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PubMed1995

Depth electrode studies and intracellular dentate granule cell recordings in temporal lobe epilepsy.

Hippocampal depth electrodes are often used to localize seizure onset in patients who may have temporal lobe epilepsy (TLE). A number of features of the spontaneous seizures and of their ictal onset patterns can be analyzed from these recordings. We compared a number of the typical electroencephalographic (EEG) changes at seizure onset with several cellular parameters recorded in dentate granule cells from the same 14 patients diagnosed with medial temporal sclerosis (MTS) to examine the pathophysiological correlates of this spontaneous EEG activity in this form of TLE. The intracellularly recorded parameters include the propensity to fire evoked epileptiform bursts, the absence of evoked inhibitory potentials, the presence of polysynaptic excitatory postsynaptic potentials, and the presence of spontaneous excitatory activity. We noted several correlations between the EEG data and the intracellular recordings. The absence of synaptically evoked bursts was correlated with the presence of low-voltage fast activity at seizure onset. In addition, the loss of inhibitory postsynaptic potentials was correlated with the presence of periodic spiking pre-ictally. Several other correlations were also noted. These data indicate that EEG findings may be predictive of anatomical and cellular pathological changes and provide clues to the physiological mechanisms involved in this form of epilepsy.

Action Potentials↗

PubMed2006

Properties of propriospinal neurons in the C3-C4 segments mediating disynaptic pyramidal excitation to forelimb motoneurons in the macaque monkey.

Candidate propriospinal neurons (PNs) that mediate disynaptic pyramidal excitation to forelimb motoneurons were studied in the C3-C4 segments in anesthetized macaque monkeys (n = 10). A total of 177 neurons were recorded (145 extracellularly, 48 intracellularly, and 16 both) in laminae VI-VII. Among these, 86 neurons (73 extracellularly, 14 intracellularly and 1 both) were antidromically activated from the forelimb motor nucleus or from the ventrolateral funiculus just lateral to the motor nucleus in the C6/C7 segments and thus are identified as PNs. Among the 73 extracellularly recorded PNs, 60 cells were fired by a train of four stimuli to the contralateral pyramid with segmental latencies of 0.8-2.2 ms, with most of them (n = 52) in a monosynaptic range (<1.4 ms including one synaptic delay and time to firing). The firing probability was only 21% from the third pyramidal volley but increased to 83% after intravenous injection of strychnine. In most of the intracellularly recorded PNs, stimulation of the contralateral pyramid evoked monosynaptic excitatory postsynaptic potentials (EPSPs, 12/14) and disynaptic inhibitory postsynaptic potentials (14/14), which were found to be glycinergic. In contrast, cells that did not project to the C6-Th1 segments where forelimb motoneurons are located were classified as segmental interneurons. These were fired from the third pyramidal volley with a probability of 71% before injection of strychnine. It is proposed that some of these interneurons mediate feed-forward inhibition to the PNs. These results suggest that the C3-C4 PNs receive feed-forward inhibition from the pyramid in addition to monosynaptic excitation and that this inhibition is stronger in the macaque monkey than in the cat. Another difference with the cat was that only 26 of the 86 PNs (30%, as compared with 84% in the cat) with projection to the forelimb motor nuclei send ascending collaterals terminating in the lateral reticular nucleus (LRN) on the ipsilateral side of the medulla. Thus we identified C3-C4 PNs that could mediate disynaptic pyramidal excitation to forelimb motoneurons in the macaque monkey. The present findings explain why it was difficult in previous studies of the macaque monkey to evoke disynaptic pyramidal excitation via C3-C4 PNs in forelimb motoneurons and why-as compared with the cat-the monosynaptic EPSPs evoked from the LRN via C3-C4 PNs were smaller in amplitude.

Animals↗

PubMed2004

In vivo intracellular responses of the medial geniculate neurones to acoustic stimuli in anaesthetized guinea pigs.

