Spontaneous GABAA receptor-mediated inhibitory currents in adult rat somatosensory cortex

1. Spontaneous inhibitory synaptic currents (sIPSCs) were studied with whole cell voltage-clamp recordings from 131 pyramidal cells in adult rat somatosensory cortical slices. Neurons were intracellulary labeled with biocytin and classified as supragranular (SG, layers 2-3), layer IV (IV), or infragranular (IG, layer V) on the basis of the laminar localization of their somata. Somatic areas were similar for SG, IV, and IG neurons. All identified pyramidal cells generated high-frequency gamma-aminobutyric acid (GABAA) receptor-mediated synaptic events. 2. Bath application of bicuculline blocked the sIPSCs and resulted in a decrease of approximately 0.5 nS in resting conductance and an inward shift in baseline current. 3. sIPSC frequency was significantly lower in SG versus IG or IV neurons, and this difference was accounted for by the occurrence of a higher percentage of bursts of sIPSCs in the IG and IV neurons. 4. Bath application of the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) decreased the frequency of sIPSCs by 13-21%. By contrast, application of the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonovaleric acid (D-AP5) generally had no effect on spontaneous IPSC frequency, suggesting that AMPA rather than NMDA receptor activation contributed to resting discharge of inhibitory interneurons. 5. Addition of tetrodotoxin (TTX) to the perfusion medium reduced the spontaneous IPSC frequency by approximately 30-55%. The miniature IPSCs (mIPSCs) seen in TTX-containing solutions had a frequency of approximately 10 Hz and an average conductance of 0.42-0.48 nS. 6. The kinetic properties of mIPSCs generated in pyramidal cells of different layers were the same, with the rise times of approximately 0.9 ms and decay time constants of approximately 8 ms at a holding potential of 0 mV. The decay phase of mIPSCs was generally fitted by one exponential and displayed a voltage dependence with an e-fold increase in decay time constant for a every 198-mV depolarization. 7. These results show that there is ongoing spontaneous release of GABA in neocortical slices that gives rise to high-frequency impulse-related and non-impulse-related postsynaptic inhibitory currents. Activation of AMPA receptors on inhibitory interneurons accounts for only a small proportion of the GABAA receptor-mediated events. Judging from the distribution of mIPSC frequencies in neurons of different laminae, there is a relatively uniform distribution of inhibitory synapses throughout the cortex. Tonic activation of GABAA receptors on neocortical pyramidal neurons generates an increase in resting membrane conductance that may play an important role in vivo by preventing the development of hyperexcitability, modulating excitatory synaptic events, and controlling the rate and patterns of spike discharge.

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Ca(2+)-dependent non-NMDA receptor-mediated synaptic currents in ischemic CA1 hippocampal neurons

Journal of Neurophysiology ◽

10.1152/jn.1994.71.3.1190 ◽

1994 ◽

Vol 71 (3) ◽

pp. 1190-1196 ◽

Cited By ~ 43

Author(s):

H. Tsubokawa ◽

K. Oguro ◽

T. Masuzawa ◽

N. Kawai

Keyword(s):

