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PubMed2001

Dissociation between synaptic depression and block of long-term depression induced by raising the temperature in rat hippocampal slices.

The influence of raising the bath temperature (39 degrees C) on synaptic transmission and neuronal plasticity was studied in the CA1 region of the rat hippocampus using an extracellular recording technique. Increasing the bath temperature from 32 to 39 degrees C resulted in a depression of field excitatory postsynaptic potential (fEPSP). Application of the selective A(1) receptor agonist, 2-chloro-adenosine (2-CADO, 1 microM) reduced the fEPSP and subsequently occluded the raised temperature-induced synaptic depression. On the other hand, the selective adenosine A(1) receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX) blocked depression of fEPSP produced by raising the temperature. These results suggest that raising temperature-induced synaptic depression is due to an alteration of extracellular adenosine concentration. Long-term depression (LTD) could be reliably induced by the standard low-frequency stimulation (LFS, 1 Hz for 15 min) protocol at 32 degrees C but not at 39 degrees C. The raised temperature-induced block of LTD was mimicked by 2-CADO. Unexpectedly, despite the presence of DPCPX, LFS still could not elicit LTD. NMDA receptor-mediated synaptic component (fEPSP(NMDA)) was decreased when increasing the temperature to 39 degrees C and DPCPX failed to reverse such a depression. The increase in the NMDA response in 0.1 mM Mg(++) compared with 1 mM Mg(++) was significantly greater at 32 degrees C than at 39 degrees C. These results suggest that, by increasing the sensitivity of Mg(++) block, an increase in temperature modulates NMDA responses and thereby inhibits the induction of LTD.

2-Amino-5-phosphonovalerate↗
PubMed2004

Cell-specific, spike timing-dependent plasticities in the dorsal cochlear nucleus.

In the dorsal cochlear nucleus, long-term synaptic plasticity can be induced at the parallel fiber inputs that synapse onto both fusiform principal neurons and cartwheel feedforward inhibitory interneurons. Here we report that in mouse fusiform cells, spikes evoked 5 ms after parallel-fiber excitatory postsynaptic potentials (EPSPs) led to long-term potentiation (LTP), whereas spikes evoked 5 ms before EPSPs led to long-term depression (LTD) of the synapse. The EPSP-spike protocol led to LTD in cartwheel cells, but no synaptic changes resulted from the reverse sequence (spike-EPSP). Plasticity in fusiform and cartwheel cells therefore followed Hebbian and anti-Hebbian learning rules, respectively. Similarly, spikes generated by summing EPSPs from different groups of parallel fibers produced LTP in fusiform cells, and LTD in cartwheel cells. LTD could also be induced in glutamatergic inputs of cartwheel cells by pairing parallel-fiber EPSPs with depolarizing glycinergic PSPs from neighboring cartwheel cells. Thus, synaptic learning rules vary with the postsynaptic cell, and may require the interaction of different transmitter systems.

Animals↗
PubMed1997

Metabotropic glutamate receptors modulate synaptic transmission in the perforant path: pharmacology and localization of two distinct receptors.

Metabotropic glutamate receptors (mGluRs) have emerged as an interesting family of eight different receptor subtypes that can be divided into three groups according to their pharmacology and sequence similarity. In the present study, the specific mGluR agonists (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD) and L(+)-2-amino-4-phosphonobutyric acid (L-AP4) depressed field excitatory postsynaptic potentials (fEPSPs) in the rat dentate gyrus evoked by perforant path stimulation in a concentration-dependent, rapid and reversible manner (EC50: L-AP4 5.9 +/- 1.6 microM, (1S,3R)-ACPD 80 +/- 34 microM). In a 'paired-pulse' stimulation protocol, the first fEPSP showed a stronger reduction, resulting in 'paired-pulse' facilitation. The effects of L-AP4 but not of (1S,3R)-ACPD could be antagonized by the group III mGluR antagonists (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4) and (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG). Moreover, (1S,3R)-ACPD was still potently depressing fEPSPs after preperfusion of near saturating concentrations of L-AP4. Together, the results suggest that both substances act on different mGluRs. The effects of (1S,3R)-ACPD could not be further differentiated by selective group I or group II mGluR agonists. Although (2S,1'S,2'S)-2-carboxycyclopropylglycine (L-CCG-I) blocked fEPSPs at concentrations >> 1 microM, these effects, as well as L-AP4 effects, were potently antagonized by MAP4. This suggests that mGluR8 might be responsible for the actions of L-AP4 and L-CCG-I. The two different mGluRs showed a distinct distribution when fEPSPs were recorded simultaneously in the outer and middle molecular layer (OML/MML): The L-AP4 sensitive receptor, possibly mGluR8, seems to be located in the OML while (1S,3R)-ACPD showed its main effect in the MML.

