scholarly journals Strychnine-sensitive glycine receptors on pyramidal neurons in layers II/III of the mouse prefrontal cortex are tonically activated

2014 ◽  
Vol 112 (5) ◽  
pp. 1169-1178 ◽  
Author(s):  
Michael C. Salling ◽  
Neil L. Harrison
Keyword(s):  
Prefrontal Cortex ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Tonic Inhibition ◽  
Dependent Manner ◽  
Glycine Receptors ◽  
Decay Kinetics ◽  
Concentration Dependent Manner ◽  
Inhibitory Neurotransmitter ◽  
Current Shift

Processing of signals within the cerebral cortex requires integration of synaptic inputs and a coordination between excitatory and inhibitory neurotransmission. In addition to the classic form of synaptic inhibition, another important mechanism that can regulate neuronal excitability is tonic inhibition via sustained activation of receptors by ambient levels of inhibitory neurotransmitter, usually GABA. The purpose of this study was to determine whether this occurs in layer II/III pyramidal neurons (PNs) in the prelimbic region of the mouse medial prefrontal cortex (mPFC). We found that these neurons respond to exogenous GABA and to the α4δ-containing GABAA receptor (GABAAR)-selective agonist gaboxadol, consistent with the presence of extrasynaptic GABAAR populations. Spontaneous and miniature synaptic currents were blocked by the GABAAR antagonist gabazine and had fast decay kinetics, consistent with typical synaptic GABAARs. Very few layer II/III neurons showed a baseline current shift in response to gabazine, but almost all showed a current shift (15–25 pA) in response to picrotoxin. In addition to being a noncompetitive antagonist at GABAARs, picrotoxin also blocks homomeric glycine receptors (GlyRs). Application of the GlyR antagonist strychnine caused a modest but consistent shift (∼15 pA) in membrane current, without affecting spontaneous synaptic events, consistent with the tonic activation of GlyRs. Further investigation showed that these neurons respond in a concentration-dependent manner to glycine and taurine. Inhibition of glycine transporter 1 (GlyT1) with sarcosine resulted in an inward current and an increase of the strychnine-sensitive current. Our data demonstrate the existence of functional GlyRs in layer II/III of the mPFC and a role for these receptors in tonic inhibition that can have an important influence on mPFC excitability and signal processing.

scholarly journals Sphingosine 1-phosphate receptor 2 antagonist JTE-013 increases the excitability of sensory neurons independently of the receptor

2012 ◽  
Vol 108 (5) ◽  
pp. 1473-1483 ◽  
Author(s):  
Chao Li ◽  
Xian Xuan Chi ◽  
Wenrui Xie ◽  
J. A. Strong ◽  
J.-M. Zhang ◽  
...  
Keyword(s):  
G Protein ◽  
Sensory Neurons ◽  
Neuronal Excitability ◽  
Small Diameter ◽  
G Protein Coupled Receptors ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled

Previously we demonstrated that sphingosine 1-phosphate receptor 1 (S1PR1) played a prominent, but not exclusive, role in enhancing the excitability of small-diameter sensory neurons, suggesting that other S1PRs can modulate neuronal excitability. To examine the potential role of S1PR2 in regulating neuronal excitability we used the established selective antagonist of S1PR2, JTE-013. Here we report that exposure to JTE-013 alone produced a significant increase in excitability in a time- and concentration-dependent manner in 70–80% of recorded neurons. Internal perfusion of sensory neurons with guanosine 5′- O-(2-thiodiphosphate) (GDP-β-S) via the recording pipette inhibited the sensitization produced by JTE-013 as well as prostaglandin E2. Pretreatment with pertussis toxin or the selective S1PR1 antagonist W146 blocked the sensitization produced by JTE-013. These results indicate that JTE-013 might act as an agonist at other G protein-coupled receptors. In neurons that were sensitized by JTE-013, single-cell RT-PCR studies demonstrated that these neurons did not express the mRNA for S1PR2. In behavioral studies, injection of JTE-013 into the rat's hindpaw produced a significant increase in the mechanical sensitivity in the ipsilateral, but not contralateral, paw. Injection of JTE-013 did not affect the withdrawal latency to thermal stimulation. Thus JTE-013 augments neuronal excitability independently of S1PR2 by unknown mechanisms that may involve activation of other G protein-coupled receptors such as S1PR1. Clearly, further studies are warranted to establish the causal nature of this increased sensitivity, and future studies of neuronal function using JTE-013 should be interpreted with caution.

