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D Manahan-Vaughan

Publications and source records attributed to D Manahan-Vaughan.

At least 19 recordsLinked to original sources
PubMed2004

Role of the group III metabotropic glutamate receptor in LTP, depotentiation and LTD in dentate gyrus of freely moving rats.

We investigated whether group III metabotropic glutamate (mGlu) receptors are critically involved in the expression of long-term potentiation (LTP), depotentiation, or long-term depression (LTD) in the dentate gyrus of freely moving rats. Male Wistar rats (7 8 weeks) underwent implantation of stimulating and recording electrodes in the medial perforant path and dentate gyrus granule cell layer, respectively. A cannula was permanently implanted into the ipsilateral cerebral ventricle to enable drug administration. Intracerebral injection of the group III mGlu receptor agonist, L(+)-2-amino-4-phosphonobutanoic acid (AP4), significantly inhibited LTP at a concentration which unaffects basal synaptic transmission. Depotentiation. short-term depression (STD) and LTDwere unaffected by the agonist. The antagonist. (R.S)-r-cyclopropyl-4-phosphonophenylglycine (CPPG), inhibited agonist effects. but had no independent effects on basal synaptic transmission. CPPG did not affect the profile of LTP, depotentiation or STD elicited by low frequency stimulation (LFS) at 0.5 or 3 Hz. but significantly impaired LTD expression (at I Hz) and STD elicited at 5 Hz. These findings suggest that activation of group III mGlu receptors is critically required for LTD. but not LTP or depotentiation in the dentate gyrus and provide evidence for the involvement of separate mechanisms underlying LTD and depotentiation.

Animals↗
PubMed2003

An increased expression of the mGlu5 receptor protein following LTP induction at the perforant path-dentate gyrus synapse in freely moving rats.

The involvement of metabotropic glutamate (mGlu) receptors in the induction of long-term potentiation (LTP) in vivo has been consistently documented. We have investigated whether LTP induction in the dentate gyrus of rats leads to changes in expression of mGlu2/3 or -5 receptor subtypes in the hippocampus. LTP was induced at the medial perforant path-dentate gyrus synapses, and mGlu receptor expression was examined by Western blot or in situ hybridization. An up-regulation of mGlu5 receptors was observed in the hippocampus both 24 and 48 h following LTP induction. This effect was restricted to the dentate gyrus and CA1 region, whereas no changes in mGlu5 receptor protein (but an increase in mRNA levels) were observed in the CA3 region. The increased expression of mGlu5 receptors was directly related to the induction of LTP, because it was not observed when tetanic stimulation was carried out in animals treated with the NMDA receptor antagonist, 2-amino-5-phosphonopentanoate (AP5). Western blot analysis also showed a reduced expression of mGlu2/3 receptors in the whole hippocampus 24 h after LTP induction, indicating that the increased expression of mGlu5 receptors was specific. These data suggest that an up-regulation of mGlu5 receptors is a component of the plastic changes that follow the induction of LTP at the perforant path-dentate gyrus synapse.

2-Amino-5-phosphonovalerate↗
PubMed2003

Group I mGlu receptors regulate the expression of the neuronal calcium sensor protein VILIP-1 in vitro and in vivo: implications for mGlu receptor-dependent hippocampal plasticity?

Metabotropic glutamate (mGlu) receptors are involved in several forms of synaptic plasticity in the rat hippocampus. Agonists which activate group I mGlu receptors induce slow-onset potentiation without prior tetanization in the hippocampal area CA1. Activation of group I mGlu receptors induces protein synthesis which may contribute to mGlu receptor-dependent forms of long-term plasticity. Calcium-binding proteins are widely considered to comprise key elements for synaptic plasticity. Therefore, we investigated whether the calcium sensor protein VILIP-1 is associated with group I mGlu receptor-mediated plasticity in the dentate gyrus (DG) in vivo.Application of either the group I and II mGlu agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD) or the selective group I agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) resulted in slow-onset potentiation in the DG of adult rats. In hippocampal cell cultures both agonists elicited an enhanced expression of VILIP-1. In situ hybridization revealed strong hippocampal expression of VILIP-1 and intracerebral application of DHPG to adult rats significantly enhanced hippocampal VILIP-1 expression. The DHPG effects in both, hippocampal cultures and in vivo, were prevented by the group I mGlu receptor antagonist 4-Carboxyphenylglycine (4CPG). Calcium sensor proteins thus appear to be regulated by mGlu receptors in an activity-dependent manner. A specific role for group I mGlu receptors is evident. Furthermore, the sensor proteins may function as molecular switches for the long-term regulation of synaptic plasticity.

