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PubMed1997

Electrophysiological properties of rat pontine nuclei neurons In vitro II. Postsynaptic potentials.

We investigated the postsynaptic responses of neurons of the rat pontine nuclei (PN) by performing intracellular recordings in parasagittal slices of the pontine brain stem. Postsynaptic potentials (PSPs) were evoked by brief (0.1 ms) negative current pulses (10-250 microA) applied to either the cerebral peduncle or the pontine tegmentum. First, excitatory postsynaptic potentials (EPSPs) could be evoked readily from peduncular stimulation sites. These EPSPs exhibited short latencies, a nonlinear increment in response to increased stimulation currents, and an unconventional dependency on the somatic membrane potential. Pharmacological blockade of the synaptic transmission using 6,7-dinitroquinoxaline-2, 3-dione and ,-2-amino-5-phosphonovaleric acid, selective antagonists of the alpha-amino-3-hydroxy-5-methyl-4-isoxazilepropionate- (AMPA) and the N-methyl--aspartate (NMDA)-type glutamate receptors, showed that these EPSPs were mediated exclusively by excitatory amino acids via both AMPA and NMDA receptors. Moreover, the pharmacological experiments indicated the existence of voltage-sensitive but NMDA receptor-independent amplification of EPSPs. Second, stimulations at peduncular and tegmental sites also elicited inhibitory postsynaptic potentials (IPSPs) in a substantial proportion of pontine neurons. The short latencies of all IPSPs argued against the participation of inhibitory interneurons. Their sensitivity to bicuculline and reversal potentials around -70 mV suggested that they were mediated by gamma-aminobutyric acid-A (GABAA) receptors. In addition to single PSPs, sequences consisting of two to four distinct EPSPs could be recorded after stimulation of the cerebral peduncle. Most remarkably, the onset latencies of the following EPSPs were multiples of the first one indicating the involvement of intercalated synapses. Finally, we used the classic paired-pulse paradigm to study whether the temporal structure of inputs influences the synaptic transmission onto pontine neurons. Pairs of electrical stimuli applied to the cerebral peduncle resulted in a marked enhancement of the amplitude of the second EPSP for interstimulus intervals of 10-100 ms. Delays >200 ms left the EPSP amplitude unaltered. These data provide evidence for a complex synaptic integration and an intrinsic connectivity within the PN too elaborate to support the previous notion that the PN are simply a relay station.

Animals↗
PubMed2000

Cellular mechanisms for resolving phase ambiguity in the owl's inferior colliculus.

Both mammals and birds use the interaural time difference (ITD) for localization of sound in the horizontal plane. They may localize either real or phantom sound sources, when the signal consists of a narrow frequency band. This ambiguity does not occur with broadband signals. A plot of impulse rates or amplitude of excitatory postsynaptic potentials against ITDs (ITD curve) consists of peaks and troughs. In the external nucleus (ICX) of the owl's inferior colliculus, ITD curves show multiple peaks when the signal is narrow-band, such as tones. Of these peaks, one occurs at ITDi, which is independent of frequency, and others at ITDi +/- T, where T is the tonal period. The ITD curve of the same neuron shows a large peak (main peak) at ITDi and no or small peaks (side peaks) at ITDi +/- T, when the signal is broadband. ITD curves for postsynaptic potentials indicate that ICX neurons integrate the results of binaural cross-correlation in different frequency bands. However, the difference between the main and side peaks is small. ICX neurons further enhance this difference in the process of converting membrane potentials to impulse rates. Inhibition also appears to augment the difference between the main and side peaks.

Acoustic Stimulation↗
PubMedDate not supplied

Effects of lead exposure on long-term potentiation induced by 2-deoxy-D-glucose in area CA1 of rat hippocampus in vitro.

