scholarly journals Differential impact of Kv8.2 loss on rod and cone signaling and degeneration.

2021 ◽  
Author(s):  
Shivangi M Inamdar ◽  
Colten K Lankford ◽  
Deepak Poria ◽  
Joseph G Laird ◽  
Eduardo Solessio ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Ex Vivo ◽  
Light Stimulus ◽  
Resting Membrane Potential ◽  
Cone Dystrophy ◽  
Extracellular Potassium ◽  
Delayed Response ◽  
Low Frequencies ◽  
Ionic Imbalance

The voltage-gated potassium channel responsible for controlling photoreceptor signaling is a heteromeric complex of Kv2.1 subunits with a regulatory Kv8.2 subunit. Kv2.1/Kv8.2 channels are localized to the photoreceptor inner segment and carry IKx, largely responsible for setting the photoreceptor resting membrane potential. Mutations in Kv8.2 result in childhood-onset Cone Dystrophy with Supernormal Rod Response (CDSRR). We generated a Kv8.2 knockout (KO) mouse and examined retinal signaling and photoreceptor degeneration to gain deeper insight into the complex phenotypes of this disease. Using electroretinograms we show that there is a tradeoff between delayed or reduced signaling from rods depending on the intensity of the light stimulus, consistent with reduced capacity for light-evoked changes in membrane potential. The delayed response was not seen ex vivo where extracellular potassium levels are the same, so we conclude the in vivo alteration is influenced by ionic imbalance. We observed mild retinal degeneration. Signaling from cones was reduced but there was no loss of cone density. Loss of Kv8.2 altered responses to flickering light with responses attenuated at high frequencies and altered in shape at low frequencies. The Kv8.2 KO line on an all-cone retina background had reduced cone signaling associated with degeneration. We conclude that Kv8.2 is required by rods and cones for responding to dynamic changes in lighting. The timing and cell type affected by degeneration is different in the mouse and human but there is a window of time in both for therapeutic intervention.

scholarly journals In Vivo Neocortical [K]o Modulation by Targeted Stimulation of Astrocytes

2021 ◽  
Vol 22 (16) ◽  
pp. 8658
Author(s):  
Azin EbrahimAmini ◽  
Shanthini Mylvaganam ◽  
Paolo Bazzigaluppi ◽  
Mohamad Khazaei ◽  
Alexander Velumian ◽  
...  
Keyword(s):  
Nervous System ◽  
Membrane Potential ◽  
Potassium Ion ◽  
Ion Concentration ◽  
Extracellular Potassium ◽  
Spreading Depolarization ◽  
Potential Tool ◽  
Stimulation Of

A normally functioning nervous system requires normal extracellular potassium ion concentration ([K]o). Throughout the nervous system, several processes, including those of an astrocytic nature, are involved in [K]o regulation. In this study we investigated the effect of astrocytic photostimulation on [K]o. We hypothesized that in vivo photostimulation of eNpHR-expressing astrocytes leads to a decreased [K]o. Using optogenetic and electrophysiological techniques we showed that stimulation of eNpHR-expressing astrocytes resulted in a significantly decreased resting [K]o and evoked K responses. The amplitude of the concomitant spreading depolarization-like events also decreased. Our results imply that astrocytic membrane potential modification could be a potential tool for adjusting the [K]o.

Disorders of potassium homeostasis

2010 ◽  
pp. 3831-3845 ◽  
Author(s):  
J Firth
Keyword(s):  
Membrane Potential ◽  
Potassium Concentration ◽  
Resting Membrane Potential ◽  
Extracellular Potassium ◽  
Normal Range ◽  
Critical Determinant ◽  
Potassium Homeostasis ◽  
Extracellular Potassium Concentration

The normal range of potassium concentration in serum is 3.5 to 5.0 mmol/litre and within cells it is 150 to 160 mmol/litre, the ratio of intracellular to extracellular potassium concentration being a critical determinant of cellular resting membrane potential and thereby of the function of excitable tissues....

