α5GABAA Receptors Regulate the Intrinsic Excitability of Mouse Hippocampal Pyramidal Neurons

2007 ◽  
Vol 98 (4) ◽  
pp. 2244-2254 ◽  
Author(s):  
Robert P. Bonin ◽  
Loren J. Martin ◽  
John F. MacDonald ◽  
Beverley A. Orser
Keyword(s):  
Action Potential ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Physiological Role ◽  
Network Activity ◽  
Equilibrium Potential ◽  
Resting Membrane Potential ◽  
Action Potential Firing ◽  
Membrane Hyperpolarization ◽  
Hippocampal Pyramidal Neurons

GABAA receptors generate both phasic and tonic forms of inhibition. In hippocampal pyramidal neurons, GABAA receptors that contain the α5 subunit generate a tonic inhibitory conductance. The physiological role of this tonic inhibition is uncertain, although α5GABAA receptors are known to influence hippocampal-dependent learning and memory processes. Here we provide evidence that α5GABAA receptors regulate the strength of the depolarizing stimulus that is required to generate an action potential in pyramidal neurons. Neurons from α5 knock-out (α5−/−) and wild-type (WT) mice were studied in brain slices and cell cultures using whole cell and perforated-patch-clamp techniques. Membrane resistance was 1.6-fold greater in α5−/− than in WT neurons, but the resting membrane potential and chloride equilibrium potential were similar. Membrane hyperpolarization evoked by an application of exogenous GABA was greater in WT neurons. Inhibiting the function of α5GABAA receptor with nonselective (picrotoxin) or α5 subunit-selective (L-655,708) compounds depolarized WT neurons by ∼3 mV, whereas no change was detected in α5−/− neurons. The depolarizing current required to generate an action potential was twofold greater in WT than in α5−/− neurons, whereas the slope of the input-output relationship for action potential firing was similar. We conclude that shunting inhibition mediated by α5GABAA receptors regulates the firing of action potentials and may synchronize network activity that underlies hippocampal-dependent behavior.

scholarly journals β3-Adrenergic receptor-dependent modulation of the medium afterhyperpolarization in rat hippocampal CA1 pyramidal neurons

2019 ◽  
Vol 121 (3) ◽  
pp. 773-784 ◽  
Author(s):  
Timothy W. Church ◽  
Jon T. Brown ◽  
Neil V. Marrion
Keyword(s):  
Action Potential ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Intracellular Camp ◽  
Action Potential Firing ◽  
Hippocampal Pyramidal Neurons ◽  
Potential Firing ◽  
H Channels

Action potential firing in hippocampal pyramidal neurons is regulated by generation of an afterhyperpolarization (AHP). Three phases of AHP are recognized, with the fast AHP regulating action potential firing at the onset of a burst and the medium and slow AHPs supressing action potential firing over hundreds of milliseconds and seconds, respectively. Activation of β-adrenergic receptors suppresses the slow AHP by a protein kinase A-dependent pathway. However, little is known regarding modulation of the medium AHP. Application of the selective β-adrenergic receptor agonist isoproterenol suppressed both the medium and slow AHPs evoked in rat CA1 hippocampal pyramidal neurons recorded from slices maintained in organotypic culture. Suppression of the slow AHP was mimicked by intracellular application of cAMP, with the suppression of the medium AHP by isoproterenol still being evident in cAMP-dialyzed cells. Suppression of both the medium and slow AHPs was antagonized by the β-adrenergic receptor antagonist propranolol. The effect of isoproterenol to suppress the medium AHP was mimicked by two β3-adrenergic receptor agonists, BRL37344 and SR58611A. The medium AHP was mediated by activation of small-conductance calcium-activated K+ channels and deactivation of H channels at the resting membrane potential. Suppression of the medium AHP by isoproterenol was reduced by pretreating cells with the H-channel blocker ZD7288. These data suggest that activation of β3-adrenergic receptors inhibits H channels, which suppresses the medium AHP in CA1 hippocampal neurons by utilizing a pathway that is independent of a rise in intracellular cAMP. This finding highlights a potential new target in modulating H-channel activity and thereby neuronal excitability. NEW & NOTEWORTHY The noradrenergic input into the hippocampus is involved in modulating long-term synaptic plasticity and is implicated in learning and memory. We demonstrate that activation of functional β3-adrenergic receptors suppresses the medium afterhyperpolarization in hippocampal pyramidal neurons. This finding provides an additional mechanism to increase action potential firing frequency, where neuronal excitability is likely to be crucial in cognition and memory.