Chronic developmental lead exposure is known to be associated with cognitive dysfunction in children. Previous studies have demonstrated that chronic lead exposure could impair the induction and maintenance of long-term potentiation induced by high-frequency stimulation (HFS-LTP). In area CA1 of rat hippocampus, long-term potentiation could also be induced following temporary replacement of 10 mM 2-deoxy-D-glucose (2-DG) for 10 mM glucose in the normal perfusate (artificial cerebrospinal fluid). The present study was carried out to investigate whether chronic lead exposure affected long-term potentiation induced by 2-DG (2-DG-LTP). Neonatal Wistar rats were exposed to lead from parturition to weaning via milk of dams whose drinking water contained 0.2% lead acetate. Field excitatory postsynaptic potentials (EPSPs) in area CA1 of hippocampus were recorded on postnatal days 25-30. 2-DG application was followed by an increase in EPSP slopes in a time-course-dependent manner in both control and lead-exposed rats, while the amplitude of 2-DG-LTP in the lead-exposed rats (225.9+/-19.0%, n=12) was significantly greater than that in controls (155.2+/-9.8%, n=12). In contrast to the effects of lead exposure on 2-DG-LTP, the amplitude of HFS-LTP in the lead-exposed rats (121.5+/-13.7%, n=12) was significantly less than that in controls (183.9+/-18.6%, n=12). These results indicate that chronic lead exposure had opposite effects on the two types of LTP induced by HFS and 2-DG. This would suggest that the effects of lead on HFS-LTP and 2-DG-LTP are the result of different sites of lead toxicity.

Animals↗
PubMed2007

Granular cells of the mormyrid electrosensory lobe and postsynaptic control over presynaptic spike occurrence and amplitude through an electrical synapse.

Primary afferent fibers from the electroreceptors of mormyrid electric fish use a latency code to signal the intensity of electrical current evoked by the fish's own electric organ discharge (EOD). The afferent fibers terminate centrally in the deep and superficial granular layers of the electrosensory lobe with morphologically mixed chemical-electrical synapses. The granular cells in these layers seem to decode afferent latency through an interaction between primary afferent input and a corollary discharge input associated with the EOD motor command. We studied the physiology of deep and superficial granular cells in a slice preparation with whole cell patch recording and electrical stimulation of afferent fibers. Afferent stimulation evoked large all-or-none electrical excitatory postsynaptic potentials (EPSPs) and large all or none GABAergic inhibitory postsynaptic potentials (IPSPs) in both superficial and deep granular cells. The amplitudes of the electrical EPSPs depended on postsynaptic membrane potential, with maximum amplitudes at membrane potentials between -65 and -110 mV. Hyperpolarization beyond this level resulted in either the abrupt disappearance of EPSPs, a step-like reduction to a smaller EPSP, or a graded reduction in EPSP amplitude. Depolarization to membrane potentials lower than that yielding a maximum caused a linear decrease in EPSP amplitude, with EPSP amplitude reaching 0 mV at potentials between -55 and -40 mV. We suggest that the dependence of EPSP size on postsynaptic membrane potential is caused by close linkage of pre- and postsynaptic membrane potentials through a high-conductance gap junction. We also suggest that this dependence may result in functionally important nonlinear interactions between synaptic inputs.

Action Potentials↗
PubMed2002

Neonatal exposure to novelty enhances long-term potentiation in CA1 of the rat hippocampus.

Exposing rats to an enriched environment over an extended period of time has been shown to enhance hippocampal long-term potentiation (LTP). Whether such prolonged exposure to environmental manipulation is necessary for LTP enhancement and whether the environmentally induced enhancement can persist long after the cessation of the environmental manipulation remain unknown. Using a novelty exposure procedure modified from the method of neonatal handling, we exposed neonatal rats to a non-home environment for 3 min/day during the first 3 weeks of life. We examined the LTP of both population spikes and excitatory postsynaptic potentials (EPSPs), in vitro, in the CA1 of the hippocampus during adulthood (7-8 and 13-14 months of age). We found that both the LTP of population spikes and the LTP of EPSPs were enhanced among animals who experienced neonatal novelty exposure. These results demonstrate that effective environmental enhancement of LTP can be achieved by as brief and as transient a manipulation as a 3-min/day exposure over the first 3 weeks of life. The resulting enhancement can outlast the environmental manipulation by at least 1 year.