scholarly journals RGS7/Gβ5/R7BP complex regulates synaptic plasticity and memory by modulating hippocampal GABABR-GIRK signaling

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Olga Ostrovskaya ◽  
Keqiang Xie ◽  
Ikuo Masuho ◽  
Ana Fajardo-Serrano ◽  
Rafael Lujan ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Dynamic Range ◽  
Gabab Receptor ◽  
Girk Channels ◽  
Hippocampal Pyramidal Neurons ◽  
Inhibitory Neurotransmitter ◽  
Membrane Anchoring

In the hippocampus, the inhibitory neurotransmitter GABA shapes the activity of the output pyramidal neurons and plays important role in cognition. Most of its inhibitory effects are mediated by signaling from GABAB receptor to the G protein-gated Inwardly-rectifying K+ (GIRK) channels. Here, we show that RGS7, in cooperation with its binding partner R7BP, regulates GABABR-GIRK signaling in hippocampal pyramidal neurons. Deletion of RGS7 in mice dramatically sensitizes GIRK responses to GABAB receptor stimulation and markedly slows channel deactivation kinetics. Enhanced activity of this signaling pathway leads to decreased neuronal excitability and selective disruption of inhibitory forms of synaptic plasticity. As a result, mice lacking RGS7 exhibit deficits in learning and memory. We further report that RGS7 is selectively modulated by its membrane anchoring subunit R7BP, which sets the dynamic range of GIRK responses. Together, these results demonstrate a novel role of RGS7 in hippocampal synaptic plasticity and memory formation.

Specific Subtypes of GABAA Receptors Mediate Phasic and Tonic Forms of Inhibition in Hippocampal Pyramidal Neurons

2006 ◽  
Vol 96 (2) ◽  
pp. 846-857 ◽  
Author(s):  
George A. Prenosil ◽  
Edith M. Schneider Gasser ◽  
Uwe Rudolph ◽  
Ruth Keist ◽  
Jean-Marc Fritschy ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Tonic Inhibition ◽  
Mammalian Brain ◽  
Triple Mutant ◽  
Α Subunit ◽  
Hippocampal Pyramidal Neurons ◽  
Inhibitory Neurotransmitter ◽  
Ca1 Area ◽  
Hippocampal Pyramidal Cells

The main inhibitory neurotransmitter in the mammalian brain, GABA, mediates multiple forms of inhibitory signals, such as fast and slow inhibitory postsynaptic currents and tonic inhibition, by activating a diverse family of ionotropic GABAA receptors (GABAARs). Here, we studied whether distinct GABAAR subtypes mediate these various forms of inhibition using as approach mice carrying a point mutation in the α-subunit rendering individual GABAAR subtypes insensitive to diazepam without altering their GABA sensitivity and expression of receptors. Whole cell patch-clamp recordings were performed in hippocampal pyramidal cells from single, double, and triple mutant mice. Comparing diazepam effects in knock-in and wild-type mice allowed determining the contribution of α1, α2, α3, and α5 subunits containing GABAARs to phasic and tonic forms of inhibition. Fast phasic currents were mediated by synaptic α2-GABAARs on the soma and by synaptic α1-GABAARs on the dendrites. No contribution of α3- or α5-GABAARs was detectable. Slow phasic currents were produced by both synaptic and perisynaptic GABAARs, judged by their strong sensitivity to blockade of GABA reuptake. In the CA1 area, but not in the subiculum, perisynaptic α5-GABAARs contributed to slow phasic currents. In the CA1 area, the diazepam-sensitive component of tonic inhibition also involved activation of α5-GABAARs and slow phasic and tonic signals shared overlapping pools of receptors. These results show that the major forms of inhibitory neurotransmission in hippocampal pyramidal cells are mediated by distinct GABAARs subtypes.