Aminobutyrates↗
PubMed1998

Alteration of NMDA receptor-mediated synaptic responses in CA1 area of the aged rat hippocampus: contribution of GABAergic and cholinergic deficits.

Synaptic responses mediated by the N-methyl-D-aspartate receptor (NMDAr) and non-NMDAr activation were compared in CA1 hippocampal region of young (3-4 months old) and aged (25-33 months old) Sprague-Dawley rats with the use of ex vivo extracellular recordings techniques. In aged rats, the amplitude of the NMDAr-mediated field excitatory postsynaptic potentials (fEPSPs) was not altered, whereas their duration was significantly increased. In contrast, the magnitude of non-NMDAr-mediated fEPSPs was significantly smaller. The presynaptic fiber volley was not affected by age. Considering that the depression of non-NMDAr-mediated responses was previously attributed to fewer synaptic contacts between glutamatergic afferent fibers and pyramidal cells in aged animals (see Barnes et al., Hippocampus 1992;2:457-468), the absence of age-related changes in the amplitude of NMDAr-mediated fEPSPs suggests that compensatory mechanisms may occur. The contribution of gamma-aminobutyric acid (GABA) and acetylcholine to these mechanisms was addressed. The NMDAr-mediated fEPSPs were then recorded (1) in young and aged rats before and after blockade of the GABA(B) receptor-mediated inhibition by the specific antagonist CGP 55845 and (2) in young rats after a selective cholinergic denervation of the hippocampus by the immunotoxin 192 IgG-saporin. The results did not indicate statistically relevant age-related effects of CGP 55845. In contrast, the loss of the cholinergic innervation by the immunotoxin induced a significant increase in both the amplitude and duration of the NMDAr-mediated fEPSPs. Our results indicate that the functional properties of the ionotropic glutamate receptor subtypes located on CA1 pyramidal cells are differentially affected by aging and suggest that the cholinergic deficit that occurs during aging may be involved in the maintenance of robust NMDAr-mediated synaptic responses.

Acetylcholine↗
PubMed2001

Glutamate uptake inhibition modulates dorsal horn neurotransmission: a comparison between normal and arthritic rats.

This study determined the effects of glutamate uptake inhibition on primary-afferent excitatory postsynaptic potentials (DR-EPSPs) in spinal dorsal horn neurones in vitro from naive rats and rats with localised arthritis. The glutamate uptake inhibitor L-PDC (1 mM) significantly reduced DR-EPSP amplitude and duration with a greater reduction in arthritic than in naive rats. The group II/III selective metabotropic glutamate receptor antagonist CPPG (100 microM) reversed L-PDC-induced DR-EPSP inhibition in naive but not arthritic rats. L-AP4 (30 microM), a group III metabotropic agonist, inhibited DR-EPSPs with no difference between naive and arthritic rats. These data suggest the existence of an autoregulatory feedback mechanism that limits spinal postsynaptic excitation especially during inflammation. The putative contribution of metabotropic glutamate receptors to this phenomenon is discussed.

Amino Acid Transport System X-AG↗
PubMed2003

P2Y(1) receptor activation inhibits NMDA receptor-channels in layer V pyramidal neurons of the rat prefrontal and parietal cortex.

