scholarly journals Potassium channels contribute to activity-dependent scaling of dendritic inhibition

2017 ◽  
Author(s):  
Jeremy T. Chang ◽  
Michael J. Higley
Keyword(s):  
Potassium Channels ◽  
Neuronal Activity ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Critical Role ◽  
Pyramidal Cells ◽  
Gabaergic Inhibition ◽  
Voltage Gated ◽  
The Impact ◽  
Activity Dependent

AbstractGABAergic inhibition plays a critical role in the regulation of neuronal activity. In the neocortex, inhibitory interneurons that target the dendrites of pyramidal cells influence both electrical and biochemical postsynaptic signaling. Voltage-gated ion channels strongly shape dendritic excitability and the integration of excitatory inputs, but their contribution to GABAergic signaling is less well understood. By combining 2-photon calcium imaging and focal GABA uncaging, we show that voltage-gated potassium channels normally suppress the GABAergic inhibition of calcium signals evoked by back-propagating action potentials in dendritic spines and shafts of cortical pyramidal neurons. Moreover, the voltage-dependent inactivation of these channels leads to enhancement of dendritic calcium inhibition following somatic spiking. Computational modeling reveals that the enhancement of calcium inhibition involves an increase in action potential depolarization coupled with the nonlinear relationship between membrane voltage and calcium channel activation. Overall, our findings highlight the interaction between intrinsic and synaptic properties and reveal a novel mechanism for the activity-dependent scaling of GABAergic inhibition.Significance StatementGABAergic inhibition potently regulates neuronal activity in the neocortex. How such inhibition interacts with the intrinsic electrophysiological properties of single neurons is not well-understood. Here we investigate the ability of voltage-gated potassium channels to regulate the impact of GABAergic inhibition in the dendrites of neocortical pyramidal neurons. Our results show that potassium channels normally reduce inhibition directed towards pyramidal neuron dendrites. However, these channels are inactivated by strong neuronal activity, leading to an enhancement of GABAergic potency and limiting the corresponding influx of dendritic calcium. Our findings illustrate a previously unappreciated relationship between neuronal excitability and GABAergic inhibition.

scholarly journals Impact of inhibitory constraint of interneurons on neuronal excitability

2013 ◽  
Vol 110 (11) ◽  
pp. 2520-2535 ◽  
Author(s):  
Vallent Lee ◽  
Jamie Maguire
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Molecular Layer ◽  
Critical Role ◽  
Tonic Inhibition ◽  
Stratum Radiatum ◽  
Gabaergic Inhibition ◽  
Seizure Susceptibility ◽  
Ca1 Pyramidal Neurons ◽  
The Impact

Tonic inhibition is thought to dampen the excitability of principal neurons; however, little is known about the role of tonic GABAergic inhibition in interneurons and the impact on principal neuron excitability. In many brain regions, tonic GABAergic inhibition is mediated by extrasynaptic, δ-subunit-containing GABAA receptors (GABAARs). In the present study we demonstrate the importance of GABAAR δ-subunit-mediated tonic inhibition in interneurons. Selective elimination of the GABAAR δ-subunit from interneurons was achieved by crossing a novel floxed Gabrd mouse model with GAD65-Cre mice ( Gabrd/Gad mice). Deficits in GABAAR δ-subunit expression in GAD65-positive neurons result in a decrease in tonic GABAergic inhibition and increased excitability of both molecular layer (ML) and stratum radiatum (SR) interneurons. Disinhibition of interneurons results in robust alterations in the neuronal excitability of principal neurons and decreased seizure susceptibility. Gabrd/Gad mice have enhanced tonic and phasic GABAergic inhibition in both CA1 pyramidal neurons and dentate gyrus granule cells (DGGCs). Consistent with alterations in hippocampal excitability, CA1 pyramidal neurons and DGGCs from Gabrd/Gad mice exhibit a shift in the input-output relationship toward decreased excitability compared with those from Cre−/− littermates. Furthermore, seizure susceptibility, in response to 20 mg/kg kainic acid, is significantly decreased in Gabrd/Gad mice compared with Cre−/− controls. These data demonstrate a critical role for GABAAR δ-subunit-mediated tonic GABAergic inhibition of interneurons on principal neuronal excitability and seizure susceptibility.