Dual effect of glycine on isolated rat suprachiasmatic neurons

1991 ◽  
Vol 260 (2) ◽  
pp. C213-C218 ◽  
Author(s):  
C. Ito ◽  
M. Wakamori ◽  
N. Akaike
Keyword(s):  
Neural Activity ◽  
Excitatory Amino Acids ◽  
Pharmacological Properties ◽  
Dependent Manner ◽  
Intracellular Recordings ◽  
Induced Current ◽  
Patch Clamp Technique ◽  
Dual Effect ◽  
Concentration Dependent Manner ◽  
Inhibitory Neurotransmitter

Pharmacological properties of strychnine-sensitive and -insensitive glycine receptors have been investigated in rat suprachiasmatic nucleus (SCN) neurons. Because the SCN neurons were too small for stable intracellular recordings by the glass-microelectrode technique, a conventional whole cell mode patch-clamp technique was employed on the acutely dissociated SCN neurons. Dissociated SCN neurons were morphologically heterogeneous and could be distinguished into several types. All cells responded to glycine in a concentration-dependent manner. The glycine-induced current was primarily Cl- sensitive and competitively blocked by strychnine. The SCN neurons also responded to excitatory amino acids: glutamate, quisqualate, kainate, and N-methyl-D-aspartate (NMDA). Responses to glutamate and aspartate, which are endogenous neurotransmitter candidates, were enhanced by adding glycine. Glycine especially augmented the maximum response to NMDA in a full concentration range. 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX) did not suppress the strychnine-sensitive glycine response but did suppress the strychnine-insensitive NMDA response in a competitive manner for glycine. The results suggest that glycine influences neural activity in the SCN as a classical inhibitory neurotransmitter and an excitatory neuromodulator.

Serotonin-operated potassium current in CA1 neurons dissociated from rat hippocampus

1993 ◽  
Vol 69 (4) ◽  
pp. 1044-1052 ◽  
Author(s):  
H. Uneyama ◽  
S. Ueno ◽  
N. Akaike
Keyword(s):  
Pyramidal Neurons ◽  
Muscarinic Acetylcholine Receptor ◽  
Outward Current ◽  
Membrane Conductance ◽  
External Solution ◽  
Equilibrium Potential ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Hippocampal Pyramidal Neurons ◽  
Outward Currents

1. The intracellular mechanisms of serotonin (5-HT) response were investigated in dissociated rat hippocampal pyramidal neurons using the nystatin-perforated patch technique. 2. Under voltage-clamp conditions, 5-HT evoked outward currents (I5-HT) with an increase in membrane conductance at a holding potential of -40 mV. The outward current reversed at the K+ equilibrium potential, which shifted 59.4 mV with a 10-fold change in extracellular K+ concentration. 3. The first application of 5-HT on neurons perfused with Ca(2+)-free external solution induced outward currents of I5-HT but the amplitude was diminished dramatically with successive applications. Pretreatment with the membrane-permeant Ca2+ chelator 1,2-bis-(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, tetraacetoxymethyl ester (BAPTA-AM) also diminished the I5-HT amplitude. 4. Pretreatment with pertussis toxin (PTX) had no effect on I5-HT. 5. The I5-HT was not cross-desensitized with the caffeine-induced outward current but with outward current mediated by the muscarinic acetylcholine receptor. Pretreatment with Li+ significantly enhanced the I5-HT, indicating that I5-HT is involved in the elevation of intracellular free Ca2+ released from inositol triphosphate (IP3)-sensitive Ca2+ store sites but not from the caffeine-sensitive ones. 6. The calmodulin (CaM) antagonists, trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), inhibited I5-HT in a concentration-dependent manner. 7. The Ca2+/CaM-dependent protein kinase II inhibitor 1-[N,O-Bis (5-isoquinolinesulfonyl)-N-methyl-L-tyrosil]-4-phenylpiperazine depressed the I5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Quinolones and fenbufen interact with GABAA receptor in dissociated hippocampal cells of rat

