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.

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 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 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.

scholarly journals VEGF/VEGFR2 signaling regulates hippocampal axon branching during development

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Robert Luck ◽  
Severino Urban ◽  
Andromachi Karakatsani ◽  
Eva Harde ◽  
Sivakumar Sambandan ◽  
...  
Keyword(s):  
Growth Rate ◽  
Hippocampal Neurons ◽  
Angiogenic Factor ◽  
Axon Branching ◽  
Ca1 Neurons ◽  
Mouse Hippocampus ◽  
Vegfr2 Signaling ◽  
And Function

Axon branching is crucial for proper formation of neuronal networks. Although originally identified as an angiogenic factor, VEGF also signals directly to neurons to regulate their development and function. Here we show that VEGF and its receptor VEGFR2 (also known as KDR or FLK1) are expressed in mouse hippocampal neurons during development, with VEGFR2 locally expressed in the CA3 region. Activation of VEGF/VEGFR2 signaling in isolated hippocampal neurons results in increased axon branching. Remarkably, inactivation of VEGFR2 also results in increased axon branching in vitro and in vivo. The increased CA3 axon branching is not productive as these axons are less mature and form less functional synapses with CA1 neurons. Mechanistically, while VEGF promotes the growth of formed branches without affecting filopodia formation, loss of VEGFR2 increases the number of filopodia and enhances the growth rate of new branches. Thus, a controlled VEGF/VEGFR2 signaling is required for proper CA3 hippocampal axon branching during mouse hippocampus development.

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 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 Kiss1 Neurons Drastically Change Their Firing Activity in Accordance With the Reproductive State: Insights From a Seasonal Breeder

Endocrinology ◽  
2014 ◽  
Vol 155 (12) ◽  
pp. 4868-4880 ◽  
Author(s):  
Masaharu Hasebe ◽  
Shinji Kanda ◽  
Hiroyuki Shimada ◽  
Yasuhisa Akazome ◽  
Hideki Abe ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Resting Membrane Potential ◽  
Reproductive State ◽  
Firing Patterns ◽  
State Dependent ◽  
Channel Expression ◽  
Physiological Analysis ◽  
Seasonal Breeder ◽  
Green Fluorescent

Kisspeptin (Kiss) neurons show drastic changes in kisspeptin expression in response to the serum sex steroid concentration in various vertebrate species. Thus, according to the reproductive states, kisspeptin neurons are suggested to modulate various neuronal activities, including the regulation of GnRH neurons in mammals. However, despite their reproductive state-dependent regulation, there is no physiological analysis of kisspeptin neurons in seasonal breeders. Here we generated the first kiss1-enhanced green fluorescent protein transgenic line of a seasonal breeder, medaka, for histological and electrophysiological analyses using a whole-brain in vitro preparation in which most synaptic connections are intact. We found histologically that Kiss1 neurons in the nucleus ventralis tuberis (NVT) projected to the preoptic area, hypothalamus, pituitary, and ventral telencephalon. Therefore, NVT Kiss1 neurons may regulate various homeostatic functions and innate behaviors. Electrophysiological analyses revealed that they show various firing patterns, including bursting. Furthermore, we found that their firings are regulated by the resting membrane potential. However, bursting was not induced from the other firing patterns with a current injection, suggesting that it requires some chronic modulations of intrinsic properties such as channel expression. Finally, we found that NVT Kiss1 neurons drastically change their neuronal activities according to the reproductive state and the estradiol levels. Taken together with the previous reports, we here conclude that the breeding condition drastically alters the Kiss1 neuron activities in both gene expression and firing activities, the latter of which is strongly related to Kiss1 release, and the Kiss1 peptides regulate the activities of various neural circuits through their axonal projections.

FKBP51 Modulates Hippocampal Size and Function in Post-translational Regulation of Parkin

2021 ◽  
Author(s):  
Bin Qiu ◽  
Zhaohui Zhong ◽  
Shawn Righter ◽  
Yuxue Xu ◽  
Jun Wang ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Translational Regulation ◽  
Disease Onset ◽  
Fold Increase ◽  
Knock Out ◽  
Fk506 Binding Protein ◽  
Protein Levels ◽  
And Function

Abstract FK506-binding protein 51 (encoded by Fkpb51) has been associated with stress-related mental illness. To identify its function, we studied the morphological consequences of Fkbp51 deletion. Artificial Intelligence-assist morphological analysis identified that Fkbp51 knock-out (KO) mice possess more elongated CA and DG but shorter in height in coronal section when compared to WT. Primary cultured Fkbp51 KO hippocampal neurons were shown to exhibit larger dendritic outgrowth than wild-type (WT) controls, pharmacological manipulation experiments suggest that this may occur through regulation of microtubule-associated protein. Both in vitro primary culture and in vivo labeling support that FKBP51 regulates microtubule-associated protein expression. Furthermore, in the absence of differences in mRNA expression, Fkbp51 KO hippocampus exhibited decreases in βIII-tubulin, MAP2, and Tau protein levels, but a greater than 2.5-fold increase in Parkin protein. Overexpression and knock-down FKBP51 demonstrated that FKBP51 negatively regulates Parkin in a dose-dependent and ubiquitin-mediated manner. These results indicate a potential novel post-translational regulatory of Parkin by FKBP51 and significance of their interaction on disease onset.

Theta-Frequency Resonance in Hippocampal CA1 Neurons In Vitro Demonstrated by Sinusoidal Current Injection

1998 ◽  
Vol 79 (3) ◽  
pp. 1592-1596 ◽  
Author(s):  
L. Stan Leung ◽  
Hui-Wen Yu
Keyword(s):  
Resonant Frequency ◽  
Hippocampal Neurons ◽  
Ca1 Neurons ◽  
Frequency Resonance ◽  
Hippocampal Ca1 Neurons ◽  
Hippocampal Ca1 ◽  
Theta Frequency ◽  
Sinusoidal Current ◽  
Sinusoidal Currents

Leung, L. Stan and Hui-Wen Yu. Theta-frequency resonance in hippocampal CA1 neurons in vitro demonstrated by sinusoidal current injection. J. Neurophysiol. 79: 1592–1596, 1998. Sinusoidal currents of various frequencies were injected into hippocampal CA1 neurons in vitro, and the membrane potential responses were analyzed by cross power spectral analysis. Sinusoidal currents induced a maximal (resonant) response at a theta frequency (3–10 Hz) in slightly depolarized neurons. As predicted by linear systems theory, the resonant frequency was about the same as the natural (spontaneous) oscillation frequency. However, in some cases, the resonant frequency was higher than the spontaneous oscillation frequency, or resonance was found in the absence of spontaneous oscillations. The sharpness of the resonance ( Q), measured by the peak frequency divided by the half-peak power bandwidth, increased from a mean of 0.44 at rest to 0.83 during a mean depolarization of 6.5 mV. The phase of the driven oscillations changed most rapidly near the resonant frequency, and it shifted about 90° over the half-peak bandwidth of 8.4 Hz. Similar results were found using a sinusoidal function of slowly changing frequency as the input. Sinusoidal currents of peak-to-peak intensity of >100 pA may evoke nonlinear responses characterized by second and higher harmonics. The theta-frequency resonance in hippocampal neurons in vitro suggests that the same voltage-dependent phenomenon may be important in enhancing a theta-frequency response when hippocampal neurons are driven by medial septal or other inputs in vivo.

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