Conductance changes underlying a late synaptic hyperpolarization in hippocampal CA3 neurons

1987 ◽  
Vol 58 (1) ◽  
pp. 160-179 ◽  
Author(s):  
J. J. Hablitz ◽  
R. H. Thalmann
Keyword(s):  
Membrane Potential ◽  
Voltage Clamp ◽  
Time Course ◽  
Membrane Potentials ◽  
Resting Membrane Potential ◽  
Extracellular Potassium ◽  
Voltage Sensitivity ◽  
Base Line ◽  
Membrane Hyperpolarization ◽  
Ca3 Neurons

1. Single-electrode current- and voltage-clamp techniques were employed to study properties of the conductance underlying an orthodromically evoked late synaptic hyperpolarization or late inhibitory postsynaptic potential (IPSP) in CA3 pyramidal neurons in the rat hippocampal slice preparation. 2. Late IPSPs could occur without preceding excitatory postsynaptic potentials at the resting membrane potential and were graded according to the strength of the orthodromic stimulus. The membrane hyperpolarization associated with the late IPSP peaked within 140-200 ms after orthodromic stimulation of mossy fiber afferents. The late IPSP returned to base line with a half-decay time of approximately 200 ms. 3. As determined from constant-amplitude hyperpolarizing-current pulses, the membrane conductance increase during the late IPSP, and the time course of its decay, were similar whether measurements were made near the resting membrane potential or when the cell was hyperpolarized by approximately 35 mV. 4. When 1 mM cesium was added to the extracellular medium to reduce inward rectification, late IPSPs could be examined over a range of membrane potentials from -60 to -140 mV. For any given neuron, the late IPSP amplitude-membrane potential relationship was linear over the same range of membrane potentials for which the slope input resistance was constant. The late IPSP reversed symmetrically near -95 mV. 5. Intracellular injection of ethyleneglycol-bis-(beta-aminoethylether)-N,N'-tetraacetic acid or extracellular application of forskolin, procedures known to reduce or block certain calcium-dependent potassium conductances in CA3 neurons, had no significant effect on the late IPSP. 6. Single-electrode voltage-clamp techniques were used to analyze the time course and voltage sensitivity of the current underlying the late IPSP. This current [the late inhibitory postsynaptic current (IPSC)] began as early as 25 ms after orthodromic stimulation and reached a peak 120-150 ms following stimulation. 7. The late IPSC decayed with a single exponential time course (tau = 185 ms). 8. A clear reversal of the late IPSC at approximately -99 mV was observed in a physiological concentration of extracellular potassium (3.5 mM).(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of insulin on membrane potential and potassium content of rat muscle

1959 ◽  
Vol 197 (3) ◽  
pp. 515-523 ◽  
Author(s):  
Kenneth L. Zierler
Keyword(s):  
Membrane Potential ◽  
Extensor Digitorum Longus ◽  
Extensor Digitorum ◽  
Potassium Content ◽  
Resting Membrane Potential ◽  
Extracellular Potassium ◽  
Conventional Theory ◽  
Rat Muscle

Insulin increased resting membrane potential of excised rat muscle, extensor digitorum longus, by about 5 mv in less than 1 hour. In 1 hour insulin caused no increase in the ratio of intra- to extracellular potassium, but in 2–3 hours intracellular K increased by about 10%. It is concluded that the increase in intracellular K is probably too small and too late to account for the hyperpolarization on the basis of conventional theory and it is suggested that the hyperpolarization produced by insulin is the cause of the potassium shift.

Comparative responses of brain stem and hippocampal neurons to O2 deprivation: in vitro intracellular studies

1992 ◽  
Vol 262 (5) ◽  
pp. L549-L554 ◽  
Author(s):  
D. F. Donnelly ◽  
C. Jiang ◽  
G. G. Haddad
Keyword(s):  
Membrane Potential ◽  
Brain Stem ◽  
Cortical Neurons ◽  
Oxygen Deprivation ◽  
Oxygen Availability ◽  
Hypoxic Exposure ◽  
Hypoglossal Nucleus ◽  
Resting Membrane Potential ◽  
Extracellular Potassium ◽  
Motor Nucleus

