Cholinergic afferents to the locus coeruleus and noradrenergic afferents to the medial septum mediate LTP-reinforcement in the dentate gyrus by stimulation of the amygdala

Transient long-term potentiation (E-LTP) can be transformed into a long-lasting LTP (L-LTP) in the dentate gyrus (DG) by behavioral stimuli with high motivational content. Previous research from our group has identified several brain structures, such as the basolateral amygdala (BLA), the locus coeruleus (LC), the medial septum (MS) and transmitters as noradrenaline (NA) and acetylcholine (ACh) that are involved in these processes. Here we have investigated the functional interplay among brain structures and systems which result in the conversion of a E-LTP into a L-LTP (reinforcement) by stimulation of the BLA (BLA-R). We used topical application of specific drugs into DG, and other targets, while following the time course of LTP induced by stimulation of the perforant pathway (PP) to study their specific contribution to BLA-R. One injection cannula, a recording electrode in the DG and stimulating electrodes in the PP and the BLA were stereotactically implanted one week before electrophysiological experiments. Topical application of atropine or propranolol into the DG blocked BLA-R in both cases, but the effect of propranolol occurred earlier, suggesting a role of NA within the DG during an intermediate stage of LTP maintenance. The injection of lidocaine into the LC abolished BLA-R indicating that the LC is part of the functional neural reinforcing system. The effect on the LC is mediated by cholinergic afferents because application of atropine into the LC produced the same effect. Injection of lidocaine inactivating the MS also abolished BLA-R. This effect was mediated by noradrenergic afferents (probably from the LC) because the application of propranolol into the MS prevented BLA-R. These findings suggest a functional loop for BLA-R involving cholinergic afferents to the LC, a noradrenergic projection from the LC to the DG and the MS, and finally, the cholinergic projection from the MS to the DG.     

Synaptic plasticity in hippocampal CA1 neurons of mice lacking type 1 inositol-1,4,5-trisphosphate receptors

In hippocampal CA1 neurons of wild-type mice, delivery of a standard tetanus (100 pulses at 100 Hz) or a train of low-frequency stimuli (LFS; 1000 pulses at 1 Hz) to a naive input pathway induces, respectively, long-term potentiation (LTP) or long-term depression (LTD) of responses, and delivery of LFS 60 min after tetanus results in reversal of LTP (depotentiation, DP), while LFS applied 60 min before tetanus suppresses LTP induction (LTP suppression). To evaluate the role of the type 1 inositol-1,4,5-trisphosphate receptor (IP3R1) in hippocampal synaptic plasticity, we studied LTP, LTD, DP, and LTP suppression of the field excitatory postsynaptic potentials (EPSPs) in the CA1 neurons of mice lacking the IP3R1. No differences were seen between mutant and wild-type mice in terms of the mean magnitude of the LTP or LTD induced by a standard tetanus or LFS. However, the mean magnitude of the LTP induced by a short tetanus (10 pulses at 100 Hz) was significantly greater in mutant mice than in wild-type mice. In addition, DP or LTP suppression was attenuated in the mutant mice, the mean magnitude of the responses after delivery of LFS or tetanus being significantly greater than in wild-type mice. These results suggest that, in hippocampal CA1 neurons, the IP3R1 is involved in LTP, DP, and LTP suppression but is not essential for LTD. The facilitation of LTP induction and attenuation of DP and LTP suppression seen in mice lacking the IP3R1 indicates that this receptor plays an important role in blocking synaptic potentiation in hippocampal CA1 neurons.     

Enhanced proliferation of progenitor cells following long-term potentiation induction in the rat dentate gyrus

The dentate gyrus (DG) is among the few areas in the mammalian brain where production of new neurons continues in the adulthood. Although its functional significance is not completely understood, several lines of evidence suggest the role of DG neurogenesis in learning and memory. Considering that long-term potentiation (LTP) is a prime candidate for the process underlying hippocampal learning and memory, these results raise the possibility that LTP and neurogenesis are closely related. Here, we investigated whether or not LTP induction in the afferent pathway triggers enhanced proliferation of progenitor cells in the DG. LTP was induced by tetanic stimulation in perforant path-DG synapses in one hemisphere, and the number of newly generated progenitor (BrdU-labeled) cells in the DG was quantified. Compared with the control hemisphere (stimulated with low-frequency pulses), the LTP-induced hemisphere contained a significantly higher number of newly generated progenitor cells in the dorsal as well as ventral DG. When CPP, an NMDA receptor antagonist, was administered, tetanic stimulation neither induced LTP nor enhanced progenitor cell proliferation, indicating that NMDA receptor activation, rather than tetanic stimulation per se, is responsible for enhanced progenitor proliferation in the control animal. Our results show that tetanic stimulation of perforant path sufficient to induce LTP increases progenitor proliferation in adult DG in an NMDA receptor-dependent manner.     

