Excitability Of CA1 Pyramidal Cells Research Articles

Depressed Responses to Applied and Synaptically-Released GABA in CA1 Pyramidal Cells, but not in CA1 Interneurons, after Transient Forebrain Ischemia

Transient cerebral ischemia kills CA1 pyramidal cells of the hippocampus, whereas most CA1 interneurons survive. It has been proposed that calcium-binding proteins, neurotrophins, and/or inhibitory neuropeptides protect interneurons from ischemia. However, different synaptic responses early after reperfusion could also underlie the relative vulnerabilities to ischemia of pyramidal cells and interneurons. In this study, we used gramicidin perforated patch recording in ex vivo slices to investigate gamma-aminobutyric acid (GABA) synaptic function in CA1 pyramidal cells and interneurons 4 h after a bilateral carotid occlusion accompanied by hypovolemic hypotension. At this survival time, the amplitudes of both miniature inhibitory postsynaptic currents (mIPSCs) and GABA-evoked currents were reduced in CA1 pyramidal cells, but not in CA1 interneurons. In addition, the mean rise time of mIPSCs was reduced in pyramidal cells. The reversal potential for the GABA current (E(GABA)) did not shift toward depolarizing values in either cell type, indicating that the driving force for chloride was unchanged at this survival time. We conclude that early during reperfusion GABAergic neurotransmission is attenuated exclusively in pyramidal neurons. This is likely explained by reduced GABAA receptor sensitivity or clustering and possibly also reduced GABA release, rather than by an elevation of intracellular chloride. Impaired GABA function may contribute to ischemic neuronal death by enhancing the excitability of CA1 pyramidal cells and facilitating N-methyl-D-aspartic acid channel opening. Therefore, normalizing GABAergic function might be a useful pharmacological approach to counter excessive, and potentially excitotoxic, glutamatergic activity during the postischemic period.

Microinjection of carbachol in the supramammillary region suppresses CA1 pyramidal cell synaptic excitability

Previous studies have established that the posterior hypothalamus-supramammillary (SUM) region is involved in the control of the hippocampal theta rhythm and also modulates the synaptic excitation of hippocampal neurons. Particularly, the medial but not lateral SUM region mediates reticular stimulation-induced suppression of CA1 pyramidal cell synaptic excitation to Schaffer collateral stimulation. In the present study using urethane anesthetized rats, we have investigated the effect of direct chemical stimulation of the posterior hypothalamus-SUM region on CA1 pyramidal cell excitability. It was observed that microinjection of the cholinergic muscarinic receptor agonist, carbachol (0.1 microl, concentration of either 0.0052, 0.156, or 0.625 microg/microl), evoked concentration-dependent suppression of CA1 pyramidal cell excitability that was dissociated from theta activation. Further, carbachol microinjection preferentially recruited the lateral SUM region when compared with the medial SUM and the posterior hypothalamic regions. In this context, the shortest latencies to suppression at the lowest concentration of carbachol and the strongest suppression at higher concentrations were observed with lateral microinjections. The carbachol-induced suppression was attenuated by inactivation of the medial septal region by microinjection of procaine (0.5 microl, 20% w/v). These results underscore a possible role for cholinergic mechanisms in the lateral SUM region in modulation of CA1 pyramidal cell synaptic excitation via the medial septal region. Furthermore, the present findings when juxtaposed with the medial SUM mediation of reticularly-elicited suppression suggest a medial-lateral topographic organization of the SUM region in modulation of CA1 excitability.

Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: Relevance to schizophrenia

Increasing evidence suggests that the metabolism of glutathione, an endogenous redox regulator, is abnormal in schizophrenia. Patients show a deficit in glutathione levels in the cerebrospinal fluid and prefrontal cortex and a reduction in gene expression of the glutathione synthesizing enzymes. We investigated whether such glutathione deficit altered synaptic transmission and plasticity in slices of rat hippocampus, with particular emphasis on NMDA receptor function. An ∼40% decrease in brain glutathione levels was induced by s.c. administration of l-buthionine-( S, R)-sulfoximine, an inhibitor of glutathione synthesis. Such glutathione deficit did not affect the basal synaptic transmission, but produced several NMDA receptor-dependent and -independent effects. Glutathione deficit caused an increase in excitability of CA1 pyramidal cells. The paired-pulse facilitation was diminished in glutathione-depleted slices, in a manner that was independent of NMDA receptor activity. This suggests that lowering glutathione levels altered presynaptic mechanisms involved in neurotransmitter release. NMDA receptor-dependent long-term potentiation induced by high-frequency stimulation was impaired in glutathione-depleted slices. Pharmacologically isolated NMDA receptor-mediated field excitatory postsynaptic potentials were significantly smaller in l-buthionine-( S, R)-sulfoximine-treated than in control slices. Hypofunction of NMDA receptors under glutathione deficit was explained at least in part by an excessive oxidation of the extracellular redox-sensitive sites of the NMDA receptors. These results indicate that a glutathione deficit, like that observed in schizophrenics, alters short- and long-term synaptic plasticity and affects NMDA receptor function. Thus, glutathione deficit could be one causal factor for the hypofunction of NMDA receptors in schizophrenia.