Action Potentials↗
PubMed2003

Unilateral inner ear damage results in lasting changes in hippocampal CA1 field potentials in vitro.

We investigated the effects of a surgical lesion of one vestibular inner ear (unilateral vestibular damage [UVD]) on the field potential responses of CA1 neurons in vitro. Hippocampal slices were removed from rats at 4-6 weeks or 5-6 months post-UVD, and the field responses of CA1 neurons to electrical stimulation of the Schaffer collateral commissural pathway were analyzed. Compared with slices from sham and naive control animals, slices from UVD animals at 5-6 months post-UVD exhibited decreases in the population spike amplitude, the somal field excitatory postsynaptic potential (sfEPSP) slope, and the field EPSP (fEPSP) slope. For the population spike amplitude and fEPSP slope, this effect was observed in both CA1 ipsilateral and contralateral to the UVD. On both the ipsilateral and contralateral sides, paired-pulse testing showed increases in paired-pulse inhibition at the shortest interstimulus intervals (ISIs), with increases in paired-pulse facilitation at longer ISIs. This study provides the first evidence that peripheral vestibular damage can produce long-term changes in hippocampal electrophysiological activity in vitro.

Action Potentials↗
PubMed1997

Suppression of long-term potentiation in hippocampal slices by copper.

Cu(2+)-ions are known to interfere with gamma-aminobutyric acid (GABA)- and glutamate-operated ion channels from experiments with isolated neurons. Such actions are likely involved in the pathophysiology of Wilson's disease. We have now studied the effects of Cu2+ in the CA1 region of hippocampal slices. Field excitatory postsynaptic potential (EPSP) slopes in the CA1 region were unaffected by 1 microM Cu2+ but were depressed by 10 microM (to 85%) and 100 microM (to 50%). A paired-pulse test revealed no difference in facilitation in the presence or absence of Cu2+, indicating a postsynaptic action. A late component of intracellularly registered EPSPs in Mg(2+)-free solution was also reduced by Cu2+. The N-methyl-D-aspartate (NMDA) component of the field EPSP, isolated by adding CNQX and bicuculline in Mg(2+)-free solution, was reduced to 69% of control by 1 microM and to 50% of control by 10 microM Cu2+. Long-term potentiation, evoked by 3 x 50 pulses at 100 Hz, 20 s interval amounted to 132 +/- 11% 90 min after tetanization under control conditions but was absent in the presence of 1 microM Cu2+ in the bath. Thus low concentrations of copper can selectively reduce NMDA-mediated potentials and synaptic plasticity.

Animals↗
PubMed2005

Motilin inhibits ganglionic transmission in the myenteric plexus of the guinea-pig ileum.

Motilin is a key factor in triggering interdigestive migrating contractions. Our preceding study demonstrated that motilin caused membrane depolarizations in a minority of S and AH neurons in the myenteric plexus of the guinea-pig ileum after 18 h-fasting period; motilin depolarizations were small and seldom triggered action potentials. Then, the present study was undertaken to examine possible electrophysiological actions of motilin on the ganglionic transmission in the myenteric plexus. Intracellular recordings with sharp glass microelectrodes were made from myenteric S neurons having fast excitatory postsynaptic potentials (EPSPs), evoked by focal electrical stimulation. Motilin inhibited the fast EPSPs in amplitude, associated either with or without membrane depolarizations. Results obtained with the paired stimulus method suggested that the site for motilin-induced inhibition of fast EPSPs might be presynaptic. Furthermore, motilin did not decrease postsynaptic sensitivity to ACh, a main neurotransmitter mediating the fast EPSPs. Therefore, it is concluded that motilin might inhibit presynaptically ganglionic transmission in the myenteric plexus of the guinea-pig ileum.

Animals↗
PubMed1999

Glutamatergic synaptic responses and long-term potentiation are impaired in the CA1 hippocampal area of calbindin D(28k)-deficient mice.