In the 1st part of this study, monosynaptic excitatory postsynaptic potentials (EPSPs) in layer V of the rat prefrontal cortex (PFC) were evoked by electrical stimulation of layer I. Recordings with intracellular sharp, microelectrodes showed a concentration-dependent inhibition of the EPSP by adenosine 5'-O-(2-thiodiphosphate) (ADP-beta-S). Pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), when given alone depressed the EPSP and in addition antagonized the effect of ADP-beta-S. Exclusion of the N-methyl-D-aspartate (NMDA) component of the EPSP by D(.)-amino-5-phosphonopentanoic acid (AP-5) abolished the ADP-beta-S-induced depression. The pressure-application of both NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) caused reproducible depolarizations. ADP-beta-S inhibited the effect of NMDA, but did not alter that of AMPA. PPADS was also under these conditions antagonistic with ADP-beta-S. In the 2nd part of the study, NMDA-induced currents were measured by whole-cell patch-clamp pipettes. ADP-beta-S caused a concentration-dependent inhibition of the responses to NMDA. PPADS alone did not alter the NMDA-currents but again antagonized the action of ADP-beta-S; 2'-deoxy-N(6)-methyladenosine-3',5'-diphosphate (MRS 2179) also abolished the NMDA effect. The ADP-beta-S-induced inhibition persisted in the presence of tetrodotoxin (TTX) or guanosine 5'-O-(3-thiodiphosphate) (GDP-beta-S) applied to the external medium and the pipette solution, respectively. The 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) moderately decreased the ADP-beta-S effect. The inhibitory function of ADP-beta-S on EPSPs and the interaction with PPADS was observed also in layer V pyramidal neurons of the parietal somatosensory cortex. In conclusion, metabotropic P2Y(1) receptors appear to exert a new modulatory influence on fast excitatory amino acid transmission in the cerebral cortex.

Adenosine Diphosphate↗
PubMed2001

Presynaptic group II mGluR inhibition of short-term depression in the medial perforant path of the dentate gyrus in vitro.

Inhibition of short-term plasticity by activation of presynaptic group II metabotropic glutamate receptors (group II mGluR) was investigated in the medial perforant path of the dentate gyrus in the hippocampus in vitro. Brief trains of stimulation (10 stimuli at 1--200 Hz) evoked short-term depression of field excitatory postsynaptic potentials (EPSPs). The steady-state level of depression, measured after 10 stimuli, was frequency dependent, increasing between 1 and 200 Hz. Activation of group II mGluR by the selective agonist LY354740 did not alter short-term depression evoked by frequencies up to 10 Hz, but did inhibit short-term depression evoked at higher frequencies in a frequency- and concentration-dependent manner. The time-averaged postsynaptic response (EPSP per unit time) was found to increase linearly with frequency up to approximately 20 Hz. At higher frequencies, the response plateaued, thereby becoming independent of frequency. Frequencies above this were differentiated only during the transient postsynaptic response that accompanies changes in firing rates. Activation of presynaptically located group II mGluR increased the frequency at which the EPSP per unit time plateaued up to 30-50 Hz.

Animals↗
PubMed1998

Optical imaging of hippocampal neurons with a chloride-sensitive dye: early effects of in vitro ischemia.

We determined if changes in intraneuronal Cl- occur early after ischemia in the hippocampal slice. Slices from juvenile rats (14-19 days old) were loaded with the cell-permeant form of 6-methoxy-N-ethylquinolinium chloride (MEQ), a Cl(-)-sensitive fluorescent dye. Real-time changes in intracellular chloride concentration ([Cl-]i) were measured with UV laser scanning confocal microscopy in multiple neurons within each slice. In vitro ischemia (26-28 degrees C, 10 min) was confirmed by the loss of synaptic transmission (evoked field excitatory postsynaptic potentials) from pyramidal cells in area CA1. After ischemia and reoxygenation (10 min), MEQ fluorescence decreased significantly in CA1 pyramidal cells and interneurons. The decreased fluorescence corresponded to an ischemia-induced increase in [Cl-]i of approximately 10 mM. Pretreatment with the GABA(A)-gated Cl- channel antagonist picrotoxin (100 microM) blocked the ischemia-induced change in [Cl-]i. Analysis of the superfusates indicated that ischemia also caused a transient amino acid (GABA, glutamate, and aspartate) release that was maximal at approximately 10 min, returning to baseline shortly thereafter. Recovery from ischemia was confirmed by the return of synaptic transmission in area CA1, the return toward baseline of the ischemia-induced decrease in MEQ fluorescence, and exclusion of propidium iodide from MEQ fluorescent cells. Furthermore, pyramidal cells did not undergo cell swelling during this early phase of reoxygenation, as indicated by the volume-sensitive dye calcein. Thus, mild ischemia induces the accumulation of [Cl-]i secondary to GABA(A) receptor activation, in the absence of cellular swelling or death. In contrast, depolarization of the slice with K+ (50 mM) decreased MEQ fluorescence significantly but caused cell swelling. Picrotoxin did not prevent the K+-induced increase in [Cl-]i. It is possible that an increased [Cl-]i, following either an ischemic event or an episode of depolarization, would reduce the Cl- driving force and thereby limit synaptic transmission by GABA. To support this hypothesis, ischemia caused a reduction in the ability of the GABA agonist muscimol to increase [Cl-]i after 20-min reoxygenation.