Effects of a novel glutamate transporter blocker, (2 S, 3 S)-3-{3-[4-(trifluoromethyl)benzoylamino]benzyloxy}aspartate (TFB-TBOA), on activities of hippocampal neurons

Glutamate transporters rapidly take up synaptically released glutamate and maintain the glutamate concentration in the synaptic cleft at a low level. (2 S, 3 S)-3-{3-[4-(trifluoromethyl)benzoylamino]benzyloxy}aspartate (TFB-TBOA) is a novel glutamate transporter blocker that potently suppresses the activity of glial transporters. TFB-TBOA inhibited synaptically activated transporter currents (STCs) in astrocytes in the stratum radiatum in rat hippocampal slices in a dose-dependent manner with an IC 50 of 13 nM, and reduced them to approximately 10% of the control at 100 nM. We investigated the effects of TFB-TBOA on glutamatergic synaptic transmission and cell excitability in CA1 pyramidal cells. TFB-TBOA (100 nM) prolonged the decay of N-methyl- d-aspartic acid receptor (NMDAR)-mediated excitatory postsynaptic currents (EPSCs), whereas it prolonged that of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated EPSCs only when the desensitization of AMPARs was reduced by cyclothiazide (CTZ). Furthermore, long-term application of TFB-TBOA induced spontaneous epileptiform discharges with a continuous depolarization shift of membrane potential. These epileptiform activities were mainly attributed to NMDAR activation. Even after pharmacological block of NMDARs, however, TFB-TBOA induced similar changes by activating AMPARs in the presence of CTZ. Thus, the continuous uptake of synaptically released glutamate by glial transporters is indispensable for protecting hippocampal neurons from glutamate receptor-mediated hyperexcitabilities.

Small physiologic changes in calcium and magnesium alter excitability and burst firing of CA1 pyramidal cells in rat hippocampal slices.

The effects of small physiologic changes in Ca and Mg concentrations on neuronal burst firing were examined. Intracellular electrophysiologic recordings were made from CA1 pyramidal neurons in rat hippocampal slices. There was no difference in the resting potential or the input resistance of neurons bathed in the lower Ca-Mg artificial Cerebrospinal fluid (aCSF) (1.4 mM Ca; 1.3 mM Mg) compared with the higher Ca-Mg aCSF (2 mM Ca; 2 mM Mg). However, neurons in the lower Ca-Mg aCSF, but not the higher Ca-Mg aCSF, demonstrated depolarizing waves and bursts of action potentials; no single component of the aCSF accounted for this difference. Reducing the Ca from 2 to 1 mM in the higher Ca-Mg aCSF increased the mean frequency of action potentials from 28 to 171 Hz; the addition of 6-cyano-7-nitroquinoxaline-2,3-dione did not reduce the frequency. The threshold of potassium for inducing bursts was 5.25 with 1 mM Ca, 7.25 with 2 mM Ca, and 11.25 with 3 mM Ca. When Mg was reduced from 2 to 1 mM, the number of potassium-induced bursts increased to 190%; increasing Mg from 2 to 3 mM reduced the bursts to 58% (frequency with 2 mM Mg set to 100%). Small decreases in extracellular Ca and/or Mg led to increased excitability and burst firing, which may alter physiologic and pathophysiologic processes such as enhancing long-term potentiation, pain transmission, epileptogenesis, and neuronal damage and decreasing anesthetic potency. Increases in extracellular Ca and/or Mg would have the opposite effect on these processes. These effects of extracellular divalent ions on burst firing may explain some of the pathophysiologic effects of hypocalcemia and hypomagnesemia.