Post-training administration of corticosterone enhances consolidation of contextual fear memory and hippocampal long-term potentiation in rats

This study was designed to examine the effect of corticosterone on consolidation of contextual fear memory and hippocampal long-term potentiation (LTP) in rats. In Experiment 1, dose–response effects of corticosterone on consolidation of contextual fear memory were determined. Immediately after training in contextual fear conditioning task, rats received different doses of corticosterone. Testing 24 h later, it revealed that corticosterone enhanced memory consolidation in an inverted U shape as evidenced in increased freezing behavior of corticosterone-treated animals. The most effective dose was 3 mg/kg. In Experiment 2, LTP was examined in rats whose memory consolidation has been enhanced with corticosterone. The rats were trained as the above and received corticosterone (3 mg/kg) immediately after training. Immediately or up to one day after retention test, rats were anesthetized with urethane for LTP experiments. For LTP induction, three episodes of high frequency stimuli, 30 s apart, were delivered to the perforant path, each consisting of 10 stimuli at 250 Hz. LTP was assessed by measuring the increase in the initial slope of the population excitatory post-synaptic potentials and the amplitude of the population spikes. Data indicated that animals whose memory has been enhanced by corticosterone, also displayed enhanced hippocampal LTP. The above findings suggest that glucocorticoids may enhance contextual fear memory consolidation via enhancing hippocampal LTP.     

Endogenous opioid peptides contribute to associative LTP in the hippocampal CA3 region

The medial and lateral perforant path projections to the hippocampal CA3 region display distinct mechanisms of long-term potentiation (LTP) induction, N-methyl-d-aspartate (NMDA) and opioid receptor dependent, respectively. However, medial and lateral perforant path projections to the CA3 region display associative LTP with coactivation, suggesting that while they differ in receptors involved in LTP induction they may share common downstream mechanisms of LTP induction. Here we address this interaction of LTP induction mechanisms by evaluating the contribution of opioid receptors to the induction of associative LTP among the medial and lateral perforant path projections to the CA3 region in vivo. Local application of the opioid receptor antagonists naloxone or Cys2-Tyr3-Orn5-Pen7-amide (CTOP) normally block induction of lateral perforant path-CA3 LTP. However, these opioid receptor antagonists failed to block associative LTP in lateral perforant path-CA3 synapses when it was induced by strong coactivation of the medial perforant pathway which displays NMDAR-dependent LTP. Thus strong activation of non-opioidergic afferents can substitute for the opioid receptor activation required for lateral perforant path LTP induction. Conversely, medial perforant path-CA3 associative LTP was blocked by opioid receptor antagonists when induced by strong coactivation of the opioidergic lateral perforant path. These data indicate endogenous opioid peptides contribute to associative LTP at coactive synapses when induced by strong coactivation of an opioidergic afferent system. These data further suggest that associative LTP induction is regulated by the receptor mechanisms of the strongly stimulated pathway. Thus, while medial and lateral perforant path synapses differ in their mechanisms of LTP induction, associative LTP at these synapses share common downstream mechanisms of induction.     