scholarly journals The mechanisms shaping CA2 pyramidal neuron action potential bursting induced by muscarinic acetylcholine receptor activation

2020 ◽  
Vol 152 (4) ◽  
Author(s):  
Vincent Robert ◽  
Ludivine Therreau ◽  
M. Felicia Davatolhagh ◽  
F. Javier Bernardo-Garcia ◽  
Katie N. Clements ◽  
...  
Keyword(s):  
Action Potential ◽  
Synaptic Transmission ◽  
Pyramidal Neurons ◽  
Membrane Resistance ◽  
Receptor Activation ◽  
Resting Membrane Potential ◽  
Intrinsic Properties ◽  
Action Potential Firing ◽  
Cholinergic Tone ◽  
Induced Changes

Recent studies have revealed that hippocampal area CA2 plays an important role in hippocampal network function. Disruption of this region has been implicated in neuropsychiatric disorders. It is well appreciated that cholinergic input to the hippocampus plays an important role in learning and memory. While the effect of elevated cholinergic tone has been well studied in areas CA1 and CA3, it remains unclear how changes in cholinergic tone impact synaptic transmission and the intrinsic properties of neurons in area CA2. In this study, we applied the cholinergic agonist carbachol and performed on-cell, whole-cell, and extracellular recordings in area CA2. We observed that under conditions of high cholinergic tone, CA2 pyramidal neurons depolarized and rhythmically fired bursts of action potentials. This depolarization depended on the activation of M1 and M3 cholinergic receptors. Furthermore, we examined how the intrinsic properties and action-potential firing were altered in CA2 pyramidal neurons treated with 10 µM carbachol. While this intrinsic burst firing persisted in the absence of synaptic transmission, bursts were shaped by synaptic inputs in the intact network. We found that both excitatory and inhibitory synaptic transmission were reduced upon carbachol treatment. Finally, we examined the contribution of different channels to the cholinergic-induced changes in neuronal properties. We found that a conductance from Kv7 channels partially contributed to carbachol-induced changes in resting membrane potential and membrane resistance. We also found that D-type potassium currents contributed to controlling several properties of the bursts, including firing rate and burst kinetics. Furthermore, we determined that T-type calcium channels and small conductance calcium-activated potassium channels play a role in regulating bursting activity.

Identification of a spontaneously active, Na+-permeable channel in guinea pig gallbladder smooth muscle

2005 ◽  
Vol 289 (3) ◽  
pp. G501-G507 ◽  
Author(s):  
Georgi V. Petkov ◽  
Onesmo B. Balemba ◽  
Mark T. Nelson ◽  
Gary M. Mawe
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Guinea Pig ◽  
Action Potential ◽  
Equilibrium Potential ◽  
Resting Membrane Potential ◽  
Action Potential Generation ◽  
Potential Generation ◽  
Membrane Hyperpolarization ◽  
Permeable Channel

The action potential in gallbladder smooth muscle (GBSM) is caused by Ca2+ entry through voltage-dependent Ca2+ channels (VDCC), which contributes to the GBSM contractions. Action potential generation in GBSM is critically dependent on the resting membrane potential (about −50 mV), which is ∼35 mV more positive of the K+ equilibrium potential. We hypothesized that a tonic, depolarizing conductance is present in GBSM and contributes to the regulation of the resting membrane potential and action potential frequency. GBSM cells were isolated from guinea pig gallbladders, and the whole cell patch-camp technique was used to record membrane currents. After eliminating the contribution of VDCC and K+ channels, we identified a novel spontaneously active cation conductance ( Icat) in GBSM. This Icat was mediated predominantly by influx of Na+. Na+ substitution with N-methyl-d-glucamine (NMDG), a large relatively impermeant cation, caused a negative shift in the reversal potential of the ramp current and reduced the amplitude of the inward current at −50 mV by 65%. Membrane potential recordings with intracellular microelectrodes or in current-clamp mode of the patch-clamp technique indicated that the inhibition of Icat conductance by NMDG is associated with membrane hyperpolarization and inhibition of action potentials. Extracellular Ca2+, Mg2+, and Gd3+ attenuated the Icat in GBSM. Muscarinic stimulation did not activate the Icat. Our results indicate that, in GBSM, an Na+-permeable channel contributes to the maintenance of the resting membrane potential and action potential generation and therefore plays a critical role in the regulation of GBSM excitability and contractility.

scholarly journals Spike-frequency dependent inhibition and excitation of neural activity by high-frequency ultrasound