The contribution of the cytosolic calcium binding protein calbindin D(28K) (CaBP) to glutamatergic neurotransmission and synaptic plasticity was investigated in hippocampal CA1 area of wild-type and antisense transgenic CaBP-deficient mice, with the use of extracellular recordings in the ex vivo slice preparation. The amplitude of non-N-methyl-D-aspartate receptor (non-NMDAr)-mediated extracellular field excitatory postsynaptic potentials (fEPSPs) recorded in control medium was significantly greater in CaBP-deficient mice, whereas the afferent fiber volley was not affected. In contrast, the amplitude of NMDAr-mediated fEPSPs isolated in a magnesium-free medium after blockade of non-NMDAr and GABAergic receptors was significantly depressed in these animals. No alteration in the magnitude of paired-pulse facilitation was found, indicating that the presynaptic calcium mechanisms controlling glutamate release were not altered in CaBP-deficient mice. The magnitude and time course of the short-term potentiation (STP) of fEPSPs induced by a 30 Hz conditioning stimulation, which was blocked by the NMDAr antagonist 2-amino-5-phosphonovalerate acid (2-APV), was not impaired in the transgenic mice, whereas long-term potentiation (LTP) induced by a 100 Hz tetanus was not maintained. The long-term depression (LTD) induced by low-frequency stimulation (1 Hz, 15 min) in the presence of the GABA antagonist bicuculline was not altered. These results argue for a contribution of CaBP to the mechanisms responsible for the maintenance of long-term synaptic potentiation, at least in part by modulating the activation of NMDA receptors.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2000

Reduced long-term potentiation in hippocampal slices prepared using sucrose-based artificial cerebrospinal fluid.

Sucrose-based artificial cerebrospinal fluid (aCSF) is sometimes used to prepare brain slices for in vitro electrophysiological experiments. This study compared the effect of preparing brain slices using chilled sucrose-based aCSF versus the conventional method using chilled aCSF on hippocampal synaptic plasticity. Brain slices from each treatment group were transferred to normal aCSF before electrophysiological recordings were made. The stimulus-response relationship of field excitatory postsynaptic potentials (fEPSPs) in the CA1 region was indistinguishable between the two treatment groups. However, the amount of LTP induced by either a &theta;-burst (four stimuli at 100 Hz repeated ten times at 200 ms intervals) or tetanic stimulation (100 Hz for 1 s) was significantly reduced in slices that had been prepared using sucrose-based aCSF. This was associated with reduced facilitation of the fEPSPs during the high frequency stimulus, reduced post-tetanic potentiation and short-term potentiation. In sucrose-cut slices the fEPSPs were slightly shorter in duration (29%, P<0.01), and during paired-pulse stimulation the broadening of the second fEPSP was enhanced. The LTP deficit in sucrose-cut slices was reversed by blocking GABA(A) receptor function with picrotoxin. These data suggest that the use of sucrose based aCSF better preserves GABA-mediated synaptic transmission, which limits the induction of LTP in hippocampal brain slices.

Action Potentials↗
PubMed2002

Octopus cells of the mammalian ventral cochlear nucleus sense the rate of depolarization.

Whole cell patch recordings in slices show that the probability of firing of action potentials in octopus cells of the ventral cochlear nucleus depends on the dynamic properties of depolarization. Octopus cells fired only when the rate of rise of a depolarization exceeded a threshold value that varied between 5 and 15 mV/ms among cells. The threshold rate of rise was independent of whether depolarizations were evoked synaptically or by the intracellular injection of current. Previous work showed that octopus cells are contacted by many auditory nerve fibers, each providing less than 1-mV depolarization. Summation of synaptic input from multiple fibers is required for an octopus cell to reach threshold. In firing only when synaptic depolarization exceeds a threshold rate, octopus cells fire selectively when synaptic input is sufficiently large and synchronized for the small, brief unitary excitatory postsynaptic potentials (EPSPs) to sum to produce a rapidly rising depolarization. The sensitivity to rate of depolarization is governed by a low-threshold, alpha-dendrotoxin-sensitive potassium conductance (g(KL)). This conductance also shapes the peaks of action potentials, contributing to the precision in their timing. Firing in neighboring T stellate cells depends much less strongly on the rate of rise. They lack strong alpha-dendrotoxin-sensitive conductances. Octopus cells appear to be specialized to detect synchronization in the activation of groups of auditory nerve fibers, a common pattern in responses to natural sounds, and convey its occurrence with temporal precision.