Nmda Receptor ◽

Receptor Antagonist ◽

Time Constant ◽

Decay Time ◽

Nmda Receptor Antagonist ◽

Decay Time Constant ◽

Disulfonic Acid ◽

Time Constants ◽

Bath Application ◽

Nmda Current

1. The changes in excitatory postsynaptic currents (EPSCs) after transient cerebral ischemia were studied using whole-cell recording from CA1 pyramidal neurons in gerbils. In 64% (18 of 28) neurons recorded 1.5-3 days after ischemia, EPSCs showed a markedly slowed time course that was never seen in normal control neurons. 2. The slow EPSCs were not affected by an N-methyl-D-aspartate (NMDA) receptor antagonist [DL-2-aminophosphonovalerate (APV); 100 microM] but were abolished by a non-NMDA receptor antagonist [6-cyano-7-nitroquinoxaline-2,3-dione (CNQX); 10 microM], indicating that the slow EPSCs were mostly composed of non-NMDA current. 3. The slow non-NMDA EPSCs had rise times ranging from 1.2 to 7.3 ms and decay time constants between 11.5 and 56.3 ms. In normal neurons the rise time of the non-NMDA component of EPSCs ranged from 1.6 to 7.5 ms and the decay time constants ranged from 4.9 to 27.3 ms. 4. The reversal potential of the slow EPSCs in ischemic neurons was not changed by replacing 50% of the NaCl in the external solution with sodium isethionate. Bath application of 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS; 100 microM) had no effect on the slow EPSCs. Therefore Cl- current is not responsible for the slow EPSCs. 5. When external Ca2+ concentration was reduced to half of control, the decay time constant of the slow EPSCs decreased to 50 +/- 25%, mean +/- SD. In addition, bath application of a cell-permeable Ca2+ chelator, 1,2-bis(o-aminophenoxy)ethane-N,N,-N',N'-tetraacetyl,tetr aacetoxymethyl ester(BAPTA-AM), reduced the decay time constant.(ABSTRACT TRUNCATED AT 250 WORDS)

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Levetiracetam induction of theta frequency oscillations in rodent hippocampus in vitro

10.21203/rs.2.13686/v2 ◽

2019 ◽

Author(s):

Hang Xing ◽

Sihan Xu ◽

Xin'e Xie ◽

Yuan Wang ◽

Cheng Biao Lu ◽

...

Keyword(s):

Cognitive Function ◽

Nmda Receptor ◽

Receptor Antagonist ◽

Gabaa Receptor ◽

Theta Rhythm ◽

Receptor Activation ◽

Local Network ◽

Receptor Antagonists ◽

Theta Oscillation ◽

Theta Power

Abstract Background Levetiracetam (LEV), an antiepileptic drug, has been recently demonstrated to improve the cognitive function. Hippocampal theta rhythm (4–12 Hz) is associated with a variety of cognitively related behaviors, such as exploration, locomotion and spatial memory in both humans and animal models. We investigated the effects of LEV on the theta rhythm in the rat hippocampal CA3 area. Results We found that LEV increased the power of theta oscillation in a dose-dependent manner. The increase in theta power can be blocked by GABAA receptor or NMDA receptor antagonists but not by AMPA receptor antagonist, indicating the involvement of GABAA receptor and NMDA receptor in the induction of theta activity. Interestingly, LEV enhancement of theta power can be also blocked by taurine or THIP, indicating that LEV induction of theta may be related to the indirect boosting of GABA action via reduction of extrasynaptic GABAA receptor activation. Furthermore, the increased theta power can be partially reduced by mACh receptor antagonist atropine but not by nACh receptor antagonists, suggesting that mACh receptor activation provides excitatory input into local network responsible for LEV induction of theta. Conclusions Our study demonstrated that induction of a synchronized network oscillation, a novel role of LEV may especially benefit for the treatment of the neuronal disorders with impaired theta oscillation and cognitive function.

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Levetiracetam induction of theta frequency oscillations in rodent hippocampus in vitro

10.21203/rs.2.13686/v1 ◽

2019 ◽

Author(s):

Hang Xing ◽

Cheng Biao Lu ◽

Xiong Han ◽

Xin'e Xie ◽

Yuan Wang

Keyword(s):

Cognitive Function ◽

Nmda Receptor ◽

Receptor Antagonist ◽

Gabaa Receptor ◽

Theta Rhythm ◽

Receptor Activation ◽

Local Network ◽

Receptor Antagonists ◽

Theta Oscillation ◽

Theta Power

Abstract Background Levetiracetam (LEV), an antiepileptic drug, has been recently demonstrated to improve the cognitive function. Hippocampal theta rhythm (4–12 Hz) is associated with a variety of cognitively related behaviors, such as exploration, locomotion and spatial memory in both humans and animal models. We investigated the effects of LEV on the theta rhythm in the rat hippocampal CA3 area. Results We found that LEV increased the power of theta oscillation in a dose-dependent manner. The increase in theta power can be blocked by GABAA receptor or NMDA receptor antagonists but not by AMPA receptor antagonist, indicating the involvement of GABAA receptor and NMDA receptor in the induction of theta activity. Interestingly, LEV enhancement of theta power can be also blocked by taurine, indicating that LEV induction of theta may be related to the indirect boosting of GABA action via reduction of extrasynaptic GABAA receptor activation. Furthermore, the increased theta power can be partially reduced by mACh receptor antagonist atropine but not by nACh receptor antagonists, suggesting that mACh receptor activation provides excitatory input into local network responsible for LEV induction of theta. Conclusions Our study demonstrated that induction of a synchronized network oscillation, a novel role of LEV may especially benefit for the treatment of the neuronal disorders with impaired theta oscillation and cognitive function.