Animals↗
PubMed2006

Nitric oxide-induced adenosine inhibition of hippocampal synaptic transmission depends on adenosine kinase inhibition and is cyclic GMP independent.

Adenosine is an important inhibitory neuromodulator that regulates neuronal excitability. Several studies have shown that nitric oxide induces release of adenosine. Here we investigated the mechanism of this release. We studied the effects of nitric oxide on evoked field excitatory postsynaptic potentials (fEPSPs) recorded in the CA1 area of rat hippocampal slices. The nitric oxide donor 1,1-diethyl-2-hydroxy-2-nitroso-hydrazine sodium (DEA/NO; 100 microm) depressed the fEPSP by 77.6 +/- 4.1%. This effect was abolished by the adenosine A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 400 nm), indicating that the nitric oxide effect was mediated by adenosine accumulation. The DEA/NO effect was unaltered by the 5'-ectonucleotidase inhibitor alpha,beta-methylene-adenosine 5'-diphosphate (AMP-CP; 100 microm), indicating that extracellular adenosine did not derive from ATP or cAMP release. The guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxaline-1-one (ODQ; 5 microm) did not affect nitric oxide depression of the fEPSPs, indicating that nitric oxide-mediated adenosine release was not mediated through a cGMP signaling cascade. This conclusion was confirmed by the observation that 8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphate (8-pCPT-cGMP; 1 mm) reversibly depressed the fEPSP by 24.9 +/- 4.5%, but this effect was not blocked by adenosine antagonists. Adenosine kinase inhibitor 5-iodotubercidin (ITU; 7 microm) occluded the nitric oxide effects by 74%, suggesting that inhibition of adenosine kinase activity contributes to adenosine release. In conclusion, exogenous nitric oxide evokes adenosine release by a cGMP-independent pathway. Intracellular cGMP elevation partially inhibits the fEPSP but not through adenosine release. Although a direct block of adenosine kinase by nitric oxide can not be excluded, the depression of adenosine kinase activity may be due to inhibition by its own substrate adenosine.

Adenosine↗
PubMed2006

Cortical feedback to the thalamus is selectively enhanced by nitric oxide.

The brain somehow merges visual information with the behavioral context in which it is being processed, a task that is often attributed to the cerebral cortex. We have identified a new role of the gaseous neurotransmitter, nitric oxide (NO), in the early selective enhancement of corticogeniculate communication that may participate in this process at the level of the thalamus. Visual information is dynamically gated through the thalamus by brainstem neurons that release acetylcholine and NO. Using in vitro electrophysiology, we characterized NO effects on excitatory postsynaptic potentials and currents (EPSCs) elicited from retinal and cortical pathways in the lateral geniculate nucleus of the ferret. NO selectively and reversibly increased cortically-evoked postsynaptic responses, and this effect was mimicked by cyclic guanosine 3',5'-monophosphate (cGMP). Conversely, NO inhibited retinally-evoked responses independently of cGMP. We demonstrated that these differential effects were specific to postsynaptic N-methyl-d-aspartate (NMDA) receptors by studying treatment effects on pharmacologically isolated EPSCs from each pathway. We propose that when brainstem activity is increased during behavioral arousal or rapid eye movement sleep, NO may increase the relative sensitivity of relay neurons to corticogeniculate feedback. The net effect of these changes in synaptic processing may be to selectively suppress peripheral information while unifying data carried by reentrant corticogeniculate loops with the behavioral context in which the visual information is processed.