Animals↗
PubMed2001

Long-term depression: a cellular basis for learning?

Long-term depression (LTD) comprises a persistent activity-dependent reduction in synaptic efficacy which typically occurs following repeated low frequency afferent stimulation. Hippocampal LTD has been a subject of particular interest due to the established role of the hippocampus in certain forms of information storage and retrieval. Recently, it was reported that LTD in the CA1 region may be associated with novelty acquisition in rats. CA1 LTD expression may also be increased in stressful conditions. This suggests a more complex role for this form of plasticity than the oft-cited hypothesis that it simply serves to prevent synapse saturation, by means, for example, of enabling reversal of long-term potentiation (LTP). One possibility is that LTD may be directly involved in the creation of a memory trace. Alternatively, LTD may prime a synapse in readiness for the expression of LTP, thereby contributing indirectly to information storage. There is increasing evidence that LTD is not mechanistically the reverse of LTP. Although some common processes exist, molecular, biochemical, electrophysiological and pharmacological studies all point to several quite distinct induction and maintenance mechanisms for this form of synaptic plasticity. Taken together these findings suggest that hippocampal LTD must be considered in a new light. This review focuses on the interpretation of novel and established information with regard to LTD in the hippocampal CA1 region in terms of its possible role as a cellular basis for learning and memory.

Animals↗
PubMed2000

Requirement of translation but not transcription for the maintenance of long-term depression in the CA1 region of freely moving rats.

Hippocampal long-term depression (LTD) comprises a persistent reduction in synaptic strength that can be induced in the CA1 region by repeated low-frequency stimulation (LFS). Previous studies have demonstrated that hippocampal long-term potentiation requires de novo protein synthesis. Whether hippocampal LTD is also protein synthesis-dependent is not known. In this study, we investigated if the previous administration of translation inhibitors (anisomycin or emetine) or a transcription inhibitor (actinomycin-D) influenced the profile of LTD in freely moving adult Wistar rats. Seven- to 8-week-old animals underwent chronic implantation of a recording electrode in the CA1 stratum radiatum and a stimulation electrode in the Schaffer collateral/commissural fiber pathway. A cannula was implanted in the ipsilateral cerebral ventricle to enable drug administration. Experiments were commenced 10 d after the implantation procedure. Immediately after application of LFS (1 Hz, 900 pulses) robust LTD was seen that persisted for >8 hr in control animals. Application of anisomycin (240 microg/5 microl) emetine (240 microg/5 microl) before LFS prevented the expression of LTD or approximately 4.5 hr after LFS. Previous administration of actinomycin D (72 microg/12 microl) had no effect on the expression of LTD. None of the compounds elicited significant effects on basal synaptic transmission when administered in the absence of LFS. These data suggest that LTD in the CA1 region in vivo is protein synthesis-dependent. Furthermore, persistent LTD can be established through the translation of existing mRNA, whereas de novo mRNA transcription does not appear to be necessary.

Animals↗
PubMed2000

Group III metabotropic glutamate receptors modulate long-term depression in the hippocampal CA1 region of two rat strains in vivo.

Hippocampal long-term depression (LTD) involves a long-lasting decrease in synaptic transmission which is induced by low-frequency stimulation (LFS). Evidence exists that variability in the responsiveness of rat strains to LFS occurs. Thus, Wistar rats readily express LTD in vivo, whereas Hooded Lister rats demonstrate at best short-term depression (STD) in response to LFS. Group III metabotropic glutamate receptor (mGluR)-involvement in the induction of LTD in freely moving rats has not yet been investigated. This study therefore examined the effect of group III mGluR activation and inhibition on LTD expression, and evaluated these effects in Wistar and Hooded Lister rats. Animals were chronically implanted with recording and bipolar stimulating electrodes in the CA1 region, and an injection cannula in the lateral cerebral ventricle. LFS (1 Hz, 900 pulses) induced LTD in Wistar, and STD in Hooded Lister rats. Agonist priming with L-2-amino-4-phosphonobutanoic acid (AP4, 400 nmol/5 microl) facilitated LTD expression in Hooded Lister but not Wistar rats. The antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine inhibited the facilitatory effects of AP4 in Hooded Lister- and impaired LTD expression in Wistar rats. These data imply a role for group III mGluRs in hippocampal LTD in vivo, and suggest that differences in this mGluR system may account, in part, for strain-dependent variations in LTD expression.

