Field Excitatory Postsynaptic Potential Slope Research Articles

Acute adolescent morphine exposure improves dark avoidance memory and enhances long-term potentiation of ventral hippocampal CA1 during adulthood in rats.

Adolescence represents a distinctive vulnerable period when exposure to stressful situations including opioid exposure can entail lasting effects on brain and can change neural mechanisms involved in memory formation for drug-associated cues, possibly increasing vulnerability of adolescents to addiction. Herein, the effects of acute adolescent morphine exposure (AAME, two injections of 2.5mg/kg SC morphine on PND 31) were therefore investigated 6 weeks later (adulthood) on avoidance memory and hippocampal long-term potentiation (LTP) at Schaffer collateral-CA1 synapses in transvers slices from the ventral hippocampus in adult male rats using field recordings technique. Animal body weight was measured from PND 31 throughout PND 40 and also in four time points with 1 week intervals from adolescence to adulthood (PNDs 48, 55, 62 and 69) to evaluate the effect of AAME on the weight gain. We showed that there were no effects on body weight, anxiety-like behaviour and locomotor activity, even until adulthood. There was an improved dark avoidance memory during adulthood. Finally, AAME had no effects on baseline synaptic responses and resulted in a decrease in the mean values of the field excitatory postsynaptic potential slopes required to evoke the half-maximal population spike amplitude and an enhancement of LTP magnitude (%) in the ventral CA1 during adulthood. Briefly, our results suggest long-lasting effects of acute adolescent morphine exposure on the ventral hippocampus, which begin the enhancing of synaptic plasticity and the improving of emotional memory in adulthood.

P-Coumaric acid mitigates passive avoidance memory and hippocampal synaptic plasticity impairments in aluminum chloride-induced Alzheimer's disease rat model

The present study was designed to determine the effects of p-coumaric acid (p-CA), a phenolic compound, on passive avoidance memory function and hippocampal long-term potentiation (LTP) in an Alzheimer's disease (AD) rat model induced by aluminum chloride (AlCl3). p-CA (100 mg/kg; P.O.) was administered concomitantly with AlCl3 (100 mg/kg; P.O.) for 42 consecutive days. Results of this study revealed an attenuation of memory capacity, which was accompanied by a reduction in both components of LTP (field excitatory postsynaptic potentials slope and population spike amplitude) and an increase in amyloid-beta (Aβ) plaques production in the AlCl3-exposed rats. Intriguingly, treatment with p-CA improved passive avoidance memory dysfunction, ameliorated hippocampal LTP impairment, and hindered Aβ plaque accumulation in the hippocampal dentate gyrus of AlCl3-treated rats. This data provides evidence that p-CA improves AlCl3-induced passive avoidance memory decline, which may be partly related to amelioration of synaptic dysfunction and suppression of Aβ plaque formation.

Sodium salicylate enhances neural excitation via reducing GABAergic transmission in the dentate gyrus area of rat hippocampus in vivo.

Sodium salicylate, one of the non-steroidal anti-inflammatory drugs, is widely prescribed in the clinic, but a high dose of usage can cause hyperactivity in the central nervous system, including the hippocampus. At present, the neural mechanism underlying the induced hyperactivity is not fully understood, in particular, in the hippocampus under an in vivo condition. In this study, we found that systemic administration of sodium salicylate increased the field excitatory postsynaptic potential slope and the population spike amplitude in a dose-dependent manner in the hippocampal dentate gyrus area of rats with in vivo field potential extracellular recordings, which indicates that sodium salicylate enhances basal synaptic transmission and neural excitation. In the presence of picrotoxin, a GABA-A receptor antagonist, sodium salicylate failed to increase the initial slope of the field excitatory postsynaptic potential and the amplitude of the population spike in vivo. To further explore how sodium salicylate enhances the neural excitation, we made whole-cell patch-clamp recordings from hippocampal slices. We found that perfusion of the slice with sodium salicylate decreased electrically evoked GABA receptor-mediated currents, increased paired-pulse ratio, and lowered frequency and amplitude of miniature inhibitory postsynaptic currents. Together, these results demonstrate that sodium salicylate enhances the neural excitation through suppressing GABAergic synaptic transmission in presynaptic and postsynaptic mechanisms in the hippocampal dentate gyrus area. Our findings may help understand the side effects caused by sodium salicylate in the central nervous system.