Animals↗
PubMed2004

VIP enhances both pre- and postsynaptic GABAergic transmission to hippocampal interneurones leading to increased excitatory synaptic transmission to CA1 pyramidal cells.

Vasoactive intestinal peptide (VIP) is present in the hippocampus in three subtypes of GABAergic interneurones, two of which innervate preferentially other interneurones, responsible for pyramidal cell inhibition. We investigated how pre- and postsynaptic modulation of GABAergic transmission (to both pyramidal cells and interneurones) by VIP could influence excitatory synaptic transmission in the CA1 area of the hippocampus. VIP (0.1-100 nM) increased [(3)H]GABA release from hippocampal synaptosomes (maximum effect at 1 nM VIP; 63.8 +/- 4.0%) but did not change [(3)H]glutamate release. VIP (0.3-30 nM) enhanced synaptic transmission in hippocampal slices (maximum effect at 1 nM VIP; field excitatory postsynaptic potentials (epsp) slope: 23.7 +/- 1.1%; population spike amplitude: 20.3 +/- 1.7%). The action on field epsp slope was fully dependent on GABAergic transmission since it was absent in the presence of picrotoxin (50 microM) plus CGP55845 (1 microM). VIP (1 nM) did not change paired-pulse facilitation but increased paired-pulse inhibition in CA1 pyramidal cells (16.0 +/- 0.9%), reinforcing the involvement of GABAergic transmission in the action of VIP. VIP (1 nM) increased muscimol-evoked inhibitory currents by 36.4 +/- 8.7% in eight out of ten CA1 interneurones in the stratum radiatum. This suggests that VIP promotes increased inhibition of interneurones that control pyramidal cells, leading to disinhibition of synaptic transmission to pyramidal cell dendrites. In conclusion, concerted pre- and postsynaptic actions of VIP lead to disinhibition of pyramidal cell dendrites causing an enhancement of synaptic transmission.

Animals↗
PubMed1998

Regulation of synaptic depression rates in the cricket cercal sensory system.

To assess the roles of pre- and postsynaptic mechanisms in the regulation of depression, short-term synaptic depression was characterized at the synapses between sensory neurons and two interneurons in the cricket cercal sensory system. Changes in excitatory postsynaptic potential (EPSP) amplitude with repetitive stimulation at 5 and 20 Hz were quantified and fitted to the depletion model of transmitter release. The depression rates of different sensory neuron synapses on a single interneuron varied with the age of the sensory neurons such that old sensory neuron synapses depressed faster than young synapses. Although all synapses showed depression, short-term facilitation was selectively expressed only at sensory neuron synapses on one interneuron, the medial giant interneuron (MGI). These synapses showed concurrent facilitation and depression with high-frequency stimulation (100 Hz), whereas the synapses on another interneuron, 10-3, showed only depression at all stimulus frequencies. A previous study showed that the ability of a synapse to facilitate is correlated with the identity of the postsynaptic neuron. The present results indicate that depression and facilitation are regulated independently. Depression is regulated presynaptically in a manner related to sensory neuron age; whereas, facilitation is regulated by the postsynaptic target.

Animals↗
PubMed2001

Altered effects of ethanol in NR2A(DeltaC/DeltaC) mice expressing C-terminally truncated NR2A subunit of NMDA receptor.