Most mammalian neurons are known to be sensitive to oxygen availability, but the nature of the sensitivity is not well understood. Previous results have suggested that brain stem neurons may respond differently than cortical neurons during oxygen deprivation. We pursued this hypothesis by examining the time course of change in membrane potential (Vm) and input resistance (Rn) during periods of reduced oxygen availability in a tissue slice preparation. Since extracellular potassium is an important factor determining resting membrane potential, extracellular K+ activity, (K+o), was also measured. Adult rat neurons from three regions were recorded: hippocampal CA1 region, hypoglossal nucleus (XII), and dorsal vagal motor nucleus (DMNX). At the end of a 5-min hypoxic exposure, all neurons depolarized and this depolarization was greatest in XII (28.8 +/- 3.2 mV) compared with DMNX (17.8 +/- 3.7 mV) and CA1 (6.7 +/- 4.4 mV). K+o increased in all regions and was larger in DMNX (7.1 +/- 2.6 mM) and XII (5.3 +/- 2.1 mM) compared with CA1 (2.2 +/- 1.4 mM). During more severe oxygen deprivation (anoxia), neurons also depolarized at different rates with XII greater than DMNX greater than CA1. K+o increased markedly (28–36 mM) by 5 min into anoxia, and no statistical difference was observed between regions. From these results we conclude that 1) all cells tested were depolarized after 5 min of hypoxia; however, regional variability exists in the sensitivity to hypoxia; brain stem neurons depolarize faster than cortical neurons; 2) during anoxia, all brain stem and cortical neurons show a major depolarization, and 3) these differences in membrane potential cannot be solely attributed to changes in extracellular K+.

scholarly journals Network activity influences the subthreshold and spiking visual responses of pyramidal neurons in a three-layer cortex

2016 ◽  
Author(s):  
Nathaniel C. Wright ◽  
Ralf Wessel
Keyword(s):  
Membrane Potential ◽  
Cortical Neurons ◽  
Visual Stimulation ◽  
Ex Vivo ◽  
Network Activity ◽  
Visual Responses ◽  
Cortical Function ◽  
Sensory Evoked ◽  
High Conductance

A primary goal of systems neuroscience is to understand cortical function, which typically involves studying spontaneous and sensory-evoked cortical activity. Mounting evidence suggests a strong and complex relationship between the ongoing and evoked state. To date, most work in this area has been based on spiking in populations of neurons. While advantageous in many respects, this approach is limited in scope; it records the activities of a minority of neurons, and gives no direct indication of the underlying subthreshold dynamics. Membrane potential recordings can fill these gaps in our understanding, but are difficult to obtain in vivo. Here, we record subthreshold cortical visual responses in the ex vivo turtle eye-attached whole-brain preparation, which is ideally-suited to such a study. In the absence of visual stimulation, the network is “synchronous”; neurons display network-mediated transitions between low- and high-conductance membrane potential states. The prevalence of these slow-wave transitions varies across turtles and recording sessions. Visual stimulation evokes similar high-conductance states, which are on average larger and less reliable when the ongoing state is more synchronous. Responses are muted when immediately preceded by large, spontaneous high-conductance events. Evoked spiking is sparse, highly variable across trials, and mediated by concerted synaptic inputs that are in general only very weakly correlated with inputs to nearby neurons. Together, these results highlight the multiplexed influence of the cortical network on the spontaneous and sensory-evoked activity of individual cortical neurons.

In vivo membrane potentials of smooth muscle cells in the caudal artery of the rat

1985 ◽  
Vol 249 (1) ◽  
pp. C78-C83 ◽  
Author(s):  
H. J. Bryant ◽  
D. R. Harder ◽  
M. B. Pamnani ◽  
F. J. Haddy
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Membrane Potentials ◽  
Resting Membrane Potential ◽  
Humoral Factors ◽  
Caudal Artery ◽  
Blood Pressures

Membrane potentials measured in vivo may differ significantly from those measured in vitro in part due to humoral factors, innervation, and wall tension. These studies were initiated to determine whether it is feasible to record membrane potentials from vascular smooth muscle cells in vivo in the caudal artery of the pentobarbital-anesthetized male Wistar rat. Membrane potentials were measured using glass microelectrodes and correlated with systolic, diastolic, and mean blood pressures. For systolic blood pressures between 100 and 140 mmHg the average resting membrane potential was -38.4 +/- 0.48 mV. There was good correlation of systolic, diastolic, and mean blood pressures with membrane potential between 100 and 140 mmHg (r = 0.89, 0.75, and 0.89, respectively). Below 80 mmHg the arterial muscle cells became more depolarized than would be expected if the membrane potential were determined solely by transmural pressure. The depolarized membrane potential at low arterial pressures may be due to enhanced neural input. Spontaneous electrical activity was observed in some of the in vivo cells. When action potentials were present, they were generated at rates between 1-2/s and 6-7/min. These studies indicate that it is feasible to measure membrane potentials from arterial smooth muscle cells in vivo in the caudal artery of the rat.