Identification of vagus nerve stimulation parameters affecting rat hippocampal electrophysiology without temperature effects

BackgroundRecent experiments in rats have demonstrated significant effects of VNS on hippocampal excitability but were partially attributed to hypothermia, induced by the applied VNS parameters. ObjectiveTo allow meaningful preclinical research on the mechanisms of VNS and translation of rodent results to clinical VNS trials, we aimed to identify non-hypothermia inducing VNS parameters that significantly affect hippocampal excitability. MethodsVNS was administered in cycles of 30 s including either 0.1, 0.16, 0.25, 0.5, 1.5, 3 or 7 s of VNS ON time (biphasic pulses, 250μs/phase, 1 mA, 30 Hz) and the effect of different VNS ON times on brain temperature was evaluated. VNS paradigms with and without hypothermia were compared for their effects on hippocampal neurophysiology in freely moving rats. ResultsUsing VNS parameters with an ON time/OFF time of up to 0.5 s/30 s did not cause hypothermia, while clear hypothermia was detected with ON times of 1.5, 3 and 7 s/30 s. Relative to SHAM VNS, the normothermic 0.5 s VNS condition significantly decreased hippocampal EEG power and changed dentate gyrus evoked potentials with an increased field excitatory postsynaptic potential slope and a decreased population spike amplitude. ConclusionVNS can be administered in freely moving rats without causing hypothermia, while profoundly affecting hippocampal neurophysiology suggestive of reduced excitability of hippocampal neurons despite increased synaptic transmission efficiency.

Ablation of the presynaptic organizer Bassoon in excitatory neurons retards dentate gyrus maturation and enhances learning performance

Bassoon is a large scaffolding protein of the presynaptic active zone involved in the development of presynaptic terminals and in the regulation of neurotransmitter release at both excitatory and inhibitory brain synapses. Mice with constitutive ablation of the Bassoon (Bsn) gene display impaired presynaptic function, show sensory deficits and develop severe seizures. To specifically study the role of Bassoon at excitatory forebrain synapses and its relevance for control of behavior, we generated conditional knockout (Bsn cKO) mice by gene ablation through an Emx1 promoter-driven Cre recombinase. In these animals, we confirm selective loss of Bassoon from glutamatergic neurons of the forebrain. Behavioral assessment revealed that, in comparison to wild-type littermates, Bsn cKO mice display selectively enhanced contextual fear memory and increased novelty preference in a spatial discrimination/pattern separation task. These changes are accompanied by an augmentation of baseline synaptic transmission at medial perforant path to dentate gyrus (DG) synapses, as indicated by increased ratios of field excitatory postsynaptic potential slope to fiber volley amplitude. At the structural level, an increased complexity of apical dendrites of DG granule cells can be detected in Bsn cKO mice. In addition, alterations in the expression of cellular maturation markers and a lack of age-dependent decrease in excitability between juvenile and adult Bsn cKO mice are observed. Our data suggest that expression of Bassoon in excitatory forebrain neurons is required for the normal maturation of the DG and important for spatial and contextual memory.

Sevoflurane Blocks the Induction of Long-term Potentiation When Present during, but Not When Present Only before, the High-frequency Stimulation.