scholarly journals Somatic and dendritic GABAB receptors regulate neuronal excitability via different mechanisms

2012 ◽  
Vol 108 (10) ◽  
pp. 2810-2818 ◽  
Author(s):  
Jean-Didier Breton ◽  
Greg J. Stuart
Keyword(s):  
Potassium Channels ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Barrel Cortex ◽  
Receptor Activation ◽  
Gabab Receptors ◽  
Membrane Properties ◽  
Dendritic Excitability ◽  
The Impact ◽  
Neuronal Output

GABAB receptors play a key role in regulating neuronal excitability in the brain. Whereas the impact of somatic GABAB receptors on neuronal excitability has been studied in some detail, much less is known about the role of dendritic GABAB receptors. Here, we investigate the impact of GABAB receptor activation on the somato-dendritic excitability of layer 5 pyramidal neurons in the rat barrel cortex. Activation of GABAB receptors led to hyperpolarization and a decrease in membrane resistance that was greatest at somatic and proximal dendritic locations. These effects were occluded by low concentrations of barium (100 μM), suggesting that they are mediated by potassium channels. In contrast, activation of dendritic GABAB receptors decreased the width of backpropagating action potential (APs) and abolished dendritic calcium electrogenesis, indicating that dendritic GABAB receptors regulate excitability, primarily via inhibition of voltage-dependent calcium channels. These distinct actions of somatic and dendritic GABAB receptors regulated neuronal output in different ways. Activation of somatic GABAB receptors led to a reduction in neuronal output, primarily by increasing the AP rheobase, whereas activation of dendritic GABAB receptors blocked burst firing, decreasing AP output in the absence of a significant change in somatic membrane properties. Taken together, our results show that GABAB receptors regulate somatic and dendritic excitability of cortical pyramidal neurons via different cellular mechanisms. Somatic GABAB receptors activate potassium channels, leading primarily to a subtractive or shunting form of inhibition, whereas dendritic GABAB receptors inhibit dendritic calcium electrogenesis, leading to a reduction in bursting firing.

scholarly journals Opening of KATP Channel Regulates Tonic Currents From Pyramidal Neurons in Rat Brain

2017 ◽  
Vol 44 (6) ◽  
pp. 718-725
Author(s):  
Zhongxia Li ◽  
Jiangping Wang ◽  
Huimin Yu ◽  
Kewen Jiang
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Cortical Layer ◽  
Gaba A ◽  
Gaba Inhibition ◽  
Ambient Gaba ◽  
Neuronal Functions ◽  
Tonic Current ◽  
The Impact

AbstractBackground: ATP-sensitive K+ (KATP) channels couple metabolic state to cellular excitability. Activation of neuronal and astrocytic mitochondrial KATP (mitoKATP) channels regulates a variety of neuronal functions. However, less is known about the impact of mitoKATP on tonic γ-aminobutyric acid (GABA) inhibition. Tonic GABA inhibition is mediated by the binding of ambient GABA on extrasynaptic GABA A-type receptors (GABAARs) and is involved in regulating neuronal excitability. Methods: We determined the impact of activation of KATP channels with diazoxide (DIZ) on tonic inhibition and recorded tonic current from rat cortical layer 5 pyramidal cells by patch-clamp recordings. Results: We found that neonatal tonic current increased with an increase in GABA concentration, which was partially mediated by the GABA A-type receptor (GABAAR) α5, and likely the δ subunits. Activation of KATP channels resulted in decreased tonic current in newborns, but there was increased tonic current during the second postnatal week. Conclusions: These findings suggest that activation of KATP channels with DIZ regulates GABAergic transmission in neocortical pyramidal cells during development.

scholarly journals SUMO modification of cell surface Kv2.1 potassium channels regulates the activity of rat hippocampal neurons