The neural cell adhesion molecule-derived peptide FGL facilitates long-term plasticity in the dentate gyrus in vivo

The neural cell adhesion molecule (NCAM) is known to play a role in developmental and structural processes but also in synaptic plasticity and memory of the adult animal. Recently, FGL, a NCAM mimetic peptide that binds to the Fibroblast Growth Factor Receptor 1 (FGFR-1), has been shown to have a beneficial impact on normal memory functioning, as well as to rescue some pathological cognitive impairments. Whether its facilitating impact may be mediated through promoting neuronal plasticity is not known. The present study was therefore designed to test whether FGL modulates the induction and maintenance of synaptic plasticity in the dentate gyrus (DG) in vivo. For this, we first assessed the effect of the FGL peptide on synaptic functions at perforant path-dentate gyrus synapses in the anesthetized rat. FGL, or its control inactive peptide, was injected locally 60 min before applying high-frequency stimulation (HFS) to the medial perforant path. The results suggest that although FGL did not alter basal synaptic transmission, it facilitated both the induction and maintenance of LTP. Interestingly, FGL also modified the heterosynaptic plasticity observed at the neighboring lateral perforant path synapses. The second series of experiments, using FGL intracerebroventricular infusion in the awake animal, confirmed its facilitating effect on LTP for up to 24 h. Our data also suggest that FGL could alter neurogenesis associated with LTP. In sum, these results show for the first time that enhancing NCAM functions by mimicking its heterophilic interaction with FGFR facilitates hippocampal synaptic plasticity in the awake, freely moving animal.     

Long-term potentiation in the dentate gyrus in freely moving rats is reinforced by intraventricular application of norepinephrine, but not oxotremorine

Growing evidence suggests that processes of synaptic plasticity, such as long-term potentiation (LTP) occurring in one synaptic population, can be modulated by consolidating afferents from other brain structures. We have previously shown that an early-LTP lasting less than 4 h (E-LTP) in the dentate gyrus can be prolonged by stimulating the basolateral amygdala, the septum or the locus coeruleus within a specific time window. Pharmacological experiments have suggested that noradregeneric (NE) and/or cholinergic systems might be involved in these effects. We have therefore investigated whether the direct intraventricular application of agonists for NE- or muscarinic receptors is able to modulate synaptic plasticity. E-LTP was induced at the dentate gyrus of freely moving rats using a mild tetanization protocol that induces only an E-LTP. NE or oxotremorine (OXO) were applied icv 10 min after the tetanus. Results show that low doses of NE (1.5 and 5 nM) effectively prolong LTP. A higher dose (50 nM) was not effective. None of the OXO doses employed (5, 25, and 50 nM) showed similar effects. These results stress the importance of transmitter-specific modulatory influences on the time course of synaptic plasticity, in particular NE whose application mimics the reinforcing effect of directly stimulating limbic structures on LTP.     

Impairment of spatial learning and hippocampal synaptic potentiation in c-kit mutant rats

The c-kit receptor tyrosine kinase encoded by the white-spotting (W) gene is highly expressed in rat hippocampal CA1–CA4 regions. We found an impaired spatial learning and memory in homozygous c-kit (Ws/Ws) mutant rats that have a 12-base deletion in the tyrosine kinase domain of the c-kit gene and a very low kinase activity. Electrophysiological studies in hippocampal slices revealed that the long-term potentiation (LTP) induced by the tetanic stimulation (100 Hz, 1 sec) in the mossy fiber (MF)–CA3 pathway, but not in the Schaffer collaterals/commissural–CA1 pathway, was significantly reduced in c-kit mutants compared with wild-type (+/+) rats. The paired-pulse facilitation (PPF) was measured before the tetanus and after the establishment of the LTP in each slice. The initial PPF in the MF–CA3 pathway positively correlated with the amplitude of the LTP in the wild-type rats but not in the c-kit mutant rats. Furthermore, they failed to show the normal characteristics observed in the MF–CA3 pathway of +/+ rats; that is, the negative correlation between the initial PPF and the changes in PPF measured after the LTP. These findings suggest an involvement of SCF/c-kit signaling in hippocampal synaptic potentiation and spatial learning and memory.     

On the Respective Roles of Nitric Oxide and Carbon Monoxide in Long-Term Potentiation in the Hippocampus