This study tests the hypothesis that sevoflurane blocks long-term potentiation only if it is present during the high-frequency stimulation that induces long-term potentiation. Long-term potentiation, an electrophysiologic correlate of memory, was induced by high-frequency stimulation and measured as a persistent increase in the field excitatory postsynaptic potential slope in the CA1 region. Long-term potentiation was induced in the no sevoflurane group (171 ± 58% vs. 96 ± 11%; n = 13, mean ± SD); when sevoflurane (4%) was present during the high-frequency stimulation, long-term potentiation was blocked (92 ± 22% vs. 99 ± 7%, n = 6). While sevoflurane reduced the size of the field excitatory postsynaptic potential to single test stimuli by 59 ± 17%, it did not significantly reduce the size of the field excitatory postsynaptic potentials during the 100 Hz high-frequency stimulation. If sevoflurane was removed from the artificial cerebrospinal fluid superfusing the slices 10 min before the high-frequency stimulation, then long-term potentiation was induced (185 ± 48%, n = 7); this was not different from long-term potentiation in the no sevoflurane slices (171 ± 58). Sevoflurane before, but not during, ⊖-burst stimulation, a physiologic stimulus, did not block the induction of long-term potentiation (151 ± 37% vs. 161 ± 34%, n = 7). Sevoflurane blocks long-term potentiation formation if present during the high-frequency stimulation; this blockage of long-term potentiation does not persist if sevoflurane is discontinued before the high-frequency stimulation. These results may explain why short periods of insufficient sevoflurane anesthesia may lead to recall of painful or traumatic events during surgery.

Cognitive effects of electro-acupuncture and pregabalin in a trigeminal neuralgia rat model induced by cobra venom.

ObjectiveThe objective of this study was to investigate the effects of electro-acupuncture (EA) and pregabalin on cognition impairment induced by chronic trigeminal neuralgia (TN) in rats.DesignControlled animal study.SettingDepartment of Anesthesiology, Pain Medicine and Critical Care Medicine, Aviation General Hospital of China Medical University.SubjectsForty adult male Sprague Dawley rats.MethodsRats were randomly divided into four groups. The TN model was induced by administration of cobra venom to the left infraorbital nerve. On postoperative day 14, either EA or pregabalin was administered, free behavioral activities were observed. Spatial learning and memory abilities were determined in the Morris water maze. The ultrastructural alterations of the Gasserian ganglion, medulla oblongata and hippocampus were examined by electron microscopy. The changes on long-term potentiation were investigated.ResultsAfter treatment, the exploratory behavior increased and the grooming behavior decreased (P<0.05) for the EA group and pregabalin group compared with the cobra venom group; moreover, demyelination of neurons in Gasserian ganglion and medulla oblongata was reversed. The number of platform site crossings, the average percentages of time in the target quadrant and the field excitatory postsynaptic potential slopes increased (P<0.05) in the EA group compared to the cobra venom group. However, the pregabalin group showed no differences compared to the cobra venom group (P>0.05). Vacuolar degeneration in the hippocampal neurons was mild in the EA group, while it was severe in the pregabalin group.ConclusionEA and pregabalin could alleviate TN induced by cobra venom. EA could also inhibit the cognition deficit induced by TN, while pregabalin could not.

The Effects of Different Concentrations of the α2-Adrenoceptor Agonist Medetomidine on Basal Excitatory Synaptic Transmission and Synaptic Plasticity in Hippocampal Slices of Adult Mice.

α2-Adrenoceptor agonists are used frequently in human and veterinary anesthesia as sedative/analgesic drugs. However, they can impair cognition. Little is known about the concentration-dependent effects of α2-adrenoceptor agonists on synaptic plasticity, the neurophysiological basis of learning and memory. Therefore, we investigated the effects of different concentrations of medetomidine, an α2-adrenoceptor agonist, on basal excitatory synaptic transmission and on 2 forms of synaptic plasticity: paired-pulse facilitation (PPF) and long-term potentiation (LTP). Evoked field excitatory postsynaptic potentials were recorded in Schaffer fibers-CA1 pyramidal cell synapses of mouse hippocampal slices, and the initial field excitatory postsynaptic potentials slope was measured. For basal synaptic transmission and PPF, increasing concentrations of medetomidine (1-200 μM) were applied to each slice. For LTP experiments, individual slices were used for each tested concentration of medetomidine (0.1-0.4 μM), where LTP induction and LTP maintenance were measured. The lower tested concentrations of medetomidine decreased LTP in a concentration-dependent manner, whereas greater concentrations were required to decrease fiber volley amplitude and basal excitatory synaptic transmission. PPF was only affected by the greatest concentration (200 μM). Medetomidine decreased LTP in the mouse hippocampus, in accordance with the ability of medetomidine to induce memory deficits.