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Cell-Specific Alterations in Synaptic Properties of Hippocampal CA1 Interneurons After Kainate Treatment

Journal of Neurophysiology ◽

10.1152/jn.1998.80.6.2836 ◽

1998 ◽

Vol 80 (6) ◽

pp. 2836-2847 ◽

Cited By ~ 27

Author(s):

F. Morin ◽

C. Beaulieu ◽

J.-C. Lacaille

Keyword(s):

Time Constant ◽

Decay Time ◽

Pyramidal Cells ◽

Stratum Radiatum ◽

Inhibitory Interneurons ◽

Cell Type ◽

Postsynaptic Currents ◽

Ca1 Region ◽

Hippocampal Ca1 ◽

Stratum Lacunosum Moleculare

Morin, F., C. Beaulieu, and J.-C. Lacaille. Cell-specific alterations in synaptic properties of hippocampal CA1 interneurons after kainate treatment. J. Neurophysiol. 80: 2836–2847, 1998. Hippocampal sclerosis and hyperexcitability are neuropathological features of human temporal lobe epilepsy that are reproduced in the kainic acid (KA) model of epilepsy in rats. To assess directly the role of inhibitory interneurons in the KA model, the membrane and synaptic properties of interneurons located in 1) stratum oriens near the alveus (O/A) and 2) at the border of stratum radiatum and stratum lacunosum-moleculare (LM), as well as those of pyramidal cells, were examined with whole cell recordings in slices of control and KA-lesioned rats. In current-clamp recordings, intrinsic cell properties such as action potential amplitude and duration, amplitude of fast and medium duration afterhyperpolarizations, membrane time constant, and input resistance were generally unchanged in all cell types after KA treatment. In voltage-clamp recordings, the amplitude and conductance of pharmacologically isolated excitatory postsynaptic currents (EPSCs) were significantly reduced in LM interneurons of KA-treated animals but were not significantly changed in O/A and pyramidal cells. The rise time of EPSCs was not significantly changed in any cell type after KA treatment. In contrast, the decay time constant of EPSCs was significantly faster in O/A interneurons of KA-treated rats but was unchanged in LM and pyramidal cells. The amplitude and conductance of pharmacologically isolated γ-aminobutyric acid-A (GABAA) inhibitory postsynaptic currents (IPSCs) were not significantly changed in any cell type of KA-treated rats. The rise time and decay time constant of GABAA IPSCs were significantly faster in pyramidal cells of KA-treated rats but were not significantly changed in O/A and LM interneurons. These results suggest that complex alterations in synaptic currents occur in specific subpopulations of inhibitory interneurons in the CA1 region after KA lesions. A reduction of evoked excitatory drive onto inhibitory cells located at the border of stratum radiatum and stratum lacunosum-moleculare may contribute to disinhibition and polysynaptic epileptiform activity in the CA1 region. Compensatory changes, involving excitatory synaptic transmission on other interneuron subtypes and inhibitory synaptic transmission on pyramidal cells, may also take place and contribute to the residual, functional monosynaptic inhibition observed in principal cells after KA treatment.