In the present study, we investigated the auditory response features of the medial geniculate neurones, using in vivo intracellular recordings in anaesthetized guinea pigs. Of the 76 neurones examined, 9 showed 'off' or 'on-off' responses to an acoustic stimulus and thus were defined as 'off' or 'on-off' neurones. Among the remaining 67 neurones, 42 showed an excitatory postsynaptic potential (EPSP) to acoustic stimuli and 25 showed either a pure inhibitory postsynaptic potential (IPSP, 7 neurones), or an IPSP preceded by an EPSP (EPSP-IPSP type, 18 neurones). The EPSP responses exhibited a mean latency of 15.7 +/- 6.1 ms, which was significantly shorter than that of the IPSP responses (21.3 +/- 8.6 ms, P < 0.01). The IPSP responses also showed a significantly greater duration than the EPSP responses (208.5 +/- 128.2 ms versus 122.4 +/- 84.8 ms, P < 0.05), while there were no significant differences between the amplitudes of IPSP and EPSP (8.3 +/- 3.2 mV versus 8.7 +/- 5.3 mV). Of the 11 neurones that showed EPSP responses to acoustic stimuli and were histologically labelled, 7 were located in the lemniscal medial geniculate body (MGB) and 4 in the non-lemniscal MGB. Another 6 labelled neurones that showed IPSP responses to acoustic stimuli were located in the non-lemniscal MGB. With a membrane potential of above -72 mV, the neurones showed greater EPSP or IPSP to an acoustic stimulus when their membrane potential was depolarized. However, upon hyperpolarization to below -74 mV, the neurones shifted to low-threshold calcium spikes (LTS)/LTS bursts. In response to auditory stimuli of different durations, 'off' neurones that responded to the offset of the acoustic stimulus and were located in the non-lemniscal MGB showed different response latencies or deviations of latencies in addition to exhibiting different numbers of spikes, suggesting that the timing of the spikes could be another component utilized by thalamic neurones to encode information on the stimulus. Given that some non-lemniscal neurones are multisensory and project to the entire auditory cortex, the selective corticofugal inhibition in the non-lemniscal MGB would enable the ascending pathway to prepare the auditory cortex to receive subsequent auditory information, avoiding the interference of other sensory inputs.

Acoustic Stimulation↗

PubMed1999

Miniature EPSPs and sensory encoding in the primary afferents of the vestibular lagena of the toadfish, Opsanus tau.

The synaptic activity transmitted from vestibular hair cells of the lagena to primary afferent neurons was recorded in vitro using sharp, intracellular microelectrodes. At rest, the activity was composed of miniature excitatory postsynaptic potentials (mEPSPs) at frequencies from 5 to 20/s and action potentials (APs) at frequencies betwen 0 and 10/s. mEPSPs recorded from a single fiber displayed a large variability. For mEPSPs not triggering APs, amplitudes exhibited an average coefficient of variance (CV) of 0.323 and rise times an average CV of 0.516. APs were only triggered by mEPSPs with larger amplitudes (estimated 4-6 mV) and/or steeper maximum rate of rise (10.9 mV/ms, +/- 3.7 SD, n=4 experiments) compared to (3.50 mV/ms, +/-0.07 SD, n=6 experiments) for nontriggering mEPSPs. The smallest mEPSPs showed a fast rise time (0.99 ms between 10% and 90% of peak amplitude) and limited variability across fibers (CV:0.18) confirming that they were not attenuated signals, but rather represented single-transmitter discharges (TDs). The mEPSP amplitude and rise-time relationship suggests that many mEPSPs represented several, rather than a single pulse of secretion of TDs. According to the estimated overall TD frequency, the coincidence of TDs contributing to the same mEPSP were not statistically independent, indicating a positive interaction between TDs that is reminiscent of the way subminiature signals group to form miniature signals at the neuromuscular junction. Depending on the duration and intensity of efferent stimulation, a complete block of AP initiation occurred either immediately or after a delay of a few seconds. Efferent stimulation did not significantly change AP threshold level, but abruptly decreased mEPSP frequency to a near-complete block that followed the block of APs. Maximum mEPSP rate of rise decreased during, and recovered progressively after, efferent stimulation. After termination of efferent stimulation, mEPSP amplitude did not recover instantly and for a few seconds the amplitude distribution of synaptic events showed fewer large-amplitude events than during the control period. This confirms that mEPSP amplitude and rate of rise properties, which are critical for triggering afferent APs, are modified by efferent activity. The depression of afferent AP firing during efferent stimulation corresponded to a decrease in mEPSP frequency and, to a lesser extent, a decrease in mEPSP amplitude and rate of rise, suggesting, a decrease in the level of interaction among TDs contibuting to a mEPSP.