Maternal immune activation by polyriboinosinic-polyribocytidilic acid injection produces synaptic dysfunction but not neuronal loss in the hippocampus of juvenile rat offspring

It has been suggested that maternal immune activation increases the risk of psychiatric disorders such as schizophrenia in offspring. There are many reports about hippocampal structural pathology in schizophrenia. Antipsychotic drug administration in adolescence prevented postpubertal hippocampal structural pathology in the maternal immune activation animal model. These findings suggest the possibility that maternal immune activation induces hippocampal dysfunction in juvenile offspring. To test this hypothesis, we investigated hippocampal function in juvenile offspring of maternal immune activation model rat. A synthetic double-stranded RNA polyriboinosinic-polyribocytidilic acid (Poly I:C; 4 mg/kg/day, I.P.) was injected to pregnant rats on gestation days 15 and 17, in order to cause immune activation by stimulating Toll-like receptor 3. Hippocampal synaptic function and morphology in their juvenile offspring (postnatal days 28–31) were compared to those in vehicle-injected control offspring. Field responses were recorded in the hippocampal CA1 region by stimulating commissural/Schaffer collaterals. Pre-synaptic fiber volley amplitudes (mV) and field excitatory post-synaptic potential slopes (mV/ms) were significantly lower in treated offspring. In addition, short-term synaptic plasticity, namely, the paired-pulse facilitation ratio, was significantly higher and long-term synaptic plasticity (long-term potentiation) was significantly impaired in treated offspring. Furthermore, major pre-synaptic protein (synaptophysin) expressions were decreased, but not major post-synaptic proteins (GluR1, GluR2/3, and NR1), in hippocampal CA1 of treated offspring, whereas neuronal loss was not detected in the hippocampal CA1-CA3 regions. These results indicate that maternal immune activation leads to synaptic dysfunction without neuronal loss in the hippocampus of juvenile offspring, and this may be one of the early stages of schizophrenia pathologies.

The antiepileptogenic effect of electrical stimulation at different low frequencies is accompanied with change in adenosine receptors gene expression in rats

Previous studies have shown that the anticonvulsant effects of low-frequency stimulation (LFS) can be affected by activation of adenosine receptors. In the present study, the effect of LFS at different frequencies on kindling rate and adenosine receptors gene expression was investigated. Animals were kindled by perforant path stimulation in a rapid kindling manner. LFS (0.5, 1, and 5 Hz) was applied after termination of each kindling stimulation. Seizure severity was measured according to behavioral and electrophysiologic parameters. At the end of the experiments, adenosine A(1) and A(2A) receptor gene expression were measured. The inhibitory effect of LFS on kindling acquisition was observed at all frequencies. In addition, the inhibitory action of LFS on enhancement of field excitatory postsynaptic potential slope and population spike amplitude during kindling acquisition was not affected by the LFS frequency. However, the effects of LFS on paired-pulse recordings were greater at frequency of 5 Hz. Application of LFS during kindling acquisition also prevented the kindling induced decrease in the A(1) receptor gene expression and attenuated the level of A(2A) receptor gene expression in the dentate gyrus. These effects were also greater at the frequency of 5 Hz. According to these data, it may be suggested that the antiepileptogenic effects of LFS, developed through inhibition of synaptic transmission in the dentate gyrus, is mediated somehow through preventing the decrease of A(1) receptor and through attenuating the A(2A) receptor gene expression. These effects might be dependent on the frequency of LFS.