2020 ◽  
Author(s):  
Martin Loynaz Prieto ◽  
Kamyar Firouzi ◽  
Butrus T. Khuri-Yakub ◽  
Daniel V. Madison ◽  
Merritt Maduke
Keyword(s):  
Action Potential ◽  
Sodium Channels ◽  
High Frequency ◽  
Pyramidal Neurons ◽  
Potassium Conductance ◽  
Firing Frequency ◽  
Resting Membrane Potential ◽  
Action Potential Firing ◽  
Voltage Dependent ◽  
Potential Firing

ABSTRACTUltrasound can modulate action-potential firing in vivo and in vitro, but the mechanistic basis of this phenomenon is not well understood. To address this problem, we used patch-clamp recording to quantify the effects of focused, high-frequency (43 MHz) ultrasound on evoked action potential firing in CA1 pyramidal neurons in acute rodent hippocampal brain slices. We find that ultrasound can either inhibit or potentiate firing in a spike-frequency-dependent manner: at low (near-threshold) input currents and low firing frequencies, ultrasound inhibits firing, while at higher input currents and higher firing frequencies, ultrasound potentiates firing. The net result of these two competing effects is that ultrasound increases the threshold current for action potential firing, the slope of frequency-input curves, and the maximum firing frequency. In addition, ultrasound slightly hyperpolarizes the resting membrane potential, decreases action potential width, and increases the depth of the afterhyperpolarization. All of these results can be explained by the hypothesis that ultrasound activates a sustained potassium conductance. According to this hypothesis, increased outward potassium currents hyperpolarize the resting membrane potential and inhibit firing at near-threshold input currents, but potentiate firing in response to higher input currents by limiting inactivation of voltage-dependent sodium channels during the action potential. This latter effect is a consequence of faster action-potential repolarization, which limits inactivation of voltage-dependent sodium channels, and deeper (more negative) afterhyperpolarization, which increases the rate of recovery from inactivation. Based on these results we propose that ultrasound activates thermosensitive and mechanosensitive two-pore-domain potassium (K2P) channels, through heating or mechanical effects of acoustic radiation force. Finite-element modelling of the effects of ultrasound on brain tissue suggests that the effects of ultrasound on firing frequency are caused by a small (less than 2°C) increase in temperature, with possible additional contributions from mechanical effectsSUMMARYPrieto et al. describe how ultrasound can either inhibit or potentiate action potential firing in hippocampal pyramidal neurons and demonstrate that these effects can be explained by increased potassium conductance.

Electrophysiological Properties of Cholinergic and Noncholinergic Neurons in the Ventral Pallidal Region of the Nucleus Basalis in Rat Brain Slices

2000 ◽  
Vol 83 (5) ◽  
pp. 2649-2660 ◽  
Author(s):  
C. Peter Bengtson ◽  
Peregrine B. Osborne
Keyword(s):  
Brain Slices ◽  
Physiological Role ◽  
Cholinergic Neurons ◽  
Firing Frequency ◽  
Nucleus Basalis ◽  
Morphological Properties ◽  
Inward Rectification ◽  
Resting Membrane Potential ◽  
Whole Cell ◽  
Electrophysiological Properties

The ventral pallidum is a major source of output for ventral corticobasal ganglia circuits that function in translating motivationally relevant stimuli into adaptive behavioral responses. In this study, whole cell patch-clamp recordings were made from ventral pallidal neurons in brain slices from 6- to 18-day-old rats. Intracellular filling with biocytin was used to correlate the electrophysiological and morphological properties of cholinergic and noncholinergic neurons identified by choline acetyltransferase immunohistochemistry. Most cholinergic neurons had a large whole cell conductance and exhibited marked fast (i.e., anomalous) inward rectification. These cells typically did not fire spontaneously, had a hyperpolarized resting membrane potential, and also exhibited a prominent spike afterhyperpolarization (AHP) and strong spike accommodation. Noncholinergic neurons had a smaller whole cell conductance, and the majority of these cells exhibited marked time-dependent inward rectification that was due to an h-current. This current activated slowly over several hundred milliseconds at potentials more negative than −80 mV. Noncholinergic neurons fired tonically in regular or intermittent patterns, and two-thirds of the cells fired spontaneously. Depolarizing current injection in current clamp did not cause spike accommodation but markedly increased the firing frequency and in some cells also altered the pattern of firing. Spontaneous tetrodotoxin-sensitive GABAA-mediated inhibitory postsynaptic currents (IPSCs) were frequently recorded in noncholinergic neurons. These results show that cholinergic pallidal neurons have similar properties to magnocellular cholinergic neurons in other parts of the forebrain, except that they exhibit strong spike accommodation. Noncholinergic ventral pallidal neurons have large h-currents that could have a physiological role in determining the rate or pattern of firing of these cells.