1991 ◽  
Vol 66 (2) ◽  
pp. 497-504 ◽  
Author(s):  
N. Akaike ◽  
T. Shirasaki ◽  
T. Yakushiji
Keyword(s):  
Gabaa Receptor ◽  
Pyramidal Neurons ◽  
Equilibrium Potential ◽  
Dependent Manner ◽  
Gamma Aminobutyric Acid ◽  
Patch Clamp Technique ◽  
Concentration Dependent Manner ◽  
Inflammatory Agent ◽  
Quinolone Antibiotics ◽  
Anti Inflammatory

1. Interaction of quinolone antibiotics and the anti-inflammatory agent fenbufen with the gamma-aminobutyric acid-A (GABAA) receptor-chloride channel complex in pyramidal neurons freshly dissociated from the hippocampal CA1 region of the rats was investigated in whole-cell mode, using the patch-clamp technique under voltage-clamp conditions. 2. Quinolones in clinical doses had no effects on the GABA-gated Cl- current (ICl) but slightly suppressed the response at concentrations greater than 10(-5) M. A metabolite of fenbufen, 4-biphenylacetic acid (BPA), also had little effect on the GABA response at therapeutic concentrations. 3. Coadministration of one of quinolones and BPA suppressed the GABA-gated ICl with increase in each of them in a concentration-dependent manner, and there was a parallel shift of the concentration-response curve for GABA to the right but with no effect on the maximum response, thereby indicating a competitive antagonism. The inhibitory potency of antibiotics in combination with BPA was in the order of norfloxacin much greater than enoxacin greater than cyprofloxacin greater than pipemidic acid much greater than ofloxacin greater than cinoxacin = piromidic acid = nalidixic acid = 0. 4. Norfloxacin and BPA, administered simultaneously, also strongly suppressed pentobarbital sodium (PB)-gated ICl, but they did not act on benzodiazepine (BZP) receptors. 5. Both GABA- and PB-induced ICls reversed at the Cl- equilibrium potential (ECl). In the presence of BPA, the quinolone-induced inhibition of GABA-gated ICls showed no voltage dependence. 6. It was concluded that, in the presence of an anti-inflammatory agent, the quinolone antibiotics decrease the affinity of GABAA receptors, the result being induction of epileptogenic neurotoxicities.

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 GAT3 selective substrate l-isoserine upregulates GAT3 expression and increases functional recovery after a focal ischemic stroke in mice

2017 ◽  
Vol 39 (1) ◽  
pp. 74-88 ◽  
Author(s):  
Maria EK Lie ◽  
Emma K Gowing ◽  
Nina B Johansen ◽  
Nils Ole Dalby ◽  
Louise Thiesen ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Surface Expression ◽  
Tonic Inhibition ◽  
Stroke Recovery ◽  
Gaba Uptake ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Post Stroke ◽  
Long Term Treatment

Ischemic stroke triggers an elevation in tonic GABA inhibition that impairs the ability of the brain to form new structural and functional cortical circuits required for recovery. This stroke-induced increase in tonic inhibition is caused by impaired GABA uptake via the glial GABA transporter GAT3, highlighting GAT3 as a novel target in stroke recovery. Using a photothrombotic stroke mouse model, we show that GAT3 protein levels are decreased in peri-infarct tissue from 6 h to 42 days post-stroke. Prior studies have shown that GAT substrates can increase GAT surface expression. Therefore, we aimed to assess whether the GAT3 substrate, L-isoserine, could increase post-stroke functional recovery. L-Isoserine (38 µM or 380 µM) administered directly into the infarct from day 5 to 32 post-stroke, significantly increased motor performance in the grid-walking and cylinder tasks in a concentration-dependent manner, without affecting infarct volumes. Additionally, L-isoserine induced a lasting increase in GAT3 expression in peri-infarct regions accompanied by a small decrease in GFAP expression. This study is the first to show that a GAT3 substrate can increase GAT3 expression and functional recovery after focal ischemic stroke following a delayed long-term treatment. We propose that enhancing GAT3-mediated uptake dampens tonic inhibition and promotes functional recovery after stroke.

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