Effects of Decabrominated Diphenyl Ether (PBDE 209) Exposure at Different Developmental Periods on Synaptic Plasticity in the Dentate Gyrus of Adult Rats In Vivo

Polybromininated diphenyl ethers (PBDEs) are widely used as flame-retardant additives. Previous studies have demonstrated that PBDEs exposure can lead to neurotoxicity. However, little is known about the effects of PBDE 209 on synaptic plasticity. This study investigated the effect of decabrominated diphenyl ether (PBDE 209), a major PBDEs product, on synaptic plasticity in the dentate gyrus of rats at different developmental periods. We examined the input/output functions, paired-pulse reactions, and the long-term potentiation of the field excitatory postsynaptic potential slope and the population spike amplitude in vivo. Rats were exposed to PBDE 209 during five different developmental periods: pregnancy, lactation via mother's milk, lactation via intragastric administration, after weaning, and prenatal to life. We found that exposed to PBDE 209 during different developmental periods could impair the synaptic plasticity of adult rats in different degrees. The results also showed that PBDE 209 might cause more serious effects on the postsynaptic cell excitability in synaptic plasticity, and the lactation period was the most sensitive time of development towards PBDE 209.

Effects of eicosapentaenoic acid on synaptic plasticity, fatty acid profile and phosphoinositide 3-kinase signaling in rat hippocampus and differentiated PC12 cells

Placebo-controlled clinical studies suggest that intake of n-3 polyunsaturated fatty acids improves neurological disorders such as Alzheimer's disease, Huntington's disease and schizophrenia. To evaluate the impact of eicosapentaenoic acid (EPA), we orally administered highly purified ethyl EPA (EPA-E) to rats at a dose of 1.0 mg/g per day and measured long-term potentiation of the CA1 hippocampal region, a physiological correlate of synaptic plasticity that is thought to underlie learning and memory. The mean field excitatory postsynaptic potential slope of the EPA-E group was significantly greater than that of the control group in the CA1 region. Gene expression of hippocampal p85α, one of the regulatory subunits of phosphatidylinositol 3-kinase (PI3-kinase), was increased with EPA-E administration. Investigation of fatty acid profiles of neuronal and glia-enriched fractions demonstrated that a single administration of EPA-E significantly increased neuronal and glial EPA content and glial docosahexaenoic acid content, clearly suggesting that EPA was indeed taken up by both neurons and glial cells. In addition, we investigated the direct effects of EPA on the PI3-kinase/Akt pathway in differentiated PC12 cells. Phosphorylated-Akt expression was significantly increased in EPA-treated cells, and nerve growth factor withdrawal-induced increases in cell death and caspase-3 activity were suppressed by EPA treatment. These findings suggest that EPA protects against neurodegeneration by modulating synaptic plasticity and activating the PI3-kinase/Akt pathway, possibly by its own functional effects in neurons and glial cells and by its capacity to increase brain docosahexaenoic acid.

EFFECTS OF MARGINAL VITAMIN A DEFICIENCY ON LONG-TERM POTENTIATION IN YOUNG RATS

INTRODUCTION: Vitamin A is an essential micronutrient for brain development. Marginal vitamin A deficiency (MVAD) remains a subclinical public health problem in children, but little is known about the mechanism by which it affects brain development beginning from embryonic period and early postnatal period. OBJECTIVE: The objective of this study was to study the effects of MVAD on the hippocampal CA1 long-term potentiation (LTP) in young rats. METHODS: The MVAD group was fed a vitamin A–deficient diet (400 IU/kg vitamin A), and the control group was fed a vitamin A–sufficient diet (6500 IU/kg vitamin A) at 3 weeks before coitus. Serum vitamin A was assessed by high-performance liquid chromatography. Hippocampal CA1 LTP was detected by electrophysiologic technique, and the ultrastructure of synapses was observed by electron microscope. RESULTS: The changes of field excitatory postsynaptic potentials slope (25.4% ± 2.01%) in MVAD rats aged 7 weeks was much lower than that in the control group (57.5% ± 8.6%). The changes of slope of field excitatory postsynaptic potentials induced by MVAD in young rats could be replenished after addition of retinoic acid (RA); however, LTP impairment was observed again after addition of RA antagonist into the solution of the control group. No differences of LTP were found after addition of FeSO4 or ZnSO4. The curvature of the synaptic interface of the MVAD group was less than that of the MVAD group that was supplemented with RA and of the control group. CONCLUSIONS: MVAD during the embryonic and early postnatal period can directly impair the hippocampal CA1 LTP of young rats.