2011 ◽  
Vol 137 (5) ◽  
pp. 441-454 ◽  
Author(s):  
Leigh D. Plant ◽  
Evan J. Dowdell ◽  
Irina S. Dementieva ◽  
Jeremy D. Marks ◽  
Steve A.N. Goldstein
Keyword(s):  
Potassium Channels ◽  
Cell Surface ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Voltage Gated ◽  
Sumo Modification ◽  
Maximal Activation ◽  
Sumo Pathway ◽  
Activity Dependent ◽  
The Brain

Voltage-gated Kv2.1 potassium channels are important in the brain for determining activity-dependent excitability. Small ubiquitin-like modifier proteins (SUMOs) regulate function through reversible, enzyme-mediated conjugation to target lysine(s). Here, sumoylation of Kv2.1 in hippocampal neurons is shown to regulate firing by shifting the half-maximal activation voltage (V1/2) of channels up to 35 mV. Native SUMO and Kv2.1 are shown to interact within and outside channel clusters at the neuronal surface. Studies of single, heterologously expressed Kv2.1 channels show that only K470 is sumoylated. The channels have four subunits, but no more than two non-adjacent subunits carry SUMO concurrently. SUMO on one site shifts V1/2 by 15 mV, whereas sumoylation of two sites produces a full response. Thus, the SUMO pathway regulates neuronal excitability via Kv2.1 in a direct and graded manner.

Differential Impact of Miniature Synaptic Potentials on the Soma and Dendrites of Pyramidal Neurons In Vivo

1997 ◽  
Vol 78 (3) ◽  
pp. 1735-1739 ◽  
Author(s):  
Denis Paré ◽  
Elen Lebel ◽  
Eric J. Lang
Keyword(s):  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Input Resistance ◽  
Differential Impact ◽  
Synaptic Potentials ◽  
Ampa Antagonists ◽  
Intact Brain ◽  
The Impact

Paré, Denis, Elen LeBel, and Eric J. Lang. Differential impact of miniature synaptic potentials on the somata and dendrites of pyramidal neurons in vivo. J. Neurophysiol. 78: 1735–1739, 1997. We studied the impact of transmitter release resistant to tetrodotoxin (TTX) in morphologically identified neocortical pyramidal neurons recorded intracellularly in barbiturate-anesthetized cats. It was observed that TTX-resistant release occurs in pyramidal neurons in vivo and at much higher frequencies than was previously reported in vitro. Further, in agreement with previous findings indicating that GABAergic and glutamatergic synapses are differentially distributed in the somata and dendrites of pyramidal cells, we found that most miniature synaptic potentials were sensitive to γ-aminobutyric acid-A (GABAA) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists in presumed somatic and dendritic impalements, respectively. Pharmacological blockage of spontaneous synaptic events produced large increases in input resistance that were more important in dendritic (≈50%) than somatic (≈10%) impalements. These findings imply that in the intact brain, pyramidal neurons are submitted to an intense spike-independent synaptic bombardment that decreases the space constant of the cells. These results should be taken into account when extrapolating in vitro findings to intact brains.

Dynamic regulation of the voltage-gated Kv2.1 potassium channel by multisite phosphorylation

2007 ◽  
Vol 35 (5) ◽  
pp. 1064-1068 ◽  
Author(s):  
D.P. Mohapatra ◽  
K.-S. Park ◽  
J.S. Trimmer
Keyword(s):  
Neuronal Excitability ◽  
Critical Role ◽  
Functional Characterization ◽  
K Channel ◽  
Delayed Rectifier ◽  
Dynamic Regulation ◽  
Voltage Gated ◽  
Voltage Dependent ◽  
Specific Regulation

Voltage-gated K+ channels are key regulators of neuronal excitability. The Kv2.1 voltage-gated K+ channel is the major delayed rectifier K+ channel expressed in most central neurons, where it exists as a highly phosphorylated protein. Kv2.1 plays a critical role in homoeostatic regulation of intrinsic neuronal excitability through its activity- and calcineurin-dependent dephosphorylation. Here, we review studies leading to the identification and functional characterization of in vivo Kv2.1 phosphorylation sites, a subset of which contribute to graded modulation of voltage-dependent gating. These findings show that distinct developmental-, cell- and state-specific regulation of phosphorylation at specific sites confers a diversity of functions on Kv2.1 that is critical to its role as a regulator of intrinsic neuronal excitability.