Action Potentials↗

PubMed2001

Nitric oxide in the afferent synaptic transmission of the axolotl vestibular system.

This study was performed using intracellular and multiunit extracellular recording techniques in order to characterize the role of nitric oxide in the afferent synaptic transmission of the vestibular system of the axolotl (Ambystoma tigrinum). Bath application of nitric oxide synthase inhibitors N(G)-nitro-L-arginine (0.01microM to 10microM) and N-nitro-L-arginine methyl ester hydrochloride (0.1microM to 1000microM) elicited a dose-dependent decrease in the basal discharge of the semicircular canal afferent fibers. N(G)-Nitro-L-arginine also diminished the response to mechanical stimuli. Moreover, N(G)-nitro-L-arginine (1microM) produced a hyperpolarization associated with a decrease in the spike discharge and diminished the frequency of the excitatory postsynaptic potentials on afferent fibers recorded intracellularly. Nitric oxide donors were also tested: (i) S-nitroso-N-acetyl-DL-penicillamine (0.1microM to 100microM) increased the basal discharge and the response to mechanical stimuli. At the maximum effective concentration (100microM) this drug affected neither the amplitude nor the frequency of the excitatory postsynaptic potentials. However, it slightly depolarized the afferent neurons and decreased their input resistance. (ii) 3-Morpholino-sydnonimine hydrochloride did not significantly affect the basal discharge or the mechanically evoked peak response of afferent neurons at any of the concentrations used (1microM to 1000microM). However, after 10min of perfusion in the bath, 1microM and 10microM 3-morpholino-sydnonimine hydrochloride significantly modified the baseline of the mechanically evoked response, producing an increase in the mean spike discharge of the afferent fibers. These results indicate that nitric oxide may have a facilitatory role on the basal discharge and on the response to mechanical stimuli of the vestibular afferent fibers. Thus, nitric oxide probably participates in the sensory coding and adaptative changes of vestibular input in normal and pathological conditions.

Action Potentials↗

PubMed1995

Tetanus-induced potentiation of inhibitory postsynaptic potentials in hippocampal CA1 neurons.

In the present study, tetanus-induced potentiation of inhibitory postsynaptic potentials (IPSPs), previously described by our laboratory, was further investigated in guinea pig hippocampal CA1 neurons. Tetanic stimulation of the stratum radiatum induced a long-term potentiation of the excitatory postsynaptic potential and a potentiation of the gamma-aminobutyric acid A (GABAA) receptor mediated fast IPSP without enhancing the GABAB receptor-mediated slow IPSP. During the potentiation, IPSPs evoked by stimulation of the alveus were unaffected. When slices were superfused with DL-2-amino-5-phosphonovaleric acid (an N-methyl-D-aspartate, NMDA, antagonist) and 6-cyano-7-nitroquinoxaline-2,3-dione (a non-NMDA glutamate antagonist), the potentiation of the monosynaptic fast IPSP could still be induced and maintained, suggesting that polysynaptic influences were unnecessary for this process. Finally, since the potentiation was observed in CA1 neurons in which BAPTA or K-252b was injected, this form of plasticity does not appear to be dependent on a rise in intracellular [Ca2+] or protein kinase C (PKC) activity. These results indicate that tetanic stimulation of the stratum radiatum induces a potentiation of GABAergic fast IPSPs in CA1 neurons. The potentiation may be localized to the GABAergic synapse on CA1 neurons.