MARGINAL VITAMIN A DEFICIENCY IN PREGNANCY CAN INDUCE MEMORY DEFICIT IN ADULT OFFSPRING

INTRODUCTION: Vitamin A deficiency in pregnancy has a negative impact on the development of offspring; however, little is known about the effect of maternal marginal vitamin A deficiency (MVAD) on the function of the central nervous system in children later in postnatal life. OBJECTIVE: We investigated whether MVAD during the gestational period can cause learning and memory impairment of adult offspring. METHODS: There were 2 offspring groups: an experimental group that had MVAD only in pregnancy and a control group. Serum vitamin A was monitored by high-performance liquid chromatography. Both groups were trained by Marris water maze task at 8 weeks of age. The hippocampal CA1 long-term potentiation was detected by electrophysiologic technique, and the free calcium ion concentration in cells was examined by confocal laser scanning microscopy. RESULTS: No significant difference in the serum vitamin A level was observed between the 2 groups; however, the escape latency of the experimental group (10.50 ± 1.58 seconds) was longer than that of the control group (8.75 ± 1.19 seconds) in the behavior test. Correspondingly, the changes of field excitatory postsynaptic potentials slope of the experimental group (29.5% ± 4.6%) was significantly less than that of the control group (57.5% ± 8.6%), and the lower relative intensity of fluorescence in cells was seen in the experimental group (85.8 ± 17.1) compared with the control group (113.6 ± 20.5) after the tetanus stimulation. CONCLUSIONS: MVAD in pregnancy causes learning and memory impairment of adult offspring.

Anti-glutamatergic effect of riluzole: Comparison with valproic acid

Riluzole, an anti-amyotrophic lateral sclerosis drug, known to decrease presynaptic glutamate release, is viewed as a candidate supplementary medication for epilepsy. In the present study, we compared the effects of riluzole and valproate (VPA) in the pilocarpine-induced limbic seizure model and in the γ-hydroxybutyrate lactone (GBL)-induced absence seizure model. We applied immunohistochemical study for vesicular transporter 1 (VGLUT1) and extracellular recording in the rat dentate gyrus of both pilocarpine- and GBL-induced seizure models to measure effects of riluzole and VPA. Both VPA and riluzole treatments reduced VGLUT1 immunoreactivity. Riluzole treatment completely inhibited pre-ictal spikes and spike-wave discharges in the pilocarpine- and GBL-induced epilepsy models, whereas VPA partially inhibited these phenomena. In both seizure models, the anti-epileptic effects of VPA and riluzole are basically related to anti-glutamatergic (reducing field excitatory postsynaptic potential slope and excitability ratio), not GABAergic (paired-pulse inhibition) effect. Riluzole was more effective at reducing seizure activity in both epilepsy models than VPA. These results suggest that riluzole is a potential antiepileptic drug with activity against limbic seizure and absence seizure.

Assessing the long-term role of L-type voltage dependent calcium channel blocker verapamil on short-term presynaptic plasticity at dentate gyrus of hippocampus