Mice deficient for the extracellular matrix glycoprotein tenascin-r show physiological and structural hallmarks of increased hippocampal excitability, but no increased susceptibility to seizures in the pilocarpine model of epilepsy

Recognition molecules provide important cues for neuronal survival, axonal fasciculation, axonal pathfinding, synaptogenesis, synaptic plasticity, and regeneration. Our previous studies revealed a link between perisomatic inhibition and the extracellular matrix glycoprotein tenascin-R (TN-R). Therefore, we here studied neuronal excitability and epileptic susceptibility in mice constitutively deficient in TN-R. In vitro analysis of populational spikes in hippocampal slices of TN-R-deficient mice revealed a significant increase in multiple spikes in the CA1 region, as compared with wild-type mice. This difference between genotypes was only partially reduced after blockade of GABA A receptors with picrotoxin, indicating a deficit in GABAergic inhibition and an increase in intrinsic excitability of CA1 pyramidal cells in TN-R-deficient mice. Using a battery of immunohistochemical markers and histological stainings, we were able to identify two abnormalities in the hippocampus of TN-R-deficient mice possibly related to increased excitability: the high number of glial fibrillary acidic protein-positive astrocytes and low number of calretinin-positive interneurons in the CA1 and CA3 regions. In order to test whether the revealed abnormalities give rise to increased susceptibility to seizures in TN-R-deficient mice, we used the pilocarpine model of epilepsy. No genotype-specific differences were found with regard to the time-course of pilocarpine-induced and spontaneous seizures, neuronal cell loss, aberrant sprouting and distribution of synaptic and inhibitory interneuron markers. However, pilocarpine-induced astrogliosis and reduction in calretinin-positive interneurons were less pronounced in TN-R mutants, thereby resulting in an occlusion of effects induced by TN-R deficiency and pilocarpine. Thus, TN-R-deficient mutants show several electrophysiological and morphological hallmarks of increased neuronal excitability, which, however, do not give rise to more accelerated or severe epileptogenesis in the pilocarpine model of epilepsy.

Reticular stimulation evokes suppression of CA1 synaptic responses and generation of theta through separate mechanisms.

The induction of hippocampal theta by reticular stimulation involves a relay to the hippocampus via the posterior hypothalamic-supramammillary region and then the medial septum. Interestingly, sensory- or behaviour-induced theta is accompanied by suppression of hippocampal field CA1 synaptic responses. In the present study, performed on anaesthetized rats, we observed that reticular stimulation also induced a suppression of the CA1 pyramidal cell population spike and the corresponding dendritic field excitatory postsynaptic potential evoked by field CA3 stimulation. This suppression was observed at stimulation intensity below the threshold for generation of CA1 theta and was maximal at stimulation intensities at the threshold for theta. The frequency and amplitude of theta waves, by contrast, increased further with increasing reticular stimulation voltage. Neural inactivation by microinjection of the local anaesthetic procaine (20% w/v, 0.1-0.2 microL) or the inhibitory ligand gamma aminobutyric acid (0.8 m, 0.5 micro L) in the posterior hypothalamic regions, especially the ipsilateral medial supramammillary region, or the medial septum attenuated both the suppression of CA1 pyramidal cell synaptic excitability and theta generation. However, the effects of microinjection on suppression and theta were not always in parallel. Furthermore, the effect of microinjection of gamma aminobutyric acid on reticularly elicited suppression was observed from relatively fewer sites in the posterior hypothalamus as compared with that on theta activation. These results suggest that reticular stimulation evokes an inhibition of CA1 pyramidal cell excitability that (i) is mediated, at least in part, via medial supramammillary and septal regions, but (ii) involves a separate neural pathway from theta generation.

5-HT 7 receptors increase the excitability of rat hippocampal CA1 pyramidal neurons

In the CA1 area of rat hippocampal slices, a combined application of 5-CT, a potent 5-HT 1A and 5-HT 7 receptor agonist, and WAY 100635, a selective 5-HT 1A receptor antagonist, resulted in a reversible increase of the CA1 extracellular population spike amplitude. In whole-cell recording from identified pyramidal neurons, the effects of 5-CT applied in the presence of WAY 100635 involved a reduction of the slow afterhyperpolarization (sAHP) and the frequency adaptation of action potential firing, which could be blocked by a specific 5-HT 7 receptor antagonist SB 269970. The results indicate that the activation of 5-HT 7 receptors increases the excitability of hippocampal CA1 pyramidal cells.