Phosphorylation of C-termini of receptor subunits is thought to play a significant role in modulation of N-methyl-D-aspartic acid (NMDA) receptor function. To investigate whether the C-terminus of the NR2A subunit is involved in determining the sensitivity of NMDA receptors to ethanol we compared the effects of ethanol in vitro on NMDA-mediated field excitatory postsynaptic potentials (fEPSPs) in the CA1 and dentate gyrus (DG) of adult male NR2A(DeltaC/DeltaC) mice lacking the C-terminus of NR2A subunit and in their parental strain C57Bl/6. We also tested the in vivo effects of a hypnotic dose of ethanol in C57Bl/6 and NR2A(DeltaC/DeltaC) mice and their F2 offspring. Ifenprodil (10 microM) was used to distinguish between the NR2A and NR2B components of NMDA fEPSPs. Ethanol (100 mM) in the presence of ifenprodil inhibited the CA1 NR2A-mediated component of NMDA fEPSPs two times more in NR2A(DeltaC/DeltaC) than in C57Bl/6. Ethanol inhibition of the CA1 NR2B-mediated component was five to seven times lower in NR2A(DeltaC/DeltaC) than in C57Bl/6. In the DG ethanol had similar effects in the two strains. In vivo administration of ethanol (4 g/kg) induced sedation of similar duration in both strains of mice. A second administration of ethanol 7 days after the initial injection revealed an increased ethanol sensitivity of NR2A(DeltaC/DeltaC) and F2(DeltaC/DeltaC) mice including a shortened time to loss of righting reflex and an increased sleep time. The sensitization of NR2A(DeltaC/DeltaC) mice to alcohol was not accompanied by an altered ethanol sensitivity of NMDA fEPSPs recorded in vitro. Our data are consistent with the inhibitory action of ethanol on NMDA receptors being mediated by a site other than the intracellular C-terminus of the NR2A subunit. The altered sensitivities to ethanol of both NR2A- and NR2B-mediated responses in the CA1 of NR2A(DeltaC/DeltaC) imply that NR2A- and NR2B subunit-containing NMDA receptors may be linked by a common target of ethanol.

Animals↗
PubMed2006

Inhibition of excitatory synaptic transmission by trans-resveratrol in rat hippocampus.

The red wine polyphenol trans-resveratrol has been found to exert potent protective actions in a variety of cerebral ischemia models. The neuroprotection by trans-resveratrol thus far is mainly attributed to its intrinsic antioxidant properties. In the present study, the effects of the red wine polyphenol on excitatory synaptic transmission were investigated in the CA1 region of rat hippocampal slices. Perfusion with trans-resveratrol (10-100 microM) caused a concentration-dependent inhibition on the filed excitatory postsynaptic potentials (the field EPSPs) without detectable effect on the presynaptic volleys. The inhibition had a slow onset and was reversible. Trans-resveratrol (30 microM) did not change the ratios of paired-pulse facilitation of the field EPSPs tested at intervals of 20, 40 and 80 ms, nor did it alter the membrane properties of postsynaptic CA1 pyramidal neurons. However, trans-resveratrol (30 microM) significantly suppressed glutamate-induced currents in postsynaptic CA1 pyramidal neurons. In dissociated hippocampal neurons, the IC(50) value of trans-resveratrol in inhibition of glutamate-induced currents was 53.3+/-9.4 microM. Kainite and NMDA receptors were more sensitive to the red wine polyphenol than AMPA receptors. The present study for the first time demonstrates that trans-resveratrol inhibits the postsynaptic glutamate receptors, which probably works in concert with its antioxidant action for ameliorating the brain ischemic injury. The findings also support the future use of trans-resveratrol in the treatment of various neurodegenerative disorders.

Animals↗
PubMed1998

Indications for coupling between feline spinocervical tract neurones and midlumbar interneurones.