Action Potentials↗
PubMed1998

Distribution and properties of kainate receptors distinct in the CA3 region of the hippocampus of the guinea pig.

To characterize the nature of kainate (KA) receptors distinct in the CA3 region of the hippocampus, properties of depolarizations induced by pulses of KA or AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) applied to dendrites of CA3 neurons with micropipettes were studied in thin transverse slices of the guinea pig hippocampus. KA induced depolarizations at negligible latencies only when administered to the most proximal dendritic areas. The depolarization was unaffected by tetrodotoxin or by a decrease in Ca2+ and an increase in Mg2+ concentrations. The declining slope of the KA-induced depolarization was significantly slower than that of the AMPA-induced depolarization. In comparison with the AMPA-induced depolarization, the KA-induced depolarization was much less susceptible to antagonists such as 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX) and 1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI52466). 6, 7,8,9-Tetrahydro-5-nitro-1H-benz[g]indole-2,3-dione-3-oxime (NS-102) and (2S,4R)-4-methylglutamate (SYM 2081) were without effects. The threshold concentration of pressure-ejected KA to induce depolarizations was about 200 nM. Excitatory postsynaptic potentials elicited by mossy fiber stimulation were more potently suppressed by CNQX than by GYKI52466. These results indicate that receptors responsible for the slow KA depolarization in the CA3 region of the hippocampus are not AMPA receptors but KA receptors. They are localized in the most proximal part of the apical dendrite and distinct from those observed in primary cultures of hippocampal neurons.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2002

Identification of mechanoafferent neurons in terrestrial snail: response properties and synaptic connections.

In this study, we describe the putative mechanosensory neurons, which are involved in the control of avoidance behavior of the terrestrial snail Helix lucorum. These neurons, which were termed pleural ventrolateral (PlVL) neurons, mediated part of the withdrawal response of the animal via activation of the withdrawal interneurons. Between 15 and 30 pleural mechanosensory neurons were located on the ventrolateral side of each pleural ganglion. Intracellular injection of neurobiotin revealed that all PlVL neurons sent their axons into the skin nerves. The PlVL neurons had no spontaneous spike activity or fast synaptic potentials. In the reduced "CNS-foot" preparations, mechanical stimulation of the skin covering the dorsal surface of the foot elicited spikes in the PlVL neurons without any noticeable prepotential activity. Mechanical stimulus-induced action potentials in these cells persisted in the presence of high-Mg(2+)/zero-Ca(2+) saline. Each neuron had oval-shaped receptive field 5-20 mm in length located on the dorsal surface of the foot. Partial overlapping of the receptive fields of different neurons was observed. Intracellular stimulation of the PlVL neurons produced excitatory inputs to the parietal and pleural withdrawal interneurons, which are known to control avoidance behavior. The excitatory postsynaptic potentials (EPSPs) in the withdrawal interneurons were induced in 1:1 ratio to the PlVL neuron spikes, and spike-EPSP latency was short and highly stable. These EPSPs also persisted in the high-Mg(2+)/high-Ca(2+) saline, suggesting monosynaptic connections. All these data suggest that PlVL cells were the primary mechanosensory neurons.

Animals↗
PubMedDate not supplied

Estimating the contributions of NMDA and non-NMDA currents to EPSPs in retinal ganglion cells.