Metabotropic-Mediated Kainate Receptor Regulation of I sAHP and Excitability in Pyramidal Cells

Kainate receptors (KARs) on CA1 pyramidal cells make no detectable contribution to EPSCs. We report that these receptors have a metabotropic function, as shown previously for CA1 interneurons. Brief kainate exposure caused long-lasting inhibition of a postspike potassium current (I sAHP) in CA1 pyramidal cells. The pharmacological profile was independent of AMPA receptors or the GluR5 subunit, indicating a possible role for the GluR6 subunit. KAR inhibition of I sAHP did not require ionotropic action or network activity, but was blocked by the inhibitor of pertussis toxin-sensitive G proteins, N-ethylmaleimide (NEM), or the PKC inhibitor calphostin C. These data suggest how KARs, putatively containing GluR6, directly increase excitability of CA1 pyramidal cells and help explain the propensity for seizure activity following KAR activation.

Muscarinic-induced modulation of potassium conductances is unchanged in mouse hippocampal pyramidal cells that lack functional M1 receptors

Activation of muscarinic acetylcholine (ACh) receptors (mAChRs) increases excitability of pyramidal cells by inhibiting several K+ conductances, including the after-hyperpolarization current (Iahp), the M-current (Im), and a leak K+ conductance (Ileak). Based on pharmacological evidence and the abundant localization of M1 receptors in pyramidal cells, it has been assumed that the M1 receptor is responsible for mediating these effects. However, given the poor selectivity of the pharmacological agents used to characterize these mAChR responses, rigorous characterization of the receptor subtypes that mediate these actions has not been possible. Surprisingly, patch clamp recording from CA1 pyramidal cells in M1 knockout mice revealed no significant difference in the degree of inhibition of Iahp, Im, or Ileak by the mAChR agonist, carbachol (CCh), as compared with wildtype controls. In addition, the M1-toxin was not able to block CCh's inhibition of the Iahp, Im, or Ileak. These data demonstrate that the M1 receptor is not involved in increasing CA1 pyramidal cell excitability by mediating ACh effects on these K+ conductances.

Effect of the selective 5-HT1A receptor antagonist WAY 100635 on the inhibition of e.p.s.ps produced by 5-HT in the CA1 region of rat hippocampal slices.

1. The actions of N-(2-(-4(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635), a novel and selective 5-hydroxytryptamine1A (5-HT1A) antagonist, on excitatory postsynaptic potentials (e.p.s.ps) were investigated by use of intracellular recordings in pyramidal cells of the CA1 region of rat hippocampal slices. 2. WAY 100635 (10 nM) did not affect any of the investigated parameters of cell excitability such as membrane potential, total input resistance (Rin), firing threshold, action potential amplitude, action potential frequency adaptation, and slow afterhyperpolarization (sAHP) which follows repetitive firing of action potentials. WAY 100635 did not have any effect on either the slope or the amplitude of e.p.s.ps evoked by stimulation of the CA1 stratum radiatum. 3. Bath application of either 5-hydroxytryptamine (5-HT, 10-30 microM) or 5-carboxamidotryptamine (5-CT, 300 nM) hyperpolarized the membrane potential (deltaVm = -4.1 +/- 0.9 and -6.0 +/- 0.9 mV, respectively), and reduced Rin (-25 +/- 8% and -18 +/- 1%, respectively). 5-HT blocked the action potential frequency adaptation and significantly reduced the amplitude of the sAHP that follows repetitive firing of action potentials. 4. 5-HT significantly decreased the amplitude of evoked e.p.s.ps (-14 +/- 6%). This effect was greater in the presence of the GABA(A) receptor antagonist bicuculline (10 microM, -45 +/- 12%) and was mimicked by 5-CT (-49 +/- 5%). Both AMPA and NMDA components of e.p.s.ps were significantly reduced in amplitude by 5-HT (-38 +/- 8%, n = 6, and -29 +/- 12%, n = 3, respectively; P < 0.05). 5. WAY 100635 fully antagonized the hyperpolarization, the reduction of Rin, and the decrease in amplitude of e.p.s.ps elicited by 5-HT, while it did not affect the action of 5-HT on the action potential frequency adaptation. In the presence of WAY 100635, 5-HT elicited a depolarization which was blocked by 10-30 microM RS 23597-190, a selective 5-HT4 receptor antagonist. 6. Our data demonstrate that WAY 100635 is devoid of direct effects on CA1 pyramidal cell excitability and on evoked e.p.s.ps, while it fully antagonizes the effects of 5-HT on excitatory synaptic transmission and on hyperpolarization, without affecting the 5-HT4 receptor-mediated response. Since WAY 100635 selectively antagonizes 5-HT1A receptor-mediated actions of 5-HT, our data also demonstrate that the inhibitory action of 5-HT on excitatory synaptic transmission in CA1 is mediated by 5-HT1A receptors.