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Excitatory transmission in the basolateral amygdala

Journal of Neurophysiology ◽

10.1152/jn.1991.66.3.986 ◽

1991 ◽

Vol 66 (3) ◽

pp. 986-998 ◽

Cited By ~ 129

Author(s):

D. G. Rainnie ◽

E. K. Asprodini ◽

P. Shinnick-Gallagher

Keyword(s):

Nmda Receptor ◽

Receptor Antagonist ◽

Nmda Antagonist ◽

Receptor Activation ◽

Nmda Receptor Antagonist ◽

Current Injection ◽

Membrane Hyperpolarization ◽

Postsynaptic Potentials ◽

The Mean ◽

Stimulation Of

1. Intracellular current-clamp recordings obtained from neurons of the basolateral nucleus of the amygdala (BLA) were used to characterize postsynaptic potentials elicited through stimulation of the stria terminalis (ST) or the lateral amygdala (LA). The contribution of glutamatergic receptor subtypes to excitatory postsynaptic potentials (EPSPs) were analyzed by the use of the non N-methyl-D-aspartate (non-NMDA) antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), and the NMDA antagonist, (DL)-2-amino-5-phosphonovaleric acid (APV). 2. Basic membrane properties of BLA neurons determined from membrane responses to transient current injection showed that at the mean resting membrane potential (RMP; -67.2 mV) the input resistance (RN) and time constant for membrane charging (tau) were near maximal, and that both values were reduced with membrane hyperpolarization, suggesting an intrinsic regulation of synaptic efficacy. 3. Responses to stimulation of the ST or LA consisted of an EPSP followed by either a fast inhibitory postsynaptic potential (f-IPSP) only, or by a fast- and subsequent slow-IPSP (s-IPSP). The EPSP was graded in nature, increasing in amplitude with increased stimulus intensity, and with membrane hyperpolarization after DC current injection. Spontaneous EPSPs were also observed either as discrete events or as EPSP/IPSP waveforms. 4. In physiological Mg2+ concentrations (1.2 mM), at the mean RMP, the EPSP consisted of dual, fast and slow, glutamatergic components. The fast-EPSP (f-EPSP) possessed characteristics of kainate/quisqualate receptor activation, namely, the EPSP increased in amplitude with membrane hyperpolarization, was insensitive to the NMDA receptor antagonist, APV (50 microM), and was blocked by the non-NMDA receptor antagonist, CNQX (10 microM). In contrast, the slow-EPSP (s-EPSP) decreased in amplitude with membrane hyperpolarization, was insensitive to CNQX (10 microM), and was blocked by APV (50 microM), indicating mediation by NMDA receptor activation. 5. In the presence of CNQX (10 microM), ST stimulation evoked an APV-sensitive s-EPSP. In contrast, LA stimulation evoked a f-IPSP, which when blocked by subsequent addition of bicuculline methiodide (BMI; 30 microM) revealed a temporally overlapping APV-sensitive s-EPSP. These data suggest that EPSP amplitude and duration are determined, in part, by the shunting of membrane conductance caused by a concomitant IPSP. 6. Superfusion of either CNQX or APV in BLA neurons caused membrane hyperpolarization and blockade of spontaneous EPSPs and IPSPs, suggesting that these compounds may act to block tonic excitatory amino acid (EAA) release within the nucleus, and that a degree of feed-forward inhibition occurs within the nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)

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On the synchronous activity induced by 4-aminopyridine in the CA3 subfield of juvenile rat hippocampus

Journal of Neurophysiology ◽

10.1152/jn.1993.70.3.1018 ◽

1993 ◽

Vol 70 (3) ◽

pp. 1018-1029 ◽

Cited By ~ 55

Author(s):

M. Avoli ◽

C. Psarropoulou ◽

V. Tancredi ◽

Y. Fueta

Keyword(s):