2-Amino-5-phosphonovalerate↗

PubMed2003

Anesthetic sensitivities to propofol and halothane in mice lacking the R-type (Cav2.3) Ca2+ channel.

UNLABELLED: Because inhibition of voltage-dependent Ca(2+) channels can be a mechanism underlying general anesthesia, we examined sensitivities to propofol and halothane in mice lacking the R-type (Ca(v)2.3) channel widely expressed in neurons. Sleep time after propofol injection (26 mg/kg IV) and halothane MAC(RR) and MAC (50% effective concentrations for the loss of the righting reflex and for the tail pinch/withdrawal response, respectively) were determined. Significantly shorter propofol-induced sleep time (291.6 +/- 16.8 s versus 344.4 +/- 12.1 s) and larger halothane MAC(RR) (1.11% +/- 0.04% versus 0.98% +/- 0.03%) were observed in Ca(v)2.3 channel knockouts (Ca(v)2.3(-/-)) than in wild-type (Ca(v)2.3(+/+)) litter mates. To investigate the basis of the decreased anesthetic sensitivities in vivo, field excitatory postsynaptic potentials and population spikes (PSs) were recorded from Schaffer collateral CA1 synapses in hippocampal slices. Propofol (10-30 micro M) inhibited PSs by potentiating gamma-aminobutyric acid-ergic inhibition, and this potentiation was markedly smaller at 30 micro M in Ca(v)2.3(-/-) mice, possibly accounting for the decreased propofol sensitivity in vivo. Halothane (1.4%-2.2%) inhibited field excitatory postsynaptic potentials similarly in both genotypes, whereas 1%-2% halothane depressed PSs more in Ca(v)2.3(-/-) mice, suggesting the postsynaptic role of the R-type channel in the propagation of excitation and other mechanisms underlying the increased halothane MAC(RR) in Ca(v)2.3(-/-) mice. IMPLICATIONS: Because inhibition of neuronal Ca(2+) currents can be a mechanism underlying general anesthesia, we examined anesthetic sensitivities in mice lacking the R-type (Ca(v)2.3) Ca(2+) channels both in vivo and in hippocampal slices. Decreased sensitivities in mutant mice imply a possibility that agents blocking this channel may increase the requirements of anesthetics/hypnotics.

Anesthetics, Inhalation↗

PubMed1997

Involvement of pre- and postsynaptic mechanisms in posttetanic potentiation at Aplysia synapses.

Posttetanic potentiation (PTP) is a common form of short-term synaptic plasticity that is generally thought to be entirely presynaptic. Consistent with that idea, PTP of evoked excitatory postsynaptic potentials at Aplysia sensory-motor neuron synapses in cell culture was reduced by presynaptic injection of a slow calcium chelator and was accompanied by an increase in the frequency but not the amplitude of spontaneous excitatory postsynaptic potentials. However, PTP was also reduced by postsynaptic injection of a rapid calcium chelator or postsynaptic hyperpolarization. Thus, PTP at these synapses is likely to involve a postsynaptic induction mechanism in addition to the known presynaptic mechanisms.

1-Octanol↗

PubMed1999

Topographical and electrophysiological characteristics of highly excitable S neurones in the myenteric plexus of the guinea-pig ileum.

