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 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.

Na+ Channel Expression and Neuronal Function in the Na+/H+ Exchanger 1 Null Mutant Mouse

2003 ◽  
Vol 89 (1) ◽  
pp. 229-236 ◽  
Author(s):  
Ying Xia ◽  
Peng Zhao ◽  
Jin Xue ◽  
Xiang Q. Gu ◽  
Xiaolu Sun ◽  
...  
Keyword(s):  
Current Density ◽  
Cortical Neurons ◽  
Neuronal Excitability ◽  
Epileptic Seizures ◽  
Mutant Mice ◽  
Na Channel ◽  
Membrane Excitability ◽  
Altered Expression ◽  
Ca1 Neurons ◽  
Channel Expression

Mice lacking Na+/H+ exchanger 1 (NHE1) suffer from recurrent seizures and die early postnatally. Although the mechanisms for seizures are not well established, our previous electrophysiological work has shown that neuronal excitability and Na+ current density are increased in hippocampal CA1 neurons of these mutant mice. However, it is unknown whether this increased density is related to altered expression or functional regulation of Na+ channels. In this work, we asked three questions: is the increased excitability limited to CA1 neurons, is the increased Na+ current density related to an increased Na+ channel expression, and, if so, which Na+channel subtype(s) is upregulated? Using neurophysiological, autoradiographic, and immunoblotting techniques, we showed that both CA1 and cortical neurons have an increase in membrane excitability and Na+ current density; Na+ channel density is selectively upregulated in the hippocampus and cortex ( P < 0.05); and Na+ channel subtype I is significantly increased in the hippocampus and Na+channel subtype II is increased in the cortex. Our results demonstrate that mice lacking NHE1 upregulate their Na+ channel expression in the hippocampal and cortical regions selectively; this leads to an increase in Na+ current density and membrane excitability. We speculate that neuronal overexcitability due to Na+ channel upregulation in the hippocampus and cortex forms the basis of epileptic seizures in NHE1 mutant mice.

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.

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 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.

scholarly journals Deletion of calcineurin from GFAP-expressing astrocytes impairs excitability of cerebellar and hippocampal neurons through astroglial Na+/K+ ATPase

2019 ◽  
Author(s):  
Laura Tapella ◽  
Teresa Soda ◽  
Lisa Mapelli ◽  
Valeria Bortolotto ◽  
Heather Bondi ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Normal Growth ◽  
Conditional Knockout ◽  
Protein Levels ◽  
Hippocampal Ca1 ◽  
Neuronal Functions

ABSTRACTAstrocytes perform important housekeeping functions in the nervous system including maintenance of adequate neuronal excitability, although the regulatory mechanisms are currently poorly understood. The astrocytic Ca2+/calmodulin-activated phosphatase calcineurin (CaN) is implicated in the development of reactive gliosis and neuroinflammation, but its roles, including the control of neuronal excitability, in healthy brain is unknown. We have generated a mouse line with conditional knockout (KO) of CaN B1 (CaNB1) in glial fibrillary acidic protein (GFAP)-expressing astrocytes (astroglial calcineurin knock-out, ACN-KO). Here we report that postnatal and astrocyte-specific ablation of CaNB1 did not alter normal growth and development as well as adult neurogenesis. Yet, we found that specific deletion of astrocytic CaN selectively impairs intrinsic neuronal excitability in hippocampal CA1 pyramidal neurons and cerebellar granule cells (CGCs). This impairment was associated with a decrease in after-hyperpolarization in CGC, while passive properties were unchanged, suggesting impairment of K+ homeostasis. Indeed, blockade of Na+/K+-ATPase (NKA) with ouabain phenocopied the electrophysiological alterations observed in ACN-KO CGCs. In addition, NKA activity was significantly lower in cerebellar and hippocampal lysates and in pure astrocytic cultures from ACN-KO mice. While no changes were found in protein levels, NKA activity was inhibited by the specific CaN inhibitor FK506 in both cerebellar lysates and primary astroglia from control mice, suggesting that CaN directly modulates NKA activity and in this manner controls neuronal excitability. In summary, our data provide formal evidence for the notion that astroglia is fundamental for controlling basic neuronal functions and place CaN center-stage as an astrocytic Ca2+-sensitive switch.

Synbiotic-associated improvement in liver function in cirrhotic patients: Relation to changes in circulating cytokine messenger RNA and protein levels

2007 ◽  
Vol 19 (1) ◽  
Author(s):  
Stephen M. Riordan ◽  
Narelle A. Skinner ◽  
Christopher J. Mciver ◽  
Qing Liu ◽  
Stig Bengmark ◽  
...  
Keyword(s):  
Liver Function ◽  
Messenger Rna ◽  
Protein Levels ◽  
Cirrhotic Patients

scholarly journals Chronic restraint stress impairs cognition via modulating HDAC2 expression

2021 ◽  
Vol 12 (1) ◽  
pp. 154-163
Author(s):  
Jie Wu ◽  
Cui Liu ◽  
Ling Zhang ◽  
Bing He ◽  
Wei-Ping Shi ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Hippocampal Neurons ◽  
Restraint Stress ◽  
Glucocorticoid Receptors ◽  
Chronic Restraint Stress ◽  
Akt Signaling Pathway ◽  
Object Recognition Test ◽  
Protein Levels ◽  
Synaptic Functions ◽  
Plus Maze

Abstract Background To investigate the effects of chronic restraint stress on cognition and the probable molecular mechanism in mice. Methods In the current work, a restraining tube was used as a way to induce chronic stress in mice. The protein levels were determined with ELISA and western blot. A series of behavior tests, including the Morris water maze, elevated plus maze, open field test, and novel object recognition test, were also performed to examine the anxiety and the ability of learning and memory. Moreover, murine neuroblastoma N2a cells were used to confirm the findings from mice under chronic stress. Results Decreased synaptic functions were impaired in chronic stress with the downregulation of PSD95, GluR-1, the neurotrophic factor BDNF, and immediate-onset genes Arc and Egr. Chronic restraint decreased the histone acetylation level in hippocampal neurons while HDAC2 was increased and was co-localized with glucocorticoid receptors. Moreover, chronic stress inhibited the PI3K/AKT signaling pathway and induced energy metabolism dysfunctions. Conclusion This work examining the elevated levels of HDAC2 in the hippocampus may provide new insights and targets for drug development for treating many neurodegenerative diseases.

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