High-voltage-activated Ca 2+ channels on presynaptic nerve terminals are known to play an important role in neurotransmitter release at both excitatory and inhibitory synapses. Whereas there is currently debate over the contribution of L-type voltage dependent Ca 2+ channels (L-type VDCCs) on the short-term presynaptic plasticity which is a defining feature of neuronal activity, the underlying mechanisms are poorly understood. In the present study, the L-type VDCCs chronically was inhibited with different doses of verapamil (10, 20 and 50 mg/kg; orally) to evaluate hippocampal dentate gyrus (DG) inhibitory interneuron function and its involvement on short-term plasticity using paired pulse stimulation in perforant path-DG of hippocampus. Our data show that chronic oral treatment of verapamil at dose of 50 mg/kg but not at lower doses, facilitated the excitability of DG cells at inter-stimulus intervals 20, 30 and 50 ms ( P < 0.03, 0.01 and 0.001; respectively) in population spike amplitude ratio, which is indicative of paired pulse potentiation in perforant path-DG synapses. While there are no significant differences in field excitatory postsynaptic potential slope ratio at all doses. We suggest that DG neurons facilitation is caused by inhibition of inhibitory interneurons directly and/or indirectly via inhibition of glutamate release in hippocampal DG. Therefore, these experiments indicate that chronic use of verapamil has effect on short-term presynaptic plasticity.

Metabotropic Glutamate Receptor Antagonist AIDA Blocks Induction of Mossy Fiber-CA3 LTP In Vivo

Metabotropic glutamate receptors (mGluR) are implicated in long-term memory storage. mGluR-I and mGluR-II antagonists impede various forms of learning and long-term potentiation (LTP) in animals. Despite the evidence linking mGluR to learning mechanisms, their role in mossy fiber-CA3 long-term potentiation (LTP) is not yet clear. To explain the involvement of mGluR-I in memory mechanisms, we examined the function of the mGluR-I antagonist 1-aminoindan-1, 5-dicarboxylic acid (AIDA) on the induction of mossy fiber-CA3 LTP in vivo in male Sprague Dawley and Fischer 344 (F344) rats. Acute extracellular mossy fiber (MF) responses were evoked by stimulation of the MF bundle and recorded in the stratum lucidum of CA3. The excitatory postsynaptic potential (EPSP) magnitude was measured by using the initial slope of the field EPSP slope measured 2-3 ms after response onset. After collection of baseline MF-CA3 responses at 0.05 Hz, animals received either ((+/-))-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (N-methyl-D-aspartate-R antagonist, 10 mg/kg ip), naloxone (opioid-R antagonist, 10 mg/kg ip), or AIDA (mGluR antagonist, 1 mg/kg ip or 37.5 nmol ic). LTP was induced by two 100-Hz trains at the intensity sufficient to evoke 50% of the maximal response. Responses were collected for an additional 1 h. AIDA blocked induction of LTP in the mossy fiber pathway (P < 0.05) in both strains of rats after systemic and in Sprague Dawley rats after intrahippocampal injection.

Succinate increases neuronal post-synaptic excitatory potentials in vitro and induces convulsive behavior through N-methyl- d-aspartate-mediated mechanisms

Succinate is a dicarboxylic acid that accumulates due to succinate dehydrogenase inhibition by malonate and methylmalonate exposure. These neurotoxins cause increased excitability and excitotoxic damage, which can be prevented by administering high amounts of succinate. In the present study we investigated whether succinate alters hippocampal field excitatory post-synaptic potentials. Bath application of succinate at intermediate concentrations (0.3–1 mM) increased the slope of field excitatory post-synaptic potentials in hippocampal slices, and at high concentrations (above 1 mM) did not alter or decrease field excitatory post-synaptic potentials slope. Succinate-induced enhancement of field excitatory post-synaptic potentials slope was abolished by the addition of d-2-amino-5-phosphonovaleric acid (50 μM) to the perfusate, supporting the involvement of N-methyl- d-aspartate receptors in the excitatory effect of this organic acid. Accordingly, succinate (0.8–7.5 μmol) i.c.v. administration caused dose-dependent convulsive behavior in mice. The i.c.v. co-administration of MK-801 (7 nmol) fully prevented succinate-induced convulsions, further suggesting the involvement of N-methyl- d-aspartate receptors in the convulsant action of succinate. Our data indicate that accumulation of moderate amounts of succinate may contribute to the excitotoxicity induced by succinate dehydrogenase inhibitors, through the activation of N-methyl- d-aspartate receptors.