Animals↗
PubMed2000

The neuronal EF-hand calcium-binding protein visinin-like protein-3 is expressed in cerebellar Purkinje cells and shows a calcium-dependent membrane association.

Visinin-like protein-3 is a member of the family of intracellular neuronal calcium sensors belonging to the superfamily of EF-hand proteins. Members of this family are involved in the calcium-dependent regulation of signal transduction cascades. To gain insights into the characteristics of visinin-like protein-3, we have generated specific antibodies against visinin-like protein-3 and determined the developmental and tissue distribution of the protein and its exact cellular and subcellular localization. Expression of visinin-like protein-3 protein appeared late in development mainly in the cerebellum. It is strongly expressed in cerebellar Purkinje cells. The protein expression results were further confirmed by in situ hybridization and compared with hippocalcin messenger RNA localization. Native cerebellar visinin-like protein-3 was shown to bind calcium and to associate in a calcium-dependent manner with membrane fractions during subcellular fractionation. Recombinant wild-type visinin-like protein-3 was shown to be N-terminally myristoylated in transfected cells. The membrane association was strongly reduced for the non-myristoylated mutant of visinin-like protein-3 in transfected cells. These results suggest that visinin-like protein-3, which is mainly expressed in Purkinje cells in vivo, shows a calcium-dependent association with cell membranes which is mediated by a calcium-myristoyl switch.

Aging↗
PubMed2000

Long-term depression in freely moving rats is dependent upon strain variation, induction protocol and behavioral state.

Hippocampal long-term depression (LTD) comprises a persistent decrease in synaptic transmission which is induced by repeated low-frequency stimulation (LFS). Although LTD has been widely demonstrated in the CA1 region in vitro, very few positive reports of LTD in vivo have occurred. In this study, the conditions under which homosynaptic LTD occurs in the CA1 region of freely moving rats was investigated. Three rat strains were studied: Wistar, Sprague-Dawley and Hooded Lister. Whereas Wistar and Sprague-Dawley rats expressed optimal LTD following 1 Hz LFS, Hooded Lister rats showed no LTD when tested in an LFS range of 1-10 Hz. Exposure to marked stress transiently enhanced LTD obtained in Wistar and Sprague-Dawley rats, but did not facilitate LTD induction in the LTD-resistant strain. It was possible to induce long-term potentiation with high-frequency stimulation, although the profile of LTP was different in each strain. These data suggest that the expression of LTD varies according to the strain of rat used and is tightly dependent upon stimulation frequency. In addition the behavioral state of the animal may influence LTD expression. These data may explain, in part, the conflicting reports with regard to the inducibility of hippocampal LTD in vivo.

Animals↗
PubMed2000

Depotentiation in the dentate gyrus of freely moving rats is modulated by D1/D5 dopamine receptors.

Hippocampal depotentiation comprises a reversal of tetanization- induced long-term potentiation (LTP) which occurs following low-frequency stimulation. In the CA1 region, it has been reported that agonist activation of D1/D5 dopamine receptors enhances LTP expression and inhibits depotentiation. The role of these receptors in synaptic plasticity in the dentate gyrus (DG) has not been characterized. This study therefore investigated the role of D1/D5 receptors in LTP and depotentiation in the DG of freely moving rats. Male Wistar rats underwent chronic implantation of a recording electrode in the DG granule cell layer, a bipolar stimulating electrode in the medial perforant path and a cannula in the ipsilateral cerebral ventricle (to enable drug administration). The D1/D5 agonist Chloro-PB dose-dependently inhibited depotentation in the DG. This effect was prevented by the D1/D5 antagonist SCH 23390. Neither D1/D5 agonist nor antagonist had an effect on LTP expression or basal synaptic transmission. These results highlight differences between D1/D5 receptor-involvement in LTP and depotentiation in the CA1 region and DG, and indicate that whereas D1/D5 receptor activation may not be a critical factor in LTP induction in the DG, a differential role for these receptors in the expression of depotentiation, in this hippocampal subfield, may exist.