Long-term increase of hippocampal excitability by histamine and cyclic AMP

The action of histamine (HA) on rat hippocampal CA1 pyramidal cells in vitro was investigated in slices perfused with solution containing 0.2 mM Ca 2+ 4.0 mM Mg 2+ . Extracellular recordings of the spontaneous discharges occurring under these conditions revealed that HA caused a long-lasting increase in cell firing. The HA-effects were dose-dependent, in that low concentrations of HA (0.1–0.5 μM) exhibited an initial transient depression of cell firing and practically no long-lasting action, whereas higher concentrations of HA (1–10 μM) exerted strong, non-declining increases. The H 1-receptor antagonist mepyramine (1 μM) blocked the initial depression of firing and attenuated the long-lasting HA-mediated excitation. Pure H 1-receptor activation, tested with the H 1-receptor agonist 2-(3-fluorphenyl)histamine (1–10 μM) depressed cell firing, similar to the low dose effects of HA. HA-induced excitations were prevented by the H 2-receptor antagonist cimetidine (10–50 μM), and mimicked by the very potent H 2-receptor agonist impromidine (1 or 3 μM) which was, however, less effective compared to equal concentrations of HA. H 3-receptor activation by R-α-methylhistamine had no significant effect on cell firing. Thus, histamine H 1 and H 2 receptors seem to cooperate in producing this long-lasting augmentation of excitability. 8-Bromo-cyclic AMP monophosphate (8-Br-cAMP, 50–100 μM) mimicked the long-term excitation, whereas the adenylyl-cyclase inhibitor 9-tetrahydro-2-furyladenine (THFA, 100–500 μM) or the PKA-inhibitor Rp-adenosine-3′5′-cyclic monophosphate (Rp-cAMPS, 10 μM) blocked it, indicating that the HA-mediated increase of excitability in the hippocampus is dependent on the adenylate cyclase/PKA-signal transduction cascade. dl-2-Amino-5-phosphonopentanoic acid (APV, 50 μM) significantly attenuated the magnitude of the HA-induced enhancement, indicating an NMDA receptor-dependent component. Other biogenic amines, acting through receptors positively coupled to adenylyl cyclase, elicited similar responses as HA, indicating common mechanisms by which these substances modulate excitability in CA1 pyramidal cells.

Hippocampal interneurons are excited via serotonin-gated ion channels.

Hippocampal interneurons are excited via serotonin-gated ion channels. J. Neurophysiol. 78: 2493-2502, 1997. Serotonergic neurons of the median raphe nucleus heavily innervate hippocampal GABAergic interneurons located in stratum radiatum of area CA1, suggesting that this strong subcortical projection may modulate interneuron excitability. Using whole cell patch-clamp recording from interneurons in brain slices, we tested the effects of serotonin (5-HT) on the physiological properties of these interneurons. Serotonin produces a rapid inward current that persists when synaptic transmission is blocked by tetrodotoxin and cobalt, and is unaffected by ionotropic glutamate and gamma-aminobutyric acid (GABA) receptor antagonists. The 5-HT-induced current was independent of G-protein activation. Pharmacological evidence indicates that 5-HT directly excites these interneurons through activation of 5-HT3 receptors. At membrane potentials negative to -55 mV, the current-voltage (I-V) relationship of the 5-HT current displays a region of negative slope conductance. Therefore the response of interneurons to 5-HT strongly depends on membrane potential and increases greatly as cells are depolarized. Removal of extracellular calcium, but not magnesium, increases the amplitude of 5-HT-induced currents and removes the region of negative slope conductance, thereby linearizing the I-V relationship. The axons of 5-HT-responsive interneurons ramify widely within CA1; some of these interneurons also project to and arborize extensively in the dentate gyrus. The organization of these inhibitory connections strongly suggests that these cells regulate excitability of both CA1 pyramidal cells and dentate granule cells. As our results indicate that 5-HT may mediate fast excitatory synaptic transmission onto these interneurons, serotonergic inputs can simultaneously modulate the output of both hippocampus and dentate gyrus.