Perfusion of hippocampal slices with an inhibitor of nitric oxide (NO) synthase-blocked induction of long-term potentiation (LTP) produced by a one-train tetanus and significantly reduced LTP by a two-train tetanus, but only slightly reduced LTP by a four-train tetanus. Inhibitors of heme oxygenase, the synthetic enzyme for carbon monoxide (CO), significantly reduced LTP by either a two-train or four-train tetanus. These results suggest that NO and CO are both involved in LTP but may play somewhat different roles. One possibility is that NO serves a phasic, signaling role, whereas CO provides tonic, background stimulation. Another possibility is that NO and CO are phasically activated under somewhat different circumstances, perhaps involving different receptors and second messengers. Because NO is known to be activated by stimulation of NMDA receptors during tetanus, we investigated the possibility that CO might be activated by stimulation of metabotropic glutamate receptors (mGluRs). Consistent with this idea, long-lasting potentiation by the mGluR agonist tACPD was blocked by inhibitors of heme oxygenase but not NO synthase. Potentiation by tACPD was also blocked by inhibitors of soluble guanylyl cyclase (a target of both NO and CO) or cGMP-dependent protein kinase, and guanylyl cyclase was activated by tACPD in hippocampal slices. However, biochemical assays indicate that whereas heme oxygenase is constitutively active in hippocampus, it does not appear to be stimulated by either tetanus or tACPD. These results are most consistent with the possibility that constitutive (tonic) rather than stimulated (phasic) heme oxygenase activity is necessary for potentiation by tetanus or tACPD, and suggest that mGluR activation stimulates guanylyl cyclase phasically through some other pathway.     

On the Respective Roles of Nitric Oxide and Carbon Monoxide in Long-Term Potentiation in the Hippocampus

Perfusion of hippocampal slices with an inhibitor nitric oxide (NO) synthase blocked induction of long-term potentiation (LTP) produced by a one-train tetanus and significantly reduced LTP by a two-train tetanus, but only slightly reduced LTP by a four-train tetanus. Inhibitors of heme oxygenase, the synthetic enzyme for carbon monoxide (CO), significantly reduced LTP by either a two-train or four-train tetanus. These results suggest that NO and CO are both involved in LTP but may play somewhat different roles. One possibility is that NO serves a phasic, signaling role, whereas CO provides tonic, background stimulation. Another possibility is that NO and CO are phasically activated under somewhat different circumstances, perhaps involving different receptors and second messengers. Because NO is known to be activated by stimulation of NMDA receptors during tetanus, we investigated the possibility that CO might be activated by stimulation of metabotropic glutamate receptors (mGluRs). Consistent with this idea, long-lasting potentiation by the mGluR agonist tACPD was blocked by inhibitors of heme oxygenase but not NO synthase. Potentiation by tACPD was also blocked by inhibitors of soluble guanylyl cyclase (a target of both NO and CO) or cGMP-dependent protein kinase, and guanylyl cyclase was activated by tACPD in hippocampal slices. However, biochemical assays indicate that whereas heme oxygenase is constitutively active in hippocampus, it does not appear to be stimulated by either tetanus or tACPD. These results are most consistent with the possibility that constitutive (tonic) rather than stimulated (phasic) heme oxygenase activity is necessary for potentiation by tetanus or tACPD, and suggest that mGluR activation stimulates guanylyl cyclase phasically through some other pathway.     

Corticosterone time-dependently modulates beta-adrenergic effects on long-term potentiation in the hippocampal dentate gyrus

Previous experiments in the hippocampal CA1 area have shown that corticosterone can facilitate long-term potentiation (LTP) in a rapid non-genomic fashion, while the same hormone suppresses LTP that is induced several hours after hormone application. Here, we elaborated on this finding by examining whether corticosterone exerts opposite effects on LTP depending on the timing of hormone application in the dentate gyrus as well. Moreover, we tested rapid and delayed actions by corticosterone on β-adrenergic-dependent changes in LTP. Unlike the CA1 region, our in vitro field potential recordings show that rapid effects of corticosterone do not influence LTP induced by mild tetanization in the hippocampal dentate gyrus, unless GABA_A receptors are blocked. In contrast, the β-adrenergic agonist isoproterenol does initiate a slow-onset, limited amount of potentiation. When corticosterone was applied concurrently with isoproterenol, a further enhancement of synaptic strength was identified, especially during the early stage of potentiation. Yet, treatment with corticosterone several hours in advance of isoproterenol fully prevented any effect of isoproterenol on LTP. This emphasizes that corticosterone can regulate β-adrenergic modulation of synaptic plasticity in opposite directions, depending on the timing of hormone application.     