1. Most intracellular electrical recordings from myenteric neurones have been made from the centre of large ganglia. In this study, we examined the electrophysiological properties of neurones at the corners of large ganglia close to internodal strands and in microganglia. 2. Of 150 neurones in these locations: 111 were tonic S neurones; 9 were phasic S neurones and 30 were AH neurones. 3. Tonic S neurones were characterized by: (i) low resting membrane potentials (-50 +/- 1 mV, mean +/- s.e.m.); (ii) high input impedance (522 +/- 23 MOmega); (iii) low threshold for action potential (AP) generation (0.012 +/- 0.004 nA); (iv) firing of APs throughout a depolarizing pulse (duration <= 1 s) and one to four APs following a hyperpolarizing pulse and (v) spontaneous fast excitatory postsynaptic potentials (FEPSPs). A substantial proportion of tonic S neurones (43 %) also fired APs spontaneously (7.6 +/- 0.6 Hz; range, 0.3-19 Hz). All APs were blocked by tetrodotoxin (1 microM). 4. Tonic S neurones were subclassified, according to their post-stimulus responses, as SAH or SAD neurones. Following a burst of APs, SAH neurones exhibited a prominent after-hyperpolarization (duration, 711 +/- 10 ms) and SAD neurones an after-depolarization (duration, 170 +/- 10 ms). The after-hyperpolarization was reduced in four of ten neurones by apamin (0.3 microM). 5. FEPSPs were evoked in 20 of 38 S neurones by electrical stimulation applied both oral and anal to the recording site. Repetitive stimuli evoked slow excitatory postsynaptic potentials (SEPSPs) in some tonic S neurones. 6. Three functional classes of S neurones were identified after injection of neurobiotin through the recording microelectrode: (i) longitudinal muscle motor neurones, (ii) short circular muscle motor neurones, and (iii) ascending interneurones. 7. In conclusion, there appears to be topographical organization of highly excitable, tonic S neurones within the myenteric plexus, since, in contrast to other S neurones, they can be readily impaled in myenteric ganglia close to internodal strands and in microganglia.

Action Potentials↗

PubMed1999

A model for steady isometric muscle activation.

The present model of the motoneuronal (MN) pool-muscle complex (MNPMC) is deterministic and designed for steady isometric muscle activation. Time-dependent quantities are treated as time-averages. The character of the model is continuous in the sense that the motor unit (MU) population is described by a continuous density function. In contrast to most already published models, the wiring (synaptic weight) between the input fibers to the MNPMC and the MNs (about which no detailed data are known) is deduced, whereas the input-force relation is given. As suggested by experimental data, this relation is assumed to be linear during MU recruitment, but the model allows other, nonlinear relations. The input to the MN pool is defined as the number of action potentials per second in all input fibers, and the excitatory postsynaptic potential (EPSP) conductance in MNs evoked by the input is assumed to be proportional to the input. A single compartment model with a homogeneous membrane is used for a MN. The MNs start firing after passing a constant voltage threshold. The synaptic current-frequency relation is described by a linear function and the frequency-force transformation of a MU by an exponential function. The sum of the MU contraction forces is the muscle force, and the activation of the MUs obeys the size principle. The model parameters were determined a priori, i.e., the model was not used for their estimation. The analysis of the model reveals special features of the activation curve which we define as the relation between the input normalized by the threshold input of the MN pool and the force normalized by the maximal muscle force. This curve for any muscle turned out to be completely determined by the activation factor, the slope of the linear part of the activation curve (during MU recruitment). This factor determines quantitatively the relation between MU recruitment and rate modulation. This property of the model (the only known model with this property) allows a quantification of the recruitment gain (Kernell and Hultborn 1990). The interest of the activation factor is illustrated using two human muscles, namely the first dorsal interosseus muscle, a small muscle with a relatively small force at the end of recruitment, and the medial gastrocnemius muscle, a strong muscle with a relatively large force at the end of recruitment. It is concluded that the present model allows us to reproduce the main features of muscle activation in the steady state. Its analytical character facilitates a deeper understanding of these features.

Action Potentials↗

PubMed1994

2,3-diphosphoglyceric acid blocks long-term potentiation of excitatory postsynaptic currents in hippocampal CA1 neurons of the rat.

The dependence of long-term potentiation on an intact inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] metabolism was investigated with the whole-cell voltage-clamp method in the CA1 region of hippocampal slices. The intracellular application of 2,3-diphosphoglyceric acid (1 mM), an inhibitor of the Ins(1,4,5)P3 5-phosphatase and of Ins(1,4,5)P3 3-kinase eliminated the potentiation of postsynaptic currents in pyramidal cells 30 min after paired pre- and postsynaptic activation. These data suggest a possible role of postsynaptic inositol 1,4-bisphosphate and/or inositol 1,3,4,5-tetra-kisphosphate in synaptic plasticity.