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The muscarinic acetylcholine receptor antagonist scopolamine, but not the beta-adrenoceptor antagonist propranolol or atenolol, suppressed tetanus-induced long-term potentiation (LTP) of population spikes in the rat hippocampal CA1 region. When scopolamine was coapplied with propranolol or atenolol, a synergistic effect in preventing LTP generation was observed. On the other hand, the coapplication of scopolamine and atenolol failed to affect tetanus-induced LTP of field EPSP. These findings suggest that cooperative mechanisms via muscarinic and beta-adrenergic receptor activation might contribute to LTP induction in terms of the EPSP-spike potentiation, i.e., an increase in the excitability of hippocampal CA1 pyramidal cells after tetanic stimulation, but are independent of the tetanus-evoked potentiation of a synaptic component.

Serotonergic modulation of hippocampal pyramidal cells in euthermic, cold-acclimated, and hibernating hamsters.

Serotonergic fibers project to the hippocampus, a brain area previously shown to have distinctive changes in electroencephalograph (EEG) activity during entrance into and arousal from hibernation. The EEG activity is generated by pyramidal cells in both hibernating and nonhibernating species. Using the brain slice preparation, we characterized serotonergic responses of these CA1 pyramidal cells in euthermic, cold-acclimated, and hibernating Syrian hamsters. Stimulation of Shaffer-collateral/commissural fibers evoked fast synaptic excitation of CA1 pyramidal cells, a response monitored by recording population spikes (the synchronous generation of action potentials). Neuromodulation by serotonin (5-HT) decreased population spike amplitude by 54% in cold-acclimated animals, 80% in hibernating hamsters, and 63% in euthermic animals. The depression was significantly greater in slices from hibernators than from cold-acclimated animals. In slices from euthermic animals, changes in extracellular K+ concentration between 2.5 and 5.0 mM did not significantly alter serotonergic responses. The 5-HT1A agonist 8-hydroxy-2(di-n-propylamino)tetralin mimicked serotonergic inhibition in euthermic hamsters. Results show that 5-HT is a robust neuromodulator not only in euthermic animals but also in cold-acclimated and hibernating hamsters.

Effects of the retrorubral field stimulation on the excitability of the rat hippocampus in vivo

We studied in vivo the influences exerted by the retrorubral field (RRF) on the on commissural-evoked CA1 pyramidal cell excitability in the rat hippocampal formation (HF). The stimulation of RRF before the activation of the contralateral CA3 area evoked in all the studied rats a reduction in amplitude of the evoked population spike in the CA1 pyramidal cell body layer of both the dorsal and the ventral HF. No significant differences in the intensity of the inhibitory effect were observed between dorsal and ventral parts of the HF. The stimulation of the ipsilateral RRF reduced the amplitude of the evoked population spike in a higher degree with respect to the contralateral side. Since these side-to-side differences were significant, it can be concluded that the RRF-induced inhibitory effect is stronger on the ipsilateral CA1 pyramidal cells. The inhibitory effect appears within 0.1 s of stimulating the RRF, reaches its maximal effect around 0.4–0.5 s following the conditioning train and returned to its control size after 5 s.

The effect of propofol on ca1 pyramidal cell excitability and gaba a-mediated inhibition in the rat hippocampal slice

An in vitro paired-pulse orthodromic stimulation technique was used to examine the effects of propofol on excitatory afferent terminals, CA1 pyramidal cells and recurrent collateral evoked inhibition in the rat hippocampal slice. Hippocampal slices 400 um thick were perfused with oxygenated artificial cerebrospinal fluid, and electrodes were placed in the CA1 region to record extracellular field population spike (PS) or excitatory postsynaptic potential (EPSP) responses to stimulation of Schaffer collateral/commissural fibers. Gamma-aminobutyric acid (GABA)-mediated recurrent inhibition was measured using a paired-pulse technique. The major effect of propofol (7–28 μM) was a dose and time dependent increase in the intensity and duration of GABA-mediated inhibition. This propofol effect could be rapidly and completely reversed by exposure to known GABA A antagonists, including picrotoxin, bicuculline and pentylenetetrazol. It was also reversed by the chloride channel antagonist, 4,4′-diisothiocyanostilbene-2,2′-disulfonicacid (DIDS). It was not antagonized by central (flumazenil) or peripheral (PK11195) benzodiazepire antagonists. Reversal of endogenous inhibition was also noted with the antagonists picrotoxin and pentylenetetrazol. Input/output curves constructed using stimulus propofol caused only a small enhancement of EPSPs at higher stimulus intensities but had no effect on PS amplitudes. These studies are consistent with propofol having a GABA A-chloride channel mechanism causing its effect on recurrent collateral evoked inhibition in the rat hippocampal slice.