Hippocampal CA1 kindling but not long-term potentiation disrupts spatial memory performance

Long-term synaptic enhancement in the hippocampus has been suggested to cause deficits in spatial performance. Synaptic enhancement has been reported after hippocampal kindling that induced repeated electrographic seizures or afterdischarges (ADs) and after long-term potentiation (LTP) defined as synaptic enhancement without ADs. We studied whether repeated stimulations that gave LTP or ADs resulted in spatial performance deficits on the radial arm maze (RAM) and investigated the minimal number of ADs required for such deficits. Three experimental groups were run as follows: (1) 5 hippocampal ADs in 1 d (5-AD group), (2) 10 hippocampal ADs in 2 d (10-AD group), and (3) 12 -frequency primed-burst stimulations (PBSs) in 2 d in order to induce LTP without ADs (LTP group). Each experimental group was run together with a control group during the same time period. Rats were first trained in a spatial task on a radial arm maze with four of the eight arms baited, then given control or experimental treatment, and maze performance was tested in the first week (1-4 d) and fourth week (22-25 d) after treatment. Basal dendritic population excitatory postsynaptic potentials (pEPSPs) and medial perforant path (MPP)-evoked dentate gyrus population spike and polysynaptic CA1 excitation were recorded before and after experimental and control treatment. Spatial memory errors, in particular reference memory errors, were significantly higher in the 10-AD kindled group than any other group on the first and fourth week after treatment. Spatial memory errors were not significantly different in the 5-AD and LTP groups as compared with any control groups at any time. Basal dendritic pEPSP in CA1 was enhanced for about 1 wk after 12 PBSs, 10 ADs, or 5 ADs, while the dentate gyrus population spike and CA1 polysynaptic excitation evoked by MPP was increased for up to 4 wk after 10 ADs, but not 12 PBSs. Thus, distributed alteration of multiple synaptic transmission in the entorhinal-hippocampal circuit, but not LTP at the basal dendritic synapses in CA1, may disrupt spatial performance after 10 hippocampal ADs.     

Spatial learning in the holeboard impairs an early phase of long-term potentiation in the rat hippocampal CA1-region

Long-term potentiation (LTP) and depression (LTD) are considered as cellular models for learning and memory. We studied the impact of holeboard training on LTP in the rat CA1 hippocampal region. In 7-week-old Wistar rats a recording electrode was chronically implanted into the hippocampal pyramidal cell layer of the CA1 of the right hemisphere and a stimulation electrode into the contralateral CA3 region.Two groups of animals received a spatial holeboard training of 10 or 15 trials over 2 days on a fixed pattern of baited holes. The last trial was performed 15 min after a primed burst stimulation of the contralateral CA3, which resulted in LTP in the ipsilateral CA1. A pseudo-trained group that received a 10 trial training with changing patterns of baited holes after each trial and a group that remained in the recording chambers during the experiments served as controls. Experimental rats significantly improved their spatial performance with increasing numbers of trials, indicated by decreasing times to pick up all food pellets and by decreasing numbers of reference memory errors. A learning-related impairment of CA1-LTP measured in both the population-spike amplitude as well as the fEPSP could be noted. These results show that specific (pattern-training), but not unspecific (pseudo-training) spatial information processing prior to electrical stimulation can severely affect LTP in hippocampal area CA1.     

Differential effect of TEA on long-term synaptic modification in hippocampal CA1 and dentate gyrus in vitro.

The effectiveness of tetraethylammonium (TEA) and high-frequency stimulation (HFS) in inducing long-term synaptic modification is compared in CA1 and dentate gyrus (DG) in vitro. High-frequency stimulation induces long-term potentiation (LTP) at synapses of both perforant path-DG granule cell and Schaffer collateral-CA1 pyramidal cell pathways. By contrast, TEA (25 mM) induces long-term depression in DG while inducing LTP in CA1. The mechanisms underlying the differential effect of TEA in CA1 and DG were investigated. It was observed that T-type voltage-dependent calcium channel (VDCC) blocker, Ni2+ (50 microM), partially blocked TEA-induced LTP in CA1. A complete blockade of the TEA-induced LTP occurred when Ni2+ was applied together with the NMDA receptor antagonist, D-APV. The L-type VDCC blocker, nifidipine (20 microM), had no effect on CA1 TEA-induced LTP. In DG of the same slice, TEA actually induced long-term depression (LTD) instead of LTP, an effect that was blocked by D-APV. Neither T-type nor L-type VDCC blockade could prevent this LTD. When the calcium concentration in the perfusion medium was increased, TEA induced a weak LTP in DG that was blocked by Ni2+. During exposure to TEA, the magnitude of field EPSPs was increased in both CA1 and DG, but the increase was substantially greater in CA1. Tetraethylammonium application also was associated with a large, late EPSP component in CA1 that persisted even after severing the connections between CA3 and CA1. All of the TEA effects in CA1, however, were dramatically reduced by Ni2+. The results of this study indicate that TEA indirectly acts via both T-type VDCCs and NMDA receptors in CA1 and, as a consequence, induces LTP. By contrast, TEA indirectly acts via only NMDA receptors in DG and results in LTD. The results raise the possibility of a major synaptic difference in the density and/or distribution of T-type VDCCs and NMDA receptors in CA1 and DG of the rat hippocampus.     