2,3-Diphosphoglycerate↗

PubMed1998

Neuronal coincidence detection by voltage-sensitive electrical synapses.

Coincidence detection is important for functions as diverse as Hebbian learning, binaural localization, and visual attention. We show here that extremely precise coincidence detection is a natural consequence of the normal function of rectifying electrical synapses. Such synapses open to bidirectional current flow when presynaptic cells depolarize relative to their postsynaptic targets and remain open until well after completion of presynaptic spikes. When multiple input neurons fire simultaneously, the synaptic currents sum effectively and produce a large excitatory postsynaptic potential. However, when some inputs are delayed relative to the rest, their contributions are reduced because the early excitatory postsynaptic potential retards the opening of additional voltage-sensitive synapses, and the late synaptic currents are shunted by already opened junctions. These mechanisms account for the ability of the lateral giant neurons of crayfish to sum synchronous inputs, but not inputs separated by only 100 microsec. This coincidence detection enables crayfish to produce reflex escape responses only to very abrupt mechanical stimuli. In light of recent evidence that electrical synapses are common in the mammalian central nervous system, the mechanisms of coincidence detection described here may be widely used in many systems.

Animals↗

PubMed1997

Effect of chronic ethanol treatment in vivo on excitability in mouse cortical neurones in vitro.

1. The effects of cessation of chronic ethanol ingestion on seizure activity in vivo and on the characteristics of the evoked synaptic potentials in cortical neurones in vitro have been investigated in mice. Withdrawal from chronic ethanol treatment increased handling seizure ratings in mice between 4 and 16 h post-withdrawal. This ethanol-induced increase in seizure rating was unaffected by carbamazepine (30 mg kg(-1)) but significantly reduced at a higher concentration (130 mg kg(-1)). 2. Intracellular recordings were made from cortical layer II neurones in vitro from control mice and from mice following chronic ethanol ingestion. Evoked synaptic potentials were generated in these neurones through intralaminar stimulation. 3. Neurones from control mice displayed an evoked potential consisting of a fast excitatory postsynaptic potential (e.p.s.p.) mediated by AMPA-type glutamate receptors and an inhibitory postsynaptic potential (i.p.s.p.) mediated via GABA(A) receptors. Application of pentylenetetrazole (PTZ) or bicuculline onto these neurones inhibited the i.p.s.p., caused a large increase in both the amplitude and duration of the e.p.s.p. and initiated spontaneous excitatory activity. The resulting large evoked e.p.s.p. was mediated via both NMDA- and AMPA-type glutamate receptors. 4. Most neurones (77%) from ethanol treated mice displayed an evoked potential which comprised a large e.p.s.p. and no i.p.s.p. The e.p.s.p. consisted of several distinct components and in addition these neurones displayed spontaneous paroxysmal depolarizing shifts. This multi-component e.p.s.p. was mediated through both NMDA- and AMPA-type glutamate receptors. A population (23%) of neurones from ethanol treated mice exhibited evoked potentials which possessed both inhibitory and excitatory components and these neurones were effectively identical to those obtained from control mice. 5. Carbamazepine reduced the duration of the e.p.s.p. in neurones from ethanol treated mice and in PTZ-treated control neurones. 6. Prolonged ethanol ingestion is known to create a neurochemical imbalance in cortical neurones resulting in abnormal neurotransmission. The present study highlights the functional consequences that arise as a result of these neurochemical changes leading to over-excitation of neurones and pronounced epileptiform activity.

Alcoholism↗

PubMed1990

Cyclic adenosine monophosphate (cAMP)-induced potentiation of synaptic responses in Helix neurons.

1. The effect of intracellularly injected cAMP on the amplitude of excitatory postsynaptic potentials was studied using identified neurons of the snail Helix pomatia. 2. In 25% of the experiments, postsynaptic cAMP elevation caused a pronounced augmentation of the excitatory postsynaptic potential (EPSP) amplitude, lasting up to 15-30 min. 3. The results suggest that a cAMP increase in the postsynaptic neuron may be involved in the enhancement of synaptic efficiency.