Exposure to low temperature prepares the turtle brain to withstand anoxic environments during overwintering

2021 ◽  
Author(s):  
Ebrahim Lari ◽  
Leslie T. Buck
Keyword(s):  
Membrane Potential ◽  
Low Temperature ◽  
Action Potential ◽  
Pyramidal Neurons ◽  
Cellular Damage ◽  
Severe Hypoxia ◽  
Painted Turtle ◽  
Whole Cell ◽  
Voltage Gated ◽  
The Impact

In most vertebrates, anoxia drastically reduces the production of the essential adenosine triphosphate (ATP) to power its many necessary functions, and consequently, cell death occurs within minutes. However, some vertebrates, such as the painted turtle (Chrysemys picta bellii), have evolved the ability to survive months without oxygen by simultaneously decreasing ATP supply and demand, surviving the anoxic period without any apparent cellular damage. The impact of anoxia on the metabolic function of painted turtles has received a lot of attention. Still, the impact of low temperature has received less attention and the interactive effect of anoxia and temperature even less. In the present study, we investigated the interactive impacts of reduced temperature and severe hypoxia on the electrophysiological properties of pyramidal neurons in painted turtle cerebral cortex. Our results show that an acute reduction in temperature from 20 to 5°C decreases membrane potential, action potential width and amplitude, and whole-cell conductance. Importantly, acute exposure to 5°C considerably slows membrane repolarization by voltage-gated K+ channels. Exposing pyramidal cells to severe hypoxia in addition to an acute temperature change slightly depolarized membrane potential but did not alter action potential amplitude or width and whole-cell conductance. These results suggest that acclimation to low temperatures, preceding severe environmental hypoxia, induces cellular responses in pyramidal neurons that facilitate survival under low oxygen concentration. In particular, our results show that temperature acclimation invokes a change in voltage-gated K+ channel kinetics that overcomes the acute inhibition of the channel.

scholarly journals Of mice and intrinsic excitability: genetic background affects the size of the postburst afterhyperpolarization in CA1 pyramidal neurons

2011 ◽  
Vol 106 (3) ◽  
pp. 1570-1580 ◽  
Author(s):  
Shannon J. Moore ◽  
Benjamin T. Throesch ◽  
Geoffrey G. Murphy
Keyword(s):  
Genetic Background ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Critical Role ◽  
Genetically Engineered ◽  
Gradual Transition ◽  
Cellular Mechanisms ◽  
Ca1 Pyramidal Neurons ◽  
Genetically Engineered Mice ◽  
Cell Current

As the use of genetically engineered mice has become increasingly prevalent in neurobiological research, evidence has steadily accumulated that substantial differences exist between strains. Although a number of studies have reported effects of genetic background on behavior, few have focused on differences in neurophysiology. The postburst afterhyperpolarization (AHP) is an important determinant of intrinsic neuronal excitability and has been suggested to play a critical role in the cellular mechanisms underlying learning and memory. Using whole cell current-clamp recordings of CA1 pyramidal neurons, we examined the magnitude of different phases of the AHP (peak, medium, and slow) in two commonly used genetic backgrounds, C57BL/6 (B6) and 129SvEv (129), as well as in an F2 hybrid B6:129 background (F2). We found that neurons from B6 and F2 animals exhibited a significantly larger AHP compared with 129 animals and that this difference was consistent across all phases. Furthermore, our recordings revealed a marked dichotomy in the shape of the AHP waveform, which was independent of genetic background. Approximately 60% of cells exhibited an AHP with a sharp transition between the peak AHP and medium AHP, whereas the remaining 40% exhibited a more gradual transition. Our data add to the growing body of work suggesting that genetic background can affect neuronal function as well as behavior. In addition, these results highlight the innate heterogeneity of CA1 pyramidal neurons, even within a single genetic background. These differences should be taken into consideration during the analysis and comparison of experimental results.