scholarly journals Constitutive activity of dopamine receptor type 1 (D1R) increases CaV2.2 currents in PFC neurons

2020 ◽  
Vol 152 (5) ◽  
Author(s):  
Clara Inés McCarthy ◽  
Cambria Chou-Freed ◽  
Silvia Susana Rodríguez ◽  
Agustín Yaneff ◽  
Carlos Davio ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
Pyramidal Neurons ◽  
Critical Role ◽  
Intraperitoneal Administration ◽  
Brain Slices ◽  
Physiological Role ◽  
Receptor Type ◽  
Constitutive Activity ◽  
Medial Pfc

Alterations in dopamine receptor type 1 (D1R) density are associated with cognitive deficits of aging and schizophrenia. In the prefrontal cortex (PFC), D1R plays a critical role in the regulation of working memory, which is impaired in these cognitive deficit states, but the cellular events triggered by changes in D1R expression remain unknown. A previous report demonstrated that interaction between voltage-gated calcium channel type 2.2 (CaV2.2) and D1R stimulates CaV2.2 postsynaptic surface location in medial PFC pyramidal neurons. Here, we show that in addition to the occurrence of the physical receptor-channel interaction, constitutive D1R activity mediates up-regulation of functional CaV2.2 surface density. We performed patch-clamp experiments on transfected HEK293T cells and wild-type C57BL/6 mouse brain slices, as well as imaging experiments and cAMP measurements. We found that D1R coexpression led to ∼60% increase in CaV2.2 currents in HEK293T cells. This effect was occluded by preincubation with a D1/D5R inverse agonist, chlorpromazine, and by replacing D1R with a D1R mutant lacking constitutive activity. Moreover, D1R-induced increase in CaV2.2 currents required basally active Gs protein, as well as D1R-CaV2.2 interaction. In mice, intraperitoneal administration of chlorpromazine reduced native CaV currents’ sensitivity to ω-conotoxin-GVIA and their size by ∼49% in layer V/VI pyramidal neurons from medial PFC, indicating a selective effect on CaV2.2. Additionally, we found that reducing D1/D5R constitutive activity correlates with a decrease in the agonist-induced D1/D5R inhibitory effect on native CaV currents. Our results could be interpreted as a stimulatory effect of D1R constitutive activity on the number of CaV2.2 channels available for dopamine-mediated modulation. Our results contribute to the understanding of the physiological role of D1R constitutive activity and may explain the noncanonical postsynaptic distribution of functional CaV2.2 in PFC neurons.

scholarly journals Heterogeneity in Kv2 Channel Expression Shapes Action Potential Characteristics and Firing Patterns in CA1 versus CA2 Hippocampal Pyramidal Neurons

eNeuro ◽  
2017 ◽  
Vol 4 (4) ◽  
pp. ENEURO.0267-17.2017 ◽  
Author(s):  
Stephanie Palacio ◽  
Vivien Chevaleyre ◽  
David H. Brann ◽  
Karl D. Murray ◽  
Rebecca A. Piskorowski ◽  
...  
Keyword(s):  
Action Potential ◽  
Pyramidal Neurons ◽  
Firing Patterns ◽  
Hippocampal Pyramidal Neurons ◽  
Channel Expression

scholarly journals The GABA Developmental Shift Is Abolished by Maternal Immune Activation Already at Birth

2018 ◽  
Vol 29 (9) ◽  
pp. 3982-3992 ◽  
Author(s):  
Amandine Fernandez ◽  
Camille Dumon ◽  
Damien Guimond ◽  
Roman Tyzio ◽  
Paolo Bonifazi ◽  
...  
Keyword(s):  
Immune Activation ◽  
Pyramidal Neurons ◽  
Experimental Studies ◽  
Network Activity ◽  
Hippocampal Pyramidal Neurons ◽  
Pairwise Correlation ◽  
Maternal Immune Activation ◽  
Postsynaptic Currents ◽  
Developmental Shift ◽  
Excitatory Action