Whole-cell recordings were obtained from retinal ganglion cells of the tiger salamander (Ambystoma tigrinum) in a superfused slice preparation to evaluate contributions of NMDA (N-methyl-D-aspartate) and KA/AMPA (kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid) receptors to excitatory postsynaptic potentials (EPSPs) of retinal ganglion cells. Synaptic activation of retinal ganglion cells was achieved through the use of a brief pressure pulse of hyperosmotic Ringer (Ringer + sucrose) delivered through a microelectrode visually placed in the inner plexiform layer while whole-cell recordings were obtained from adjacent cells in the ganglion cell layer. Separation of NMDA and KA/AMPA excitatory postsynaptic currents (EPSCs) was achieved through the application of the antagonists NBQX and D-AP7, while inhibitory currents were blocked by strychnine and picrotoxin. Simple addition of the two independent EPSCs showed, most often, that the sum of the KA/AMPA and NMDA currents was less than the control response, but in some cases the sum of the two currents exceeded the magnitude of the control response. Neither result was consistent with expectations based on voltage-clamp principles and the assumption that the two currents were independent; for this reason, we considered the possibility of nonlinear interactions between KA/AMPA and NMDA receptors. Computer simulations were carried out to evaluate the summation experiments. We used both an equivalent cylinder model and a more realistic, compartmental model of a ganglion cell constrained by a passive leakage conductance, a linear KA/AMPA synaptic current, and a nonlinear NMDA current based on the well-known, voltage-sensitive Mg2+ block. Computer simulation studies suggest that the hypo- and hyper-summation of NMDA and KA/AMPA currents, observed physiologically, can be accounted for by a failure to adequately space clamp the neuron. Clamp failure leads to enhanced NMDA currents as the ion channels are relieved of the Mg2+ block; their contribution is thus exaggerated depending on the magnitude of the conductance change and the spatial location of the synaptic input.

2-Amino-5-phosphonovalerate↗
PubMed1999

17beta-estradiol enhances NMDA receptor-mediated EPSPs and long-term potentiation.

Gonadal steroid hormones influence CNS functioning through a variety of different mechanisms. To test the hypothesis that estrogen modulates synaptic plasticity in the hippocampus, in vitro hippocampal slices from 2-mo-old Sprague-Dawley male rats were used to determine the effect of 17beta-estradiol on both N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic potentials (EPSPs) through intracellular recordings and long-term potentiation (LTP) through extracellular recordings. Intracellular EPSPs and extracellular field EPSPs (fEPSPs) were recorded from CA1 pyramidal cells by stimulating Schaffer collateral fibers. In intracellular experiments, slices were perfused with medium containing bicuculline (5 microM) and low Mg2+ (0.1 mM) to enhance the NMDA receptor-mediated currents and 6, 7-dinitroquinoxaline-2,3-dione (DNQX) (10 microM) to block the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprianate (AMPA) receptor-mediated component. The effects of 17beta-estradiol on NMDA receptor-mediated activity were excitatory; concentrations >10 nM induced seizure activity, and lower concentrations (1 nM) markedly increased the amplitude of NMDA-mediated EPSPs (both the first and second responses increased during paired pulse stimulation by 180 and 197%, respectively). In extracellular experiments, slices perfused with 17beta-estradiol (100 pM) exhibited a pronounced, persisting, and significant enhancement of LTP of both the fEPSP slope (192%) and fEPSP amplitude (177%) compared with control slices (fEPSP slope = 155%; fEPSP amplitude = 156%) 30 min after high-frequency stimulation. These data demonstrate that estrogen enhances NMDA receptor-mediated currents and promotes an enhancement of LTP magnitude.

2-Amino-5-phosphonovalerate↗
PubMed2000

NMDA-Receptor-dependent synaptic activation of voltage-dependent calcium channels in basolateral amygdala.