scholarly journals Homeostatic Plasticity Hypothesis and Mechanisms of Neocortical Epilepsies

2005 ◽  
Vol 5 (4) ◽  
pp. 133-135 ◽  
Author(s):  
Jaideep Kapur ◽  
Stacey Trotter
Keyword(s):  
Synaptic Plasticity ◽  
Neuronal Activity ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Homeostatic Plasticity ◽  
Excitatory Synapses ◽  
Excitatory Postsynaptic Currents ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Homeostatic Synaptic Plasticity

Homeostatic Synaptic Plasticity Can Explain Posttraumatic Epileptogenesis in Chronically Isolated Neocortex Houweling AR, Bazhenov M, Timofeev I, Steriade M, Sejnowski TJ Cereb Cortex 2004 [Epub ahead of print] Permanently isolated neocortex develops chronic hyperexcitability and focal epileptogenesis in a period of days to weeks. The mechanisms operating in this model of posttraumatic epileptogenesis are not well understood. We hypothesized that the spontaneous burst discharges recorded in permanently isolated neocortex result from homeostatic plasticity (a mechanism generally assumed to stabilize neuronal activity) induced by low neuronal activity after deafferentation. To test this hypothesis, we constructed computer models of neocortex incorporating a biologically based homeostatic plasticity rule that operates to maintain firing rates. After deafferentation, homeostatic upregulation of excitatory synapses on pyramidal cells, either with or without concurrent downregulation of inhibitory synapses or upregulation of intrinsic excitability, initiated slowly repeating burst discharges that closely resembled the epileptiform burst discharges recorded in permanently isolated neocortex. These burst discharges lasted a few hundred milliseconds, propagated at 1 to 3 cm/s and consisted of large (10–15 mV) intracellular depolarizations topped by a small number of action potentials. Our results support a role for homeostatic synaptic plasticity as a novel mechanism of posttraumatic epileptogenesis. Excitatory and Inhibitory Postsynaptic Currents in a Rat Model of Epileptogenic Microgyria Jacobs KM, Prince DA J Neurophysiol 2005;93:687–696 Developmental cortical malformations are common in patients with intractable epilepsy; however, mechanisms contributing to this epileptogenesis are currently poorly understood. We previously characterized hyperexcitability in a rat model that mimics the histopathology of human four-layered microgyria. Here we examined inhibitory and excitatory postsynaptic currents in this model to identify functional alterations that might contribute to epileptogenesis associated with microgyria. We recorded isolated whole-cell excitatory postsynaptic currents and GABAA receptor–mediated inhibitory currents from layer V pyramidal neurons in the region previously shown to be epileptogenic (paramicrogyral area) and in homotopic control cortex. Epileptiform-like activity could be evoked in 60% of paramicrogyral (PMG) cells by local stimulation. The peak conductance of both spontaneous and evoked inhibitory postsynaptic currents was significantly larger in all PMG cells compared with controls. This difference in amplitude was not present after blockade of ionotropic glutamatergic currents or for miniature (m) inhibitory postsynaptic currents, suggesting that it was due to the excitatory afferent activity driving inhibitory neurons. This conclusion was supported by the finding that glutamatereceptor antagonist application resulted in a significantly greater reduction in spontaneous inhibitory postsynaptic current frequency in one PMG cell group (PMGE) compared with control cells. The frequency of both spontaneous and miniature excitatory postsynaptic currents was significantly greater in all PMG cells, suggesting that pyramidal neurons adjacent to a microgyrus receive more excitatory input than do those in control cortex. These findings suggest that there is an increase in numbers of functional excitatory synapses on both interneurons and pyramidal cells in the PMG cortex, perhaps due to hyperinnervation by cortical afferents originally destined for the microgyrus proper.

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