Distinct single but not necessarily repeated tetanization is required to induce hippocampal late-LTP in the rat CA1

The protein synthesis-dependent form of hippocampal long-term potentiation (late-LTP) is thought to underlie memory. Its induction requires a distinct stimulation strength, and the common opinion is that only repeated tetani result in late-LTP whereas as single tetanus only reveals a transient early-LTP. Properties of LTP induction were compared to learning processes where repetition is often the prerequisite for a long-lasting memory. However, also single events can lead to manifested memory. If LTP subserves processes of learning, similar results should be detectable for LTP. Here we show that a single tetanus is sufficient to induce late-LTP requiring dopaminergic co-transmission during induction.     

Induction and activity-dependent reversal of persistent LTP and LTD in lateral perforant path synapses in vivo

The reversibility of long-term potentiation (LTP) and heterosynaptic long-term depression (LTD) lasting weeks was examined in the lateral perforant path of freely moving adult Sprague-Dawley rats. LTP lasting weeks was rapidly reversed within minutes by high-frequency heterosynaptic stimulation of the medial perforant path, in an N-methyl-D-aspartate receptor-dependent manner. LTP reversal also occurred, albeit more slowly and to a lesser extent, when animals were given 1-3 weeks of overnight exposure to an enriched environment (EE). LTD likewise was reversed upon repeated EE exposure. A covert similarity between the degrees of LTP and LTD reversal was revealed when the small potentiation effect of EE treatment by itself on lateral path responses was taken into account. Despite its ability to reverse previously acquired synaptic plasticity, two weeks of EE treatment had no effect on animals' retention of the platform location in a spatial watermaze task, although it did facilitate new learning. These data are in agreement with the hypothesis that hippocampal synapses retain the capacity for rapid synaptic change even when otherwise relatively stable plasticity has previously been induced. Slow reversal of such plasticity did not correlate with a loss of memory retention, possibly because either slow changes permit reorganization of representations such that both old and new information can be accommodated, or else the new information is synaptically represented in orthogonal fashion to the old information.     

The Specific Role of cGMP in Hippocampal LTP

Previous results have suggested that cGMP is involved in hippocampal long-term potentiation (LTP), perhaps as the presynaptic effector of a retrograde messenger. However, other studies have failed to replicate some of those results, making the role of cGMP uncertain. We therefore reexamined this question and identified several variables that can affect the contribution of cGMP. First, brief perfusion with 8-Br–cGMP before weak tetanic stimulation produced long-lasting potentiation in the CA1 region of hippocampal slices, but more prolonged perfusion with 8-Br–cGMP before the tetanus did not produce long-lasting potentiation. Second, the activity-dependent long-lasting potentiation by cGMP analogs was reduced when NMDA receptors were completely blocked, indicating that NMDA receptor activation contributes to, but is not required for, the potentiation. The amount of reduction of the potentiation differed with different protocols, and in some cases could be complete. Third, LTP produced by strong tetanic stimulation in the stratum radiatum of CA1 (which expresses eNOS) was blocked by inhibitors of soluble guanylyl cyclase or cGMP-dependent protein kinase, but LTP in the stratum oriens (which does not express eNOS) was not. The results of these experiments should help to explain some of the discrepant findings from previous studies, and, in addition, may provide insights into the mechanisms and functional role of the cGMP-dependent component of LTP.     