Effect of low pO2 on Qo2, Na22 efflux, and contractility of muscles

1965 ◽  
Vol 208 (5) ◽  
pp. 855-860 ◽  
Author(s):  
William J. Whalen ◽  
Priscilla Bosch ◽  
Andrejs Dimants
Keyword(s):  
Lactic Acid ◽  
Membrane Potential ◽  
Gas Mixtures ◽  
Resting Membrane Potential ◽  
Minimal Level ◽  
Cellular Environment ◽  
Oxygen Tensions ◽  
Develop Tension

Previous experiments suggested that the in vivo consumption of O2 by the cell is normally limited by the pO2 in the cellular environment. We suggested that if the pO2 exceeds a certain minimal level, some or all of the energy from the "extra" respiration may be directly converted to heat. To further test the hypothesis, 39 isolated frog sartorii were placed in respirometers containing Ringer-bicarbonate solution (at 22 or 27 C) equilibrated with gas mixtures of various oxygen tensions. (All gases contained 2% CO2.) The Qo2 of muscles exposed to 98% O2 for 6–7 hr reached a stable value which was about 200% of the stable value for muscles exposed to 25% O2 for the same period of time. In other experiments the depression of the Qo2 in 25% O2 was shown to be reversible. The ability to develop tension, as judged by occasional test contractions, was not impaired in 25% O2. The amount of lactic acid liberated from the muscles was small and was independent of the pO2. In additional experiments with similar muscles exposed to either 25% O2 or 98% N2 for 5–7 hr, neither the Na22 efflux nor resting membrane potential differed significantly from the values obtained in 98% O2. The data are consistent with the hypothesis.

scholarly journals Clarithromycin increases neuronal excitability in CA3 pyramidal neurons through a reduction in GABAergic signaling

2017 ◽  
Vol 117 (1) ◽  
pp. 93-103 ◽  
Author(s):  
Edyta K. Bichler ◽  
Courtney C. Elder ◽  
Paul S. García
Keyword(s):  
Membrane Potential ◽  
Bacterial Infections ◽  
Neuronal Excitability ◽  
Ex Vivo ◽  
Pyramidal Cells ◽  
Receptor Activation ◽  
Firing Frequency ◽  
Resting Membrane Potential ◽  
Minor Effect ◽  
Burst Frequency

Antibiotics are used in the treatment and prevention of bacterial infections, but effects on neuron excitability have been documented. A recent study demonstrated that clarithromycin alleviates daytime sleepiness in hypersomnia patients (Trotti LM, Saini P, Freeman AA, Bliwise DL, García PS, Jenkins A, Rye DB. J Psychopharmacol 28: 697–702, 2014). To explore the potential application of clarithromycin as a stimulant, we performed whole cell patch-clamp recordings in rat pyramidal cells from the CA3 region of hippocampus. In the presence of the antibiotic, rheobase current was reduced by 50%, F-I relationship (number of action potentials as a function of injected current) was shifted to the left, and the resting membrane potential was more depolarized. Clarithromycin-induced hyperexcitability was dose dependent; doses of 30 and 300 μM clarithromycin significantly increased the firing frequency and membrane potential compared with controls ( P = 0.003, P < 0.0001). We hypothesized that clarithromycin enhanced excitability by reducing GABAA receptor activation. Clarithromycin at 30 μM significantly reduced ( P = 0.001) the amplitude of spontaneous miniature inhibitory GABAergic currents and at 300 μM had a minor effect on action potential width. Additionally, we tested the effect of clarithromycin in an ex vivo seizure model by evaluating its effect on spontaneous local field potentials. Bath application of 300 μM clarithromycin enhanced burst frequency twofold compared with controls ( P = 0.0006). Taken together, these results suggest that blocking GABAergic signaling with clarithromycin increases cellular excitability and potentially serves as a stimulant, facilitating emergence from anesthesia or normalizing vigilance in hypersomnia and narcolepsy. However, the administration of clarithromycin should be carefully considered in patients with seizure disorders. NEW & NOTEWORTHY Clinical administration of the macrolide antibiotic clarithromycin has been associated with side effects such as mania, agitation, and delirium. Here, we investigated the adverse effects of this antibiotic on CA3 pyramidal cell excitability. Clarithromycin induces hyperexcitability in single neurons and is related to a reduction in GABAergic signaling. Our results support a potentially new application of clarithromycin as a stimulant to facilitate emergence from anesthesia or to normalize vigilance.

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