Roles of specific metabotropic glutamate receptor subtypes in regulation of hippocampal CA1 pyramidal cell excitability.

1. Metabotropic glutamate receptors (mGluRs) are coupled to various second-messenger systems through guanosine 5'-triphosphate-binding proteins. To date, at least seven mGluRs have been cloned, and these mGluR subtypes can be divided into three major groups on the basis of similarities in amino acid sequence, coupling to second-messenger cascades in expression systems, and pharmacological profiles. These groups include group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3), and group III (mGluR4, mGluR6, and mGluR7). 2. On the basis of its selective activation of phosphoinositide hydrolysis in brain slices and its ability to activate mGluR1a expressed in Xenopus oocytes, others have suggested that 3.5-dihydroxyphenylglycine (DHPG) may be selective for group I mGluRs. Consistent with this hypothesis, we report that DHPG also activates mGluR5 expressed in oocytes, whereas it is inactive at mGluR4 and mGluR7 expressed in baby hamster kidney (BHK) cells. The compound (2S,1'R,2'R,3'R)-2-(2.3-dicarboxycyclopropyl)glycine (DCG-IV) activates both mGluR2 and mGluR3 at submicromolar concentrations, whereas it is inactive at mGluR4 and mGluR1, suggesting that this compound may be selective for group II mGluRs. Consistent with this hypothesis, we find that DCG-IV does not activate mGluR5 expressed in oocytes and does not activate mGluR7 expressed in BHK cells. These findings suggest that DHPG and DCG-IV are highly selective agonists for group I and group II mGluRs, respectively. 3. Previous studies that have examined the physiological roles of mGluRs have generally used agonists that do not differentiate between the various subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological differentiation of the effects of co-activation of β-adrenergic and metabotropic glutamate receptors in rat hippocampus

Activation of metabotropic glutamate receptors (mGluRs) can potentiate the cAMP response elicited by activation of β-adrenergic receptors (βARs) in the hippocampus. We have shown that co-activation of mGluRs and βARs induces both an acute depression of excitatory synaptic transmission and a long-lasting excitation of CA1 pyramidal cells. However, these studies were performed using a non-selective mGluR agonist. We have now used subtype selective mGluR agonists, and report that while the acute depression of transmission exhibits a pharmacology consistent with mediation by this mGluR subtype, the lasting excitation of CA1 pyramidal cells may be mediated by an interaction between βARs and mGluRs that are coupled to phosphoinositide hydrolysis.

Monosynaptic excitation of hippocampal CA1 pyramidal cells by afferents from the entorhinal cortex.

HippocampusVolume 5, Issue 2 p. 108-114 Article Monosynaptic excitation of hippocampal CA1 pyramidal cells by afferents from the entorhinal cortex Mark F. Yeckel, Corresponding Author Mark F. Yeckel Department of Biomedical Engineering, Neurobiology and Neuroscience Programs, University of Southern California, Los Angeles, California403 Hedco Neurosciences Building, University of Southern California, Los Angeles, CA 90089-2520Search for more papers by this authorTheodore W. Berger, Theodore W. Berger Department of Biomedical Engineering, Neurobiology and Neuroscience Programs, University of Southern California, Los Angeles, CaliforniaSearch for more papers by this author Mark F. Yeckel, Corresponding Author Mark F. Yeckel Department of Biomedical Engineering, Neurobiology and Neuroscience Programs, University of Southern California, Los Angeles, California403 Hedco Neurosciences Building, University of Southern California, Los Angeles, CA 90089-2520Search for more papers by this authorTheodore W. Berger, Theodore W. Berger Department of Biomedical Engineering, Neurobiology and Neuroscience Programs, University of Southern California, Los Angeles, CaliforniaSearch for more papers by this author First published: 1995 https://doi.org/10.1002/hipo.450050204Citations: 31AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume5, Issue21995Pages 108-114 RelatedInformation