells isolated from the rabbit sinoatrial node

2007 ◽  
Vol 293 (5) ◽  
pp. H2986-H2994 ◽  
Author(s):  
Yi-Mei Du ◽  
Richard D. Nathan
Keyword(s):  
Steady State ◽  
Sinoatrial Node ◽  
Atrial Myocytes ◽  
Pacemaker Cells ◽  
Activation Curve ◽  
Positive Direction ◽  
Inactivation Curve ◽  
Steady State Inactivation ◽  
Rabbit Sinoatrial Node ◽  
Maximum Conductance

Ischemic-like conditions (a glucose-free, pH 6.6 Tyrode solution bubbled with 100% N2) enhance L-type Ca current ( ICa,L) in single pacemaker cells (PCs) isolated from the rabbit sinoatrial node (SAN). In contrast, studies of ventricular myocytes have shown that acidic extracellular pH, as employed in our “ischemic” Tyrode, reduces ICa,L. Therefore, our goal was to explain why ICa,L is increased by “ischemia” in SAN PCs. The major findings were the following: 1) blockade of Ca-induced Ca release with ryanodine, exposure of PCs to BAPTA-AM, or replacement of extracellular Ca2+ with Ba2+ failed to prevent the ischemia-induced enhancement of ICa,L; 2) inhibition of protein kinase A with H-89, or calcium/calmodulin-dependent protein kinase II with KN-93, reduced ICa,L but did not prevent its augmentation by ischemia; 3) ischemic Tyrode or pH 6.6 Tyrode shifted the steady-state inactivation curve in the positive direction, thereby reducing inactivation; 4) ischemic Tyrode increased the maximum conductance but did not affect the activation curve; 5) in rabbit atrial myocytes isolated and studied with exactly the same techniques used for SAN PCs, ischemic Tyrode reduced the maximum conductance and shifted the activation curve in the positive direction; pH 6.6 Tyrode also shifted the steady-state inactivation curve in the positive direction. We conclude that the acidic pH of ischemic Tyrode enhances ICa,L in SAN PCs, because it increases the maximum conductance and reduces inactivation. Furthermore, the opposite results obtained with rabbit atrial myocytes cannot be explained by differences in cell isolation or patch-clamp techniques.

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.

scholarly journals PKC-phosphorylation of Liprin-α3 triggers phase separation and controls presynaptic active zone structure

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Javier Emperador-Melero ◽  
Man Yan Wong ◽  
Shan Shan H. Wang ◽  
Giovanni de Nola ◽  
Hajnalka Nyitrai ◽  
...  
Keyword(s):  
Phase Separation ◽  
Active Zone ◽  
Neurotransmitter Release ◽  
Hippocampal Neurons ◽  
Phosphorylation Site ◽  
Double Knockout ◽  
Zone Structure ◽  
Presynaptic Nerve Terminal ◽  
Condensate Formation ◽  
And Function

AbstractThe active zone of a presynaptic nerve terminal defines sites for neurotransmitter release. Its protein machinery may be organized through liquid–liquid phase separation, a mechanism for the formation of membrane-less subcellular compartments. Here, we show that the active zone protein Liprin-α3 rapidly and reversibly undergoes phase separation in transfected HEK293T cells. Condensate formation is triggered by Liprin-α3 PKC-phosphorylation at serine-760, and RIM and Munc13 are co-recruited into membrane-attached condensates. Phospho-specific antibodies establish phosphorylation of Liprin-α3 serine-760 in transfected cells and mouse brain tissue. In primary hippocampal neurons of newly generated Liprin-α2/α3 double knockout mice, synaptic levels of RIM and Munc13 are reduced and the pool of releasable vesicles is decreased. Re-expression of Liprin-α3 restored these presynaptic defects, while mutating the Liprin-α3 phosphorylation site to abolish phase condensation prevented this rescue. Finally, PKC activation in these neurons acutely increased RIM, Munc13 and neurotransmitter release, which depended on the presence of phosphorylatable Liprin-α3. Our findings indicate that PKC-mediated phosphorylation of Liprin-α3 triggers its phase separation and modulates active zone structure and function.

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