Animals↗
PubMed1999

Novelty acquisition is associated with induction of hippocampal long-term depression.

Homosynaptic long-term depression (LTD) consists of a persistent nonpathological decrease in synaptic transmission, which is induced by low-frequency stimulation. In vivo, low-frequency stimulation (1 Hz, 900 pulses) induces LTD in Wistar but not Hooded Lister rats. In this study, we investigated the influence of behavioral learning and behavioral state on the expression of LTD in both rat strains. Recordings were taken from freely moving animals that had undergone chronic implantation of a recording electrode in the hippocampal CA1 region and a bipolar stimulating electrode in the ipsilateral Schaffer collateral-commissural pathway. Exposure of the rat strains to stress induced a significant elevation in serum corticosterone levels but did not facilitate LTD expression. However, LFS given during exploration of a novel environment resulted in LTD expression in Hooded Lister, and LTD enhancement in Wistar, rats. Reexposure to the same environment did not result in new expression of LTD. Behavioral comparison between the first and second environmental exposure confirmed that the animals had habituated to the novel environment. These observations strongly implicate an association between novelty acquisition and LTD.

Animals↗
PubMed1999

ACPD-mediated slow-onset potentiation is associated with cell death in the rat CA1 region in vivo.

Slow-onset potentiation of synaptic transmission in the hippocampus in vitro and in vivo is induced by application of the metabotropic glutamate receptor (mGluR) agonist, 1S,3R-amino cyclopentane 2,3-dicarboxylic acid (ACPD). This study investigated the cellular response in the CA1 region of freely moving rats to ACPD application. Drugs were applied via the lateral cerebral ventricle, and measurements were obtained from the CA1 region via permanently implanted electrodes. ACPD (20 nmol/5 microl) produced a dose-dependent slow-onset potentiation in the CA1 region which lasted over 4 h. Histological evaluation at either 4 h or 7 days following ACPD-injection indicated that slow-onset potentiation was associated with gradual but marked cell death in the CA1 region. Whereas 20 nmol ACPD produced significant CAI neurotoxicity, concentrations which did not induce potentiation had little or no neurotoxic effect. Both the general mGluR antagonist R,S-alpha-methyl-carboxyphenylglycine (1 micromol/5 microl), and the group 1 mGluR antagonist (S)-4-carboxyphenylglycine (4CPG, 100 nmol/5 microl) significantly inhibited ACPD-induced neuropathology. In addition, 4CPG inhibited the expression of ACPD-mediated slow-onset potentiation. These results confirm previous findings that in the CA1 region in vivo, slow-onset potentiation is mediated group 1 mGluRs, and indicate that slow-onset potentiation may involve pathological processes.

Animals↗
PubMed1999

Presynaptic group 1 metabotropic glutamate receptors may contribute to the expression of long-term potentiation in the hippocampal CA1 region.

In this study, we investigated the possible contribution of presynaptic group 1 metabotropic glutamate receptor activation to changes in synaptic efficacy by means of analysis of glutamate release in hippocampal synaptosomes. Data were interpreted in the context of group 1 metabotropic glutamate receptor involvement in synaptic plasticity in the CA1 region of freely moving rats. In synaptosomes, 3,5-dihydroxyphenylglycine enhanced diacylglycerol formation and facilitated vesicular Ca(2+)-dependent glutamate release, whereas trans-azetidine-2,4-dicarboxylic acid had no effect on these processes. Trans-azetidine-2,4-dicarboxylic acid enhanced glutamate release, but in a Ca(2+)-independent manner. This effect was mimicked by the L-glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid. (R,S)-alpha-Methyl-4-carboxyphenylglycine blocked the effects of 3,5-dihydroxyphenylglycine, but not trans-azetidine-2,4-dicarboxylic acid in synaptosomes. Short-term potentiation (100 Hz, three bursts of 10 stimuli, 0.1 ms stimulus duration, 10 s interburst interval) was induced in the CA1 region in vivo. The metabotropic glutamate receptor agonist 1S,3R-aminocyclopentane-2,3-dicarboxylic acid, or the group 1 metabotropic glutamate receptor agonists, 3,5-dihydroxyphenylglycine and trans-azetidine-2,4-dicarboxylic acid, dose-dependently facilitated short-term potentiation into long-term potentiation, which lasted > 24 h. The facilitation was inhibited by the metabotropic glutamate receptor antagonist, (R,S)-alpha-methyl-4-carboxyphenylglycine, and the group 1 metabotropic glutamate receptor antagonist, (S)-4-carboxy-phenylglycine, but not by the group 2 metabotropic glutamate receptor antagonist, (R,S)-alpha-methylserine-O-phosphate monophenyl ester. L-Trans-pyrrolidine-2,4-dicarboxylic acid dose-dependently facilitated short-term potentiation into long-term potentiation, which lasted < 4 h. These data suggest that activation of group 1 metabotropic glutamate receptors results in presynaptic modulation of glutamate release. This effect may contribute to group 1 metabotropic glutamate modulation of the expression of long-term potentiation in vivo.