Abstract Epidemiological and experimental studies suggest that maternal immune activation (MIA) leads to developmental brain disorders, but whether the pathogenic mechanism impacts neurons already at birth is not known. We now report that MIA abolishes in mice the oxytocin-mediated delivery γ-aminobutyric acid (GABA) shift from depolarizing to hyperpolarizing in CA3 pyramidal neurons, and this is restored by the NKCC1 chloride importer antagonist bumetanide. Furthermore, MIA hippocampal pyramidal neurons at birth have a more exuberant apical arbor organization and increased apical dendritic length than age-matched controls. The frequency of spontaneous glutamatergic postsynaptic currents is also increased in MIA offspring, as well as the pairwise correlation of the synchronized firing of active cells in CA3. These alterations produced by MIA persist, since at P14–15 GABA action remains depolarizing, produces excitatory action, and network activity remains elevated with a higher frequency of spontaneous glutamatergic postsynaptic currents. Therefore, the pathogenic actions of MIA lead to important morphophysiological and network alterations in the hippocampus already at birth.

Methods for intracellular recording from hippocampal brain slices under high helium pressure

1991 ◽  
Vol 71 (1) ◽  
pp. 365-371 ◽  
Author(s):  
A. P. Southan ◽  
K. T. Wann
Keyword(s):  
Intracellular Recording ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Pressure Chamber ◽  
Resting Membrane Potential ◽  
Helium Pressure ◽  
Remote Manipulation ◽  
Current Voltage ◽  
Chamber Temperature ◽  
Current Voltage Relationship

A method for intracellular recording from rat hippocampal brain slices under helium pressure is described. The preparation is mounted on a horizontal mobile platform that is rolled into the pressure chamber and can be viewed at pressure. Remote manipulation of the glass microelectrodes is achieved by a high-resolution electrically driven commercially available system. The slice is superfused continuously from a closed system within the chamber. Temperature is maintained at 37 degrees C and PO2 at 0.5 atm within the pressure chamber. A pressure of 200 ATA can be obtained, although thus far recordings have been made up to only 130 ATA. The experiments demand that a number of sample recordings be made from the same slice at both ambient and high pressure, and tests have proved that, although difficult, this can be achieved. The resting membrane potential, the current-voltage relationship, and the action potential responses to short (8 ms), medium (80 ms), and long (800 ms) depolarizing current pulses have all been measured in CA1 pyramidal neurons.

scholarly journals The antihelminthic moxidectin enhances tonic GABA currents in rodent hippocampal pyramidal neurons

2018 ◽  
Vol 119 (5) ◽  
pp. 1693-1698
Author(s):  
Jay Spampanato ◽  
Anne Gibson ◽  
F. Edward Dudek
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Gaba Receptors ◽  
Pyramidal Neurons ◽  
Ex Vivo ◽  
Companion Animals ◽  
Brain Slices ◽  
Dependent Manner ◽  
Hippocampal Pyramidal Neurons ◽  
Mammalian Central Nervous System

Macrocyclic lactones (MLs) are commonly used treatments for parasitic worm and insect infections in humans, livestock, and companion animals. MLs target the invertebrate glutamate-activated chloride channel that is not present in vertebrates. MLs are not entirely inert in vertebrates, though; they have been reported to have activity in heterologous expression systems consisting of ligand-gated ion channels that are present in the mammalian central nervous system (CNS). However, these compounds are typically not able to reach significant concentrations in the CNS because of the activity of the blood-brain barrier P-glycoprotein extrusion system. Despite this, these compounds are able to reach low levels in the CNS that may be useful in the design of novel “designer” ligand-receptor systems that can be used to directly investigate neuronal control of behavior in mammals and have potential for use in treating human neurological diseases. To determine whether MLs might affect neurons in intact brains, we investigated the activity of the ML moxidectin (MOX) at native GABA receptors. Specifically, we recorded tonic and phasic miniature inhibitory postsynaptic currents (mIPSCs) in ex vivo brain slices. Our data show that MOX potentiated tonic GABA currents in a dose-dependent manner but had no concomitant effects on phasic GABA currents (i.e., MOX had no effect on the amplitude, frequency, or decay kinetics of mIPSCs). These studies indicate that behavioral experiments that implement a ML-based novel ligand-receptor system should take care to control for potential effects of the ML on native tonic GABA receptors.NEW & NOTEWORTHY We have identified a novel mechanism of action in the mammalian central nervous system for the antihelminthic moxidectin, commonly prescribed to animals worldwide and currently being evaluated for use in humans. Specifically, moxidectin applied to rodent brain slices selectively enhanced the tonic GABA conductance of hippocampal pyramidal neurons.

Sign in / Sign up

Export Citation Format

Share Document