Differential Effect of TEA on Long-Term Synaptic Modification in Hippocampal CA1 and Dentate Gyrus in vitro

The effectiveness of tetraethylammonium (TEA) and high-frequency stimulation (HFS) in inducing long-term synaptic modification is compared in CA1 and dentate gyrus (DG) in vitro. High-frequency stimulation induces long-term potentiation (LTP) at synapses of both perforant path-DG granule cell and Schaffer collateral-CA1 pyramidal cell pathways. By contrast, TEA (25 mM) induces long-term depression in DG while inducing LTP in CA1. The mechanisms underlying the differential effect of TEA in CA1 and DG were investigated. It was observed that T-type voltage-dependent calcium channel (VDCC) blocker, Ni²⁺ (50 μM), partially blocked TEA-induced LTP in CA1. A complete blockade of the TEA-induced LTP occurred when Ni²⁺ was applied together with the NMDA receptor antagonist, D-APV. The L-type VDCC blocker, nifidipine (20 μM), had no effect on CA1 TEA-induced LTP. In DG of the same slice, TEA actually induced long-term depression (LTD) instead of LTP, an effect that was blocked by D-APV. Neither T-type nor L-type VDCC blockade could prevent this LTD. When the calcium concentration in the perfusion medium was increased, TEA induced a weak LTP in DG that was blocked by Ni²⁺. During exposure to TEA, the magnitude of field EPSPs was increased in both CA1 and DG, but the increase was substantially greater in CA1. Tetraethylammonium application also was associated with a large, late EPSP component in CA1 that persisted even after severing the connections between CA3 and CA1. All of the TEA effects in CA1, however, were dramatically reduced by Ni²⁺. The results of this study indicate that TEA indirectly acts via both T-type VDCCs and NMDA receptors in CA1 and, as a consequence, induces LTP. By contrast, TEA indirectly acts via only NMDA receptors in DG and results in LTD. The results raise the possibility of a major synaptic difference in the density and/or distribution of T-type VDCCs and NMDA receptors in CA1 and DG of the rat hippocampus.     

Predator (cat hair)-induced enhancement of hippocampal long-term potentiation in rats: involvement of acetylcholine

Extensive literature has demonstrated that arousal and fear modify memory acquisition and consolidation. Predator hair and odors increase arousal in rats and, therefore, may influence information encoding and synaptic plasticity in the rodent nervous system. In behavioral experiments, we confirm that laboratory-bred Long Evans rats avoid cat hair. Electrophysiological work in vivo showed that long-term potentiation (LTP) in the dentate gyrus induced by perforant path stimulation was enhanced for 5-7 days when LTP induction occurred in the presence of cat hair relative to fake hair. The muscarinic receptor antagonist scopolamine (i.p.) reversed the cat hair-elicited LTP enhancement without affecting weaker LTP elicited in the presence of fake hair. Thus, exposure to a predator stimulus elicits a cholinergically-dependent state of heightened plasticity that may serve to facilitate information storage in hippocampal circuits.     

On the delay-dependent involvement of the hippocampus in object recognition memory

The role of the hippocampus in object recognition memory processes is unclear in the current literature. Conflicting results have been found in lesion studies of both primates and rodents. Procedural differences between studies, such as retention interval, may explain these discrepancies. In the present study, acute lidocaine administration was used to temporarily inactivate the hippocampus prior to training in the spontaneous object recognition task. Male C57BL/6J mice were administered bilateral lidocaine (4%, 0.5 microl/side) or aCSF (0.5 microl/side) directly into the CA1 region of the dorsal hippocampus 5 min prior to sample object training, and object recognition memory was tested after a short ( 5 min) or long (24 h) retention interval. There was no effect of intra-hippocampal lidocaine on the time needed for mice to accumulate sample object exploration, suggesting that inactivation of the hippocampus did not affect sample session activity or the motivation to explore objects. Lidocaine-treated mice exhibited impaired object recognition memory, measured as reduced novel object preference, after a 24 h but not a 5 min retention interval. These data support a delay-dependent role for the hippocampus in object recognition memory, an effect consistent with the results of hippocampal lesion studies conducted in rats. However, these data are also consistent with the view that the hippocampus is involved in object recognition memory regardless of retention interval, and that object recognition processes of parahippocampal structures (e.g., perirhinal cortex) are sufficient to support object recognition memory over short retention intervals.