Animals↗
PubMed1999

Time-dependent induction of depotentiation in the dentate gyrus of freely moving rats: involvement of group 2 metabotropic glutamate receptors.

Depotentiation comprises a reversal of tetanization-induced long-term potentiation (LTP) which occurs following low-frequency stimulation (LFS) in the hippocampus in vivo. Although depotentiation has been consistently demonstrated in the CA1 region, no positive reports of the existence of depotentiation in the dentate gyrus in vivo have occurred. This study therefore investigated whether depotentiation is possible in the dentate gyrus in vivo. We found that depotentiation can be induced, but it is very tightly dependent on the interval between tetanization and LFS. Thus, LFS given 2 or 5 min following tetanization produced significant depotentiation, whereas LFS given 10-30 min following tetanization had no significant effect on the expression of LTP. Depotentiation occurred in two phases: a transient depression of evoked responses to below pre-tetanization values, which occurred in the first 60 min following LFS, and a recovery of this response to a stable level of synaptic transmission which comprised a significant reduction in the magnitude of LTP. Group 2 metabotropic glutamate receptors (mGluRs) play an important role in the expression of long-term depression in vivo. We therefore investigated whether group 2 mGluRs contribute to depotentiation. The group 2 antagonist (2S)-alpha-ethylglutamic acid (EGLU) inhibited the early transient depression at a concentration which inhibits LTD in vivo, but did not block the expression of depotentiation. EGLU also inhibited the transient depression induced by 5 Hz given alone. Increasing the concentration of EGLU prevented depotentiation, however. The group 2 agonist (S)-4-carboxy-3-hydroxyphenyl- glycine (4C3HPG) inhibited LTP and enhanced depotentiation. These data suggest a role for group 2 mGluRs in depotentiation.

Animals↗
PubMed1998

Long-term potentiation in vivo increases rat hippocampal tenascin-C expression.

We investigated the expression of the extracellular matrix glycoprotein tenascin-C after induction of long-term potentiation (LTP) by high-frequency tetanization (HFT) in the rat dentate gyrus in vivo. Expression of tenascin-C was evaluated at the mRNA and protein levels by in situ hybridization and immunocytochemistry, respectively. Whereas no tenascin-C mRNA was detectable in control animals, an increase in tenascin-C mRNA levels was observed in the granule cell layer of the dentate gyrus 4 h after HFT. At 24 h after HFT, tenascin-C mRNA had returned to control levels. Expression of tenascin-C protein 4 h after HFT followed that of controls in that tenascin was detectable in the strata oriens and radiatum of CA1, in the molecular layer, and within a narrow area at the inner surface of the granule cell layer in the dentate gyrus. However, 24 h after HFT, additional patches of tenascin-C immunoreactivity were observed in the molecular layer of the dentate gyrus. No increase in tenascin mRNA or protein levels was detected in control animals that received no stimulation, low-frequency stimulation, or HFT in the presence of the N-methyl-D-aspartate receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid or the metabotropic glutamate receptor antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine. These observations implicate a role for tenascin-C in N-methyl-D-aspartate and metabotropic glutamate receptor-dependent changes accompanying induction and/or maintenance of LTP.

2-Amino-5-phosphonovalerate↗
PubMed1998

Semi-automated analysis of NMDA-mediated toxicity in digitised colour images from rat hippocampus.