The possibility of collateral segmental actions of spinocervical tract (SCT) neurones upon interneurones with input from cutaneous and group II muscle afferents was investigated in deeply anaesthetized cats. To this end, intracellular and/or extracellular recordings were made from 35 dorsal horn and 15 intermediate zone interneurones in midlumbar segments of the spinal cord and effects of stimulation of the ipsilateral dorso-lateral funiculus (DLF) at C3 and C1 levels, i.e. below and above the lateral cervical nucleus where axons of SCT cells terminate, were compared. The stimuli applied at the C3 segment were within the range of stimuli (50-100 microA) required for antidromic activation of SCT neurones in the same experiment. Those applied at the C segment (200-500 microA) were at least 3 times stronger than C3 stimuli. Under the same experimental conditions, long ascending and descending tract neurones (dorsal spino-cerebellar and rubro-spinal tract neurones) with axons in the DLF were activated at similar thresholds from the C and C3 segments. Intracellular recordings were made from 29 interneurones of which 19 (65%) were dorsal horn and 10 (35%) were intermediate zone interneurones. Excitatory postsynaptic potentials (EPSPs) evoked by single stimuli applied at the C3 segment, but not the C segment, were found in 14 (48%) of those interneurones; their latencies (3.0-5.7 ms) and frequency following with only minimal temporal facilitation were as required for potentials being evoked monosynaptically by the fastest conducting SCT neurones. Extracellular recordings were made from 30 interneurones (24 dorsal horn and 6 intermediate zone interneurones), and in these neurones spike potentials induced from the C3, but not from the C segment, were evoked only by short trains of stimuli. However, their latencies from the first effective stimulus (4.3-5.4 ms) were compatible with mono- or oligosynaptically mediated collateral actions of SCT neurones. They were found in 10 (33%) of the 30 investigated interneurones. Similar effects of C3 stimuli were found in similar proportions of dorsal horn interneurones and intermediate zone interneurones. Indications were also found for synaptic actions evoked by C3 stimuli that could not be attributed to direct collateral actions of SCT neurones. In some intracellularly recorded dorsal horn interneurones, short-latency EPSPs were evoked from the C3 segment by the 2nd or 3rd stimulus in the train, but not by single stimuli. In other dorsal horn and intermediate zone interneurones, inhibitory postsynaptic potentials (IPSPs) were evoked from the C3 segment at minimal latencies (2.7-3.2 ms), which might be too short to allow their mediation via SCT neurones. We conclude that SCT neurones might be used to forward information from muscle group II and cutaneous afferents not only to neurones in the lateral cervical nucleus and via them to thalamus and cerebral cortex but also to interneurones in spinal reflex pathways. Thereby reflex actions evoked from group II and cutaneous afferents might be co-ordinated with responses mediated by supraspinal neurones. We conclude also that dorsal horn and intermediate zone mid-lumbar interneurones might contribute to the previously reported di-and poly-synaptic excitation or inhibition of postsynaptic dorsal column (PSDC), spinothalamic tract (STT) and spinomesencephalic tract (SMT) neurones by collateral actions of SCT cells. Thereby these interneurones might contribute to the co-ordination of responses mediated by various populations of supraspinal neurones.

Animals↗
PubMed2000

Effects of 2-arachidonylglycerol, an endogenous cannabinoid, on neuronal activity in rat hippocampal slices.

The monoacylglycerol 2-arachidonylglycerol is an endogenous ligand of cannabinoid receptors. We examined whether 2-arachidonylglycerol can influence excessive neuronal activity by investigating stimulation-induced population spikes and epileptiform activity in rat hippocampal slices. For this purpose, the effects of 2-arachidonylglycerol were compared with those of the synthetic cannabinoid agonist WIN 55,212-2. At concentrations of 10-50 microM, 2-arachidonylglycerol attenuated the amplitude of the orthodromic population spike and the slope of the field excitatory postsynaptic potential (field EPSP). However, the effect of the synthetic cannabinoid WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolol[ 1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone; 0.1 microM and 1 microM) was significantly higher than that of the endogenous ligand. At a concentration of 1 microM, WIN 55,212-2 completely suppressed the field EPSP. However, none of the investigated compounds did affect the presynaptic fiber spike of the afferents. The CB1 receptor antagonist SR 141716 (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorphenyl)-4-methyl-3- pyrazole-carboxamide) blocked the inhibition evoked by the cannabinoids. Both 2-arachidonylglycerol (30 microM) and WIN 55,212-2 (100 nM) shifted the input-output curve of the postsynaptic spike and the field EPSP to the right and increased the magnitude of paired-pulse facilitation, indicating a presynaptic mechanism of action. 2-Arachidonylglycerol and WIN 55,212-2 attenuated the frequency of spontaneously occurring epileptiform burst discharges in CA3 elicited by omission of Mg2+ and elevation of K+ to 8 mM. The antiepileptiform effect of these cannabinoids was blocked by SR 141716. In conclusion, 2-arachidonylglycerol seems to limit neuronal excitability via cannabinoid receptors of the CB1 type. By acting predominantly at a presynaptic site, it is capable of reducing excitatory neurotransmission, a mechanism which might be involved in the prevention of excessive excitability leading to epileptiform activity.