Tyrosine Dephosphorylation and Ethanol Inhibition of N-Methyl-d-aspartate Receptor Function

The inhibitory effect of ethanol on N-methyl-d-aspartate receptors (NMDARs) is well documented in several brain regions. However, the molecular mechanisms by which ethanol affects NMDARs are not well understood. In contrast to the inhibitory effect of ethanol, phosphorylation of the NMDAR potentiates channel currents (Lu, W. Y., Xiong, Z. G., Lei, S., Orser, B. A., Dudek, E., Browning, M. D., and MacDonald, J. F. (1999) Nat. Neurosci. 2, 331-338). We have previously shown that protein kinase C activators induce tyrosine phosphorylation and potentiation of the NMDAR (Grosshans, D. R., Clayton, D. R., Coultrap, S. J., and Browning, M. D. (2002) Nat. Neurosci. 5, 27-33). We therefore hypothesized that the ethanol inhibition of NMDARs might be due to changes in tyrosine phosphorylation of NMDAR subunits. In support of this hypothesis, we found that tyrosine phosphorylation of both NR2A and NR2B subunits was significantly reduced following in situ exposure of hippocampal slices to 100 mm ethanol. Specifically, phosphorylation of tyrosine 1472 on NR2B was reduced 23.5%. These data suggest a possible mechanism by which ethanol may inhibit the NMDAR via activation of a tyrosine phosphatase. Electrophysiological studies demonstrated that ethanol inhibited NMDAR field excitatory postsynaptic potential slope and amplitude to a similar degree as previously reported by our laboratory and others (Schummers, J., Bentz, S., and Browning, M. D. (1997) Alcohol Clin. Exp. Res. 21, 404-408). Inclusion of bpV(phen), a potent phosphotyrosine phosphatase inhibitor, in the recording chamber prior to and during ethanol exposure significantly reduced the inhibitory effect of ethanol on NMDAR field excitatory postsynaptic potentials. Taken together, these data suggest that phosphatase-mediated dephosphorylation of NMDAR subunits may play an important role in mediating the inhibitory effects of ethanol on the N-methyl-D-aspartate receptor.

Tonic activation of A(2A) adenosine receptors unmasks, and of A(1) receptors prevents, a facilitatory action of calcitonin gene-related peptide in the rat hippocampus.

1. We investigated how manipulations of the degree of activation of adenosine A(1) and A(2A) receptors influences the action of the neuropeptide, calcitonin gene-related peptide (CGRP) on synaptic transmission in hippocampal slices. Field excitatory post-synaptic potentials (EPSPs) from the CA1 area were recorded. 2. When applied alone, CGRP (1 - 30 nM) was without effect on field EPSPs. However, CGRP (10 - 30 nM) significantly increased the field EPSP slope when applied to hippocampal slices in the presence of the A(1) receptor antagonist, 1,3-dipropyl-8-cyclopenthyl xanthine (DPCPX, 10 nM), or in the presence of the A(2A) adenosine receptor agonist CGS 21680 (10 nM). 3. The A(2A) receptor antagonist, ZM 241385 (10 nM) as well as adenosine deaminase (ADA, 2 U ml(-1)), prevented the enhancement of field EPSP slope caused by CGRP (30 nM) in the presence of DPCPX (10 nM), suggesting that this effect of CGRP requires the concomitant activation of A(2A) adenosine receptors by endogenous adenosine. 4. The protein kinase-A inhibitors, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004, 10 microM) and adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS, 50 microM), as well as the inhibitor of ATP-sensitive potassium (K(ATP)) channels, glibenclamide (30 microM), prevented the facilitation of synaptic transmission caused by CGRP (30 nM) in the presence of DPCPX (10 nM), suggesting that this effect of CGRP involves both K(ATP) channels and protein kinase-A. 5. It is concluded that the ability of CGRP to facilitate synaptic transmission in the CA1 area of the hippocampus is under tight control by adenosine, with tonic A(1) receptor activation by endogenous adenosine 'braking' the action of CGRP, and the A(2A) receptors triggering this action.