Action Potentials↗

PubMed2001

beta-NAAG rescues LTP from blockade by NAAG in rat dentate gyrus via the type 3 metabotropic glutamate receptor.

N-Acetylaspartylglutamate (NAAG) is an agonist at the type 3 metabotropic glutamate receptor (mGluR3), which is coupled to a Gi/o protein. When activated, the mGluR3 receptor inhibits adenylyl cyclase and reduces the cAMP-mediated second-messenger cascade. Long-term potentiation (LTP) in the medial perforant path (MPP) of the hippocampal dentate gyrus requires increases in cAMP. The presence of mGluR3 receptors and NAAG in neurons of the dentate gyrus suggests that this peptide transmitter may inhibit LTP in the dentate gyrus. High-frequency stimulation (100 Hz; 2 s) of the MPP resulted in LTP of extracellularly recorded excitatory postsynaptic potentials at the MPP-granule cell synapse of rat hippocampal slices. Perfusion of the slice with NAAG (50 and 200 microM) blocked LTP. Neither 50 nor 200 microM NAAG produced N-methyl-D-aspartate receptor currents in the granule cells of the acute hippocampal slice. The group II mGluR antagonist ethyl glutamate (100 microM) and a structural analogue of NAAG, beta-NAAG (100 microM), prevented the blockade of LTP by NAAG. Paired-pulse depression of the excitatory postsynaptic potential at 20- and 80-ms interpulse intervals (IPI) was not affected by NAAG or beta-NAAG. beta-NAAG did not affect inositol trisphosphate production stimulated by the agonist glutamate in cells expressing the group I mGluR1alpha or mGluR5. beta-NAAG blocked the decrease in forskolin-stimulated cAMP by the group II mGluR agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) but not the group III mGluR agonist L(+)-2-amino-4-phosphonobutyric acid in cerebellar granule cells. In cells transfected with mGluR3, but not mGluR2, beta-NAAG blocked forskolin-stimulated cAMP responses to glutamate, NAAG, the nonspecific group I, II agonist trans-ACPD, and the group II agonist DCG-IV. We conclude that beta-NAAG is a selective mGluR antagonist capable of differentiating between mGluR2 and mGluR3 subtypes and that the mGluR3 receptor functions to regulate activity-dependent synaptic potentiation in the hippocampus.

Animals↗

PubMed2006

Adenosine inhibits activity of hypocretin/orexin neurons by the A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect.

Neurons in the lateral hypothalamus (LH) that contain hypocretin/orexin have been established as important promoters of arousal. Deficiencies in the hypocretin/orexin system lead to narcolepsy. The inhibition of hypocretin/orexin neurons by sleep-promoting neurotransmitters has been suggested as one part of the sleep regulation machinery. Adenosine has been identified as a sleep promoter and its role in sleep regulation in the basal forebrain has been well documented. However, the effect of adenosine on arousal-promoting hypocretin/orexin neurons has not been addressed, despite recent evidence that immunocytochemical visualization of adenosine receptors was detected in these neurons. In this study, we examined the hypothesis that adenosine inhibits the activity of hypocretin/orexin neurons by using electrophysiological methods in brain slices from mice expressing green fluorescent protein in hypocretin/orexin neurons. We found that adenosine significantly attenuated the frequency of action potentials without a change in membrane potential in hypocretin/orexin neurons. The adenosine-mediated inhibition arises from depression of excitatory synaptic transmission to hypocretin/orexin neurons because adenosine depresses the amplitude of evoked excitatory postsynaptic potential and the frequency of spontaneous and miniature excitatory postsynaptic currents in these neurons. At the cell body of the hypocretin/orexin neurons, adenosine inhibits voltage-dependent calcium currents without the induction of GIRK current. The inhibitory effect of adenosine is dose dependent, pertussis toxin sensitive, and mediated by A1 receptors. In summary, our data suggest that in addition to its effect in the basal forebrain, adenosine exerts its sleep-promoting effect in the LH by inhibition of hypocretin/orexin neurons.