Analgesics↗
PubMed2000

Hypoxia on hippocampal slices from mice deficient in dystrophin (mdx) and isoforms (mdx3cv).

Slices from control C57, mdx, and mdx3cv mice were made hypoxic until both field excitatory postsynaptic potential (fEPSP) and presynaptic afferent volley (AV) disappeared (H1). After reoxygenation and recovery of fEPSP, a second and longer hypoxic test (H2) lasted 3 minutes beyond the time required to block AV. When slices were kept in 10 mmol/L glucose, HI abolished AV 37 and 19% earlier in slices from mdr and mdx3cv mutants than in control slices (where HI = 12 +/- 4.6 minutes, mean +/- SD). During H2 or when slices were kept in 4 mmol/L glucose, AV vanished even more quickly, but the times to block did not differ significantly between slices from controls and mutants. After reoxygenation, AV fully recovered in most slices. Rates of blockade of fEPSPs were comparable in all slices, and most fEPSPs recovered fully after HI. But even in the presence of 10 mmol/L glucose, the second hypoxia suppressed fEPSPs irreversibly in some slices: 2 of 10 from control, 3 of 7 from mdx, and 1 of 6 from mdx3cv mice. Most slices in 4 mmol/L glucose showed no recovery at all: six of seven from control, three of five from mdx, and four of five from mdx3cv mice. Thus, slices from mdx mice were more susceptible than other slices to irreversible hypoxic failure when slices were kept in 10 mmol/L glucose, but they were less susceptible than other slices when kept in 4 mmol/L glucose. In conclusion, the lack of full-length dystrophin (427 kDa) predisposes to quicker loss of nerve conduction in slices from mdx and mdx3cv mutants and improved posthypoxic recovery of fEPSPs in 4 mmol/L glucose in slices from mdx but not mdx3cv mutants, perhaps because the 70-kDa and other C-terminal isoforms are still present in mdx mice.

Afferent Pathways↗
PubMed2003

Interactions between adenosine and metabotropic glutamate receptors in the rat hippocampal slice.

1. We have examined excitatory postsynaptic potentials and paired-pulse interactions in rat hippocampal slices to obtain more information about the site and mechanism of interactions between metabotropic glutamate receptors and adenosine receptors. 2. The results show that the suppression of adenosine sensitivity is explained by a selectively reduced responsiveness to A(1) receptor stimulation, and does not involve any facilitation of A(2A) adenosine receptors, since it can be obtained in the absence of endogenous adenosine and is not prevented by the A(2A) receptor blocker ZM241385. 3. The glutamate receptors involved are of the group I class since the suppression of adenosine sensitivity is produced by ACPD and the group I selective compound DHPG. Furthermore, the effects of DHPG could be prevented by LY367385, a selective antagonist at the mGlu(1a) subtype of group I receptors. The selective antagonist at mGlu(5) receptors, SIB1893, did not prevent the suppression of adenosine sensitivity by DHPG. Blockade of the DHPG/adenosine interaction was also obtained by superfusion with the protein kinasae C inhibitor chelerythrine. 4. Since the suppression of adenosine responses by metabotropic receptor agonists was seen in the paired-pulse paradigm, we conclude that the observed interactions occur at the level of the presynaptic terminals. 5. The interaction with adenosine receptors is not specific, but applies also to a suppression of responses mediated by the GABA(B) receptor agonist baclofen. 6. We conclude that activation of the mGlu1a subtype of receptor can suppress responses mediated via adenosine A1 receptors, probably by activating protein kinase C. Since the changes induced by metabotropic glutamate receptor agonists last for at least 60 min, the data also imply that these interactions could play an important role in changes of synaptic function long after even transient increases of glutamate release in the CNS.

Adenosine↗