Nmda Receptor ◽

Gabaa Receptor ◽

Action Potentials ◽

Hippocampal Slices ◽

Field Potential ◽

Pyramidal Cells ◽

Occurrence Rate ◽

Gamma Aminobutyric Acid ◽

Synchronous Activity ◽

Ca3 Pyramidal Cells

1. Extracellular field potential and intracellular recordings were made in the CA3 subfield of hippocampal slices obtained from 10- to 24-day-old rats during perfusion with artificial cerebrospinal fluid (ACSF) containing the convulsant 4-aminopyridine (4-AP, 50 microM). 2. Three types of spontaneous, synchronous activity were recorded in the presence of 4-AP by employing extracellular microelectrodes positioned in the CA3 stratum (s.) radiatum: first, inter-ictal-like discharges that lasted 0.2-1.2 s and had an occurrence rate of 0.3-1.3 Hz; second, ictal-like events (duration: 3-40 s) that occurred at 4-38 x 10(-3) Hz; and third, large-amplitude (up to 8 mV) negative-going potentials that preceded the onset of the ictal-like events and thus appeared to initiate them. 3. None of these synchronous activities was consistently modified by addition of antagonists of the N-methyl-D-aspartate (NMDA) receptor to the ACSF. In contrast, the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 2-10 microM) reversibly blocked interictal- and ictallike discharges. The only synchronous, spontaneous activity recorded in this type of medium consisted of the negative-going potentials that were abolished by the GABAA receptor antagonists bicuculline methiodide (5-20 microM) or picrotoxin (50 microM). Hence they were mediated through the activation of the GABAA receptor. 4. Profile analysis of the 4-AP-induced synchronous activity revealed that the gamma-aminobutyric acid (GABA)-mediated field potential had maximal negative amplitude in s. lacunosum-moleculare, attained equipotentiality at the border between s. radiatum and s. pyramidale, and became positive-going in s. oriens. These findings indicated that the GABA-mediated field potential presumably represented a depolarization occurring in the dendrites of CA3 pyramidal cells. 5. This conclusion was supported by intracellular analysis of the 4-AP-induced activity. The GABA-mediated potential was reflected by a depolarization of the membrane of CA3 pyramidal cells that triggered a few variable-amplitude, fractionated spikes or fast action potentials. By contrast, the ictal-like discharge was associated with a prolonged depolarization during which repetitive bursts of action potentials occurred. Short-lasting depolarizations with bursts of action potentials occurred during each interictal-like discharge. 6. The GABA-mediated potential recorded intracellularly in the presence of CNQX consisted of a prolonged depolarization (up to 12 s) that was still capable of triggering a few fast action potentials and/or fractionated spikes.(ABSTRACT TRUNCATED AT 400 WORDS)

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Transient High-Frequency Firing in a Coupled-Oscillator Model of the Mesencephalic Dopaminergic Neuron

Journal of Neurophysiology ◽

10.1152/jn.00691.2004 ◽

2006 ◽

Vol 95 (2) ◽

pp. 932-947 ◽

Cited By ~ 56

Author(s):

Alexey S. Kuznetsov ◽

Nancy J. Kopell ◽

Charles J. Wilson

Keyword(s):

Nmda Receptor ◽

High Frequency ◽

Dopaminergic Neurons ◽

Dopaminergic Neuron ◽

Receptor Activation ◽

Oscillator Model ◽

Coupled Oscillator ◽

Depolarization Block ◽

Nmda Receptor Activation ◽

Coupled Oscillator Model

Dopaminergic neurons of the midbrain fire spontaneously at rates <10/s and ordinarily will not exceed this range even when driven with somatic current injection. When driven at higher rates, these cells undergo spike failure through depolarization block. During spontaneous bursting of dopaminergic neurons in vivo, bursts related to reward expectation in behaving animals, and bursts generated by dendritic application of N-methyl-d-aspartate (NMDA) agonists, transient firing attains rates well above this range. We suggest a way such high-frequency firing may occur in response to dendritic NMDA receptor activation. We have extended the coupled oscillator model of the dopaminergic neuron, which represents the soma and dendrites as electrically coupled compartments with different natural spiking frequencies, by addition of dendritic AMPA (voltage-independent) or NMDA (voltage-dependent) synaptic conductance. Both soma and dendrites contain a simplified version of the calcium-potassium mechanism known to be the mechanism for slow spontaneous oscillation and background firing in dopaminergic cells. The compartments differ only in diameter, and this difference is responsible for the difference in natural frequencies. We show that because of its voltage dependence, NMDA receptor activation acts to amplify the effect on the soma of the high-frequency oscillation of the dendrites, which is normally too weak to exert a large influence on the overall oscillation frequency of the neuron. During the high-frequency oscillations that result, sodium inactivation in the soma is removed rapidly after each action potential by the hyperpolarizing influence of the dendritic calcium-dependent potassium current, preventing depolarization block of the spike mechanism, and allowing high-frequency spiking.

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