Afferent stimulation of pyramidal cells in the basolateral amygdala produced mixed excitatory postsynaptic potentials (EPSPs) mediated by N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors during whole cell current-clamp recordings. In the presence of GABA(A) receptor blockade, the mixed EPSPs recruited a large "all-or-none" depolarizing event. This recruited event was voltage dependent and had a distinct activation threshold. An analogous phenomenon elicited by exogenous glutamate in the presence of tetrodotoxin (TTX) was blocked by Cd(2+), suggesting that the event was a Ca(2+) spike. Selective glutamatergic blockade revealed that these Ca(2+) spikes were recruited readily by single afferent stimulus pulses that elicited NMDA EPSPs. In contrast, non-NMDA EPSPs induced by single stimuli failed to elicit the Ca(2+) spike even at maximal stimulus intensities although these non-NMDA EPSPs depolarized the soma more effectively than mixed EPSPs. Elongation of non-NMDA EPSPs by cyclothiazide or brief trains of stimulation were also unable to elicit the Ca(2+) spike. Blockade of K(+) channels with intracellular Cs(+) enabled single non-NMDA EPSPs to activate the Ca(2+) spike. The finding that voltage-dependent calcium channels are activated preferentially by NMDA-receptor-mediated EPSPs provides a mechanism for NMDA-receptor-dependent plasticity independent of Ca(2+) influx through the NMDA receptor.

2-Amino-5-phosphonovalerate↗
PubMedDate not supplied

Dopamine transporter blockade increases LTP in the CA1 region of the rat hippocampus via activation of the D3 dopamine receptor.

Dopamine has been demonstrated to be involved in the modulation of long-term potentiation (LTP) in the CA1 region of the hippocampus. As monoamine transporter blockade will increase the actions of endogenous monoamine neurotransmitters, the effect of a dopamine transporter (DAT) antagonist on LTP was assessed using field excitatory postsynaptic potentials recorded in the CA1 region of the rat hippocampal slice preparation. Application of the DAT-specific blocker GBR 12,935 produced a significant enhancement in LTP of Schaffer collateral synapses in the CA1 at concentrations as low as 100 nM. A selective D1/D5 dopamine receptor antagonist (SCH 23,390, 1 microM) did not affect the ability of GBR 12,935 to enhance LTP, whereas application of the D3 dopamine receptor antagonist U 99,194 (1 microM) blocked the GBR 12,935-induced enhancement in LTP. In addition, a D3 dopamine receptor agonist (7-OH-DPAT, 1 microM) caused a significant increase in LTP, an effect that was also blocked by U 99,194 (3 microM). These results suggest that either endogenously released dopamine (facilitated by DAT blockade) or exogenously applied dopamine agonist can act to increase LTP in the CA1 of the hippocampus via activation of the D3 subtype of dopamine receptor.

Animals↗
PubMed2004

Comparative study on the effects of kynurenic acid and glucosamine-kynurenic acid.

Kynurenic acid (KYNA) is the only known endogenous N-methyl-D-aspartate (NMDA) receptor inhibitor and might therefore come into consideration as a therapeutic agent in certain neurobiological disorders. However, its use as a neuroprotective compound is practically excluded because KYNA does not readily cross the blood-brain barrier (BBB). We recently synthetized a new compound, glucosamine-kynurenic acid (KYNA-NH-GLUC), which is presumed to cross the BBB more easily. In this study, the effects of KYNA and KYNA-NH-GLUC on behavior and cortical activity were investigated in adult rats. The results show that (1) on intracerebroventricular application, the behavioral changes induced by KYNA and by KYNA-NH-GLUC are quite similar; (2) on intravenous administration, KYNA (25 mg/kg) has no effect on the somatosensory-evoked cortical potentials, whereas KYNA-NH-GLUC (25 mg/kg) causes transient but appreciable reductions in the amplitudes of the evoked responses within 5 min after application; and (3) the results of in vitro studies demonstrated that both KYNA and KYNA-NH-GLUC reduced the amplitudes of the field excitatory postsynaptic potentials (fEPSPs). These observations suggest that the two compounds have similar effects, but that KYNA-NH-GLUC passes the BBB much more readily than does KYNA. These results imply that the conjugated NH-GLUC is of importance in the passage across the BBB.

Animals↗