The evaluation of neuronal cell survival after, for example, mechanical, hypoxic or drug-mediated injury requires the analysis of a high number of histological specimens. Since this is a time-consuming occupation, we have developed a semi-automated analysis routine for the determination of the distribution of live and dead cells. After digitalization of the histological preparations, 8-bit colour bitmaps were assessed using a compiled image-analysis programme of the software package Khoros. In the current study a detailed example of the application of this image-processing approach is described for the investigation of the cell survival after intraventricular application of N-methyl-D-aspartate (NMDA). The samples were prepared as fuchsin acid/toluidine blue stained hippocampal thin slices. The calculated areas of the live and dead cells were highly correlated with manual counts of live and dead cells in the 100 samples examined in this study. Twenty-four hours following NMDA-treatment animals (n = 5) were found to have significantly fewer live and more dead hippocampal cells than the saline-treated animals (n = 5), using either automated or manual examination techniques. The automated technique also revealed that NMDA treatment resulted in a reduction in the density of live cell distribution.

Animals↗
PubMed1998

Priming of group 2 metabotropic glutamate receptors facilitates induction of long-term depression in the dentate gyrus of freely moving rats.

Activation of group 1 metabotropic glutamate receptors (mGluRs) has been shown to facilitate the induction of tetanically evoked long-term potentiation in vivo, whereas group 2 mGluR antagonists inhibit long-term depression (LTD) in the CA1 region. LTD has not been successfully demonstrated to date in the dentate gyrus of freely moving rats. In this study, it was found that 1-Hz low-frequency stimulation (LFS) when applied via a stimulating electrode chronically implanted in the perforant path, evoked short-term depression (STD) of field excitatory post-synaptic potentials and population spikes measured from the dentate gyrus granule cell layer. Application of the group 2 mGluR agonists (S)-4-carboxyphenylglycine (4C3HPG) or (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) prior to LFS facilitated the expression of LTD. Application of the group 2 mGluR antagonist (2S)-alpha-ethylglutamic acid (EGLU) prior to agonist application prevented the facilitating effect of the agonists on LFS-induced depression. EGLU did not influence the expression of LFS-induced STD. Neither 4C3HPG, DCG-IV nor EGLU had an effect on basal synaptic transmission at the concentrations used. The present study demonstrates that priming of group 2 mGluRs leads to induction of persistent LTD in the dentate gyrus in vivo, consistent with a role for group 2 mGluRs in metaplasticity.

Animals↗
PubMed1998

In vivo electrophysiological investigations into the role of histamine in the dentate gyrus of the rat.

Drugs acting at the three known classes of histamine receptors were injected intracerebroventricularly into the rat. The effects of these drugs upon synaptic potentials recorded from the dentate gyrus of the freely-moving rat were determined. Population spikes and field excitatory postsynaptic potentials were recorded from the granule cell layer of the dentate gyrus following stimulation of the perforant path. Drugs, dissolved in 0.9% NaCl were applied into the lateral cerebral ventricle in a volume of 5 microl over a period of 6 min. The histamine H1 receptor antagonist mepyramine (0.4 or 0.8 microg) had no significant effect on population spikes or field excitatory postsynaptic potentials. In contrast the H2 receptor antagonist cimetidine (3.25, 6.5 or 13 microg) showed a biphasic effect. At the lower doses (3.25 or 6.5 microg) a small (15%) depression of the field excitatory postsynaptic potentials and population spikes was observed beginning about 1 h following the infusion. At the highest dose tested (13 microg) a marked increase of the population spike was observed beginning immediately following the infusion and lasting for 90 min. Application of the H3 receptor agonist R-alpha-methylhistamine (0.2 microg) depressed the field excitatory postsynaptic potentials (15% at 4 h post-injection) and even more strongly the population spike (50%). Surprisingly, at higher doses (0.4 and 0.8 microg) no effect was seen. The H3 receptor antagonist thioperamide (0.41 and 0.82 microg) did not cause an increase in synaptic potentials but rather at the highest dose a small depression occurred at later time points (2-4 h following the infusion). At the lower dose (0.41 microg) thioperamide blocked the effect of R-alpha-methylhistamine (0.2 microg). These results show that the histaminergic system modulates information flow through the dentate gyrus in a complex manner involving both histamine H2 and H1 receptors.

Animals↗