Action Potentials↗

PubMed2000

Dorsal column nuclei neurons recorded in a brain stem-spinal cord preparation: characteristics and their responses to dorsal root stimulation.

Recordings were obtained from dorsal column nucleus (DCN) neurons in a neonatal rat brain stem-spinal cord preparation to study their basic electrophysiological properties and responses to stimulation of a dorsal root. Whole-cell patch-clamp recordings were made from 21 neurons that responded to dorsal root stimulation with a fast excitatory postsynaptic potential (EPSP). These neurons were located lateral to, but at the level of, the area postrema at depths of 100-268 microm below the dorsal surface of the brain. The neurons could be divided into groups according to the shape of their action potentials or voltage responses to hyperpolarizing current steps; however, the response profiles of the groups of neurons to dorsal root stimulation were not significantly different and all neurons were considered together. Dorsal root stimulation elicited excitatory postsynaptic potentials (EPSPs) in all neurons with a very low variability in onset latency and an ability to follow 100-Hz stimulation, indicating that they were mediated by activation of a monosynaptic pathway. The peak amplitude of the EPSP increased with membrane hyperpolarization, and applications of the non-NMDA receptor antagonists 6-nitro-7-sulfamoylbenzo[f]quinoxaline-2, 3-dione (NBQX) and 6,7-dinitroquinoxaline-2,3-dione (DNQX) decreased the amplitude of the EPSP to 14.2% of the control response (n = 6). The descending phase of the EPSP decreased with membrane hyperpolarization and was reduced by the N-methyl-D-aspartate (NMDA) receptor antagonist AP-5 (n = 2). The EPSPs were also reduced in amplitude by applications of the gamma-aminobutyric acid-B (GABA(B)) receptor agonist baclofen, which had no effect on membrane potential or input resistance. These results show that fast EPSPs in DCN neurons elicited by dorsal root stimulation are mediated by an excitatory amino acid acting at both non-NMDA and, to a lesser extent, NMDA receptors. In addition, GABA acting at presynaptic GABA(B) receptors can inhibit these responses.

Adrenergic Fibers↗

PubMed2000

Prenatal exposure to a low concentration of carbon monoxide disrupts hippocampal long-term potentiation in rat offspring.

The aim of the present study was to investigate whether functional changes at CA3-CA1 synapses in the hippocampus could underlie learning and memory deficits produced in rat offspring by a prenatal exposure model simulating the carbon monoxide (CO) exposure observed in human cigarette smokers. Electrophysiological endpoints, including long-term potentiation, were examined in 15- to 30-day-old male rats whose mothers were exposed, from day 0 to day 20 of gestation, to 150 ppm of CO resulting in blood levels of carboxyhemoglobin comparable to those found in human cigarette smokers. Evoked field excitatory postsynaptic potentials were measured in the stratum radiatum in hippocampal slices. Results show that before tetanus, input/output functions, presynaptic volley, and paired-pulse facilitation were not affected in CO-exposed offspring, indicating that basal synaptic excitability and terminal Ca(2+) influx were not influenced by prenatal exposure to this gas. Conversely, evoked field excitatory postsynaptic potentials potentiation in response to tetanization was reduced by about 23% and decayed rapidly to baseline values in slices from CO-exposed animals. No changes between and within groups were observed in paired-pulse facilitation after tetanus. The selective impairment of long-term potentiation expression exhibited by CO-exposed rats was paralleled by a significant decrease in heme-oxygenase 2 and neuronal nitric-oxide synthase in the hippocampus. No changes in either enzymatic activity were found in frontal cortex and cerebellum. These electrophysiological and biochemical alterations might account for cognitive deficits previously observed in rats exposed prenatally to CO. Our findings could have clinical implications for the offspring of mothers who smoke during pregnancy.

Animals↗