Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Perforant Pathway”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 595 records · Page 33Linked to original sources
PubMed1999

Chronic developmental lead exposure and hippocampal long-term potentiation: biphasic dose-response relationship.

Developmental exposure to lead (Pb) has long been associated with reductions in intellectual function in children and behavioral impairments in animal models of learning and memory. We have used long-term potentiation (LTP) in the dentate gyrus of the Pb-exposed rats to determine the potential of a reduced capacity for synaptic plasticity to contribute to Pb-induced cognitive dysfunction. Previous work demonstrated that developmental exposure resulting in moderate blood concentrations of Pb increase the threshold for induction of long-term potentiation (LTP) in the dentate gyrus in vivo. These findings were also suggestive of reductions in LTP magnitude (Gilbert et al., 1996). The present study was designed to further examine the effects of Pb on LTP magnitude and to determine if lower blood Pb levels commonly encountered in children are also effective in impairing synaptic plasticity in this rodent model. Pregnant dams were exposed to control tap water or 0.1, 0.2, 0.5 or 1.0% Pb-acetate in the drinking water beginning just prior to parturition (gestational day 16, GD16). Male offspring were weaned at 21 days of age (PN21) to the same solution given their dams and continued on this regimen until testing. As adults, animals were anesthetized with urethane and stimulating and recording electrodes placed in the perforant path and dentate gyrus, respectively. Post-train I/O functions taken 1 hour after delivery of a series of six high frequency (400Hz) trains revealed a reduced capacity for LTP of the PS amplitude and EPSP slope in Pb-exposed animals in all but the 1.0% group, indicative of a biphasic dose-effect relationship. The 1.0% Pb exposure was clearly less effective than the lower exposure levels in reducing LTP magnitude, and did not differ significantly from control values. The mechanisms underlying the reduced efficacy of higher exposure levels of Pb to impair LTP are not clear. Blood (26-117 microg/dl) and brain (220-1812 ng/g tissue) concentrations of Pb were elevated as a function of increasing exposure (0.1%-1.0%) and cannot readily account for the lack of an effect in the 1.0% group on LTP. We have observed a similar profile in hippocampal glutamate release employing a similar range of exposure levels, i.e., reduction of glutamate release that is absent at higher concentrations of Pb in the drinking water (Lasley et al., 1998). These and previously reported data suggest that the ability of Pb to diminish presynaptic transmitter release contributes to a reduced capacity for LTP at lower exposure levels. The reversal of the effect of Pb on glutamate release that accompanies higher exposure levels may serve to compensate for the mechanism underlying the LTP impairment and form the basis for the biphasic dose-response pattern seen with chronic developmental exposure.

Animals↗
PubMed1999

Lamina-specific synaptic activation causes domain-specific alterations in dendritic immunostaining for MAP2 and CAM kinase II.

Polyribosomal complexes are selectively localized beneath postsynaptic sites on neuronal dendrites; this localization suggests that the translation of the mRNAs that are present in dendrites may be regulated by synaptic activity. The present study tests this hypothesis by evaluating whether synaptic activation alters the immunostaining pattern for two proteins whose mRNAs are present in dendrites: the dendrite-specific cytoskeletal protein MAP2 and the alpha-subunit of CAMKII. High-frequency stimulation of the perforant path projections to the dentate gyrus, which terminate in a discrete band on the dendrites of dentate granule cells, produced a two-stage alteration in immunostaining for MAP2 in the dendritic laminae. Five minutes of stimulation (30 trains) caused a decrease in MAP2 immunostaining in the lamina in which the activated synapses terminate. After more prolonged periods of stimulation (1-2 hr), there was an increase in immunostaining in the sideband laminae just proximal and distal to the activated band of synapses. The same stimulation paradigm produced a modest increase in immunostaining for alpha-CAMKII in the activated laminae, with no detectable changes in the sideband laminae. The alterations in immunostaining for MAP2 were diminished, but not eliminated, by inhibiting protein synthesis; the increases in CAMKII were not. These findings reveal that patterned synaptic activity can produce domain-specific alterations in the molecular composition of dendrites; these alterations may be caused in part by local protein synthesis and in part by other mechanisms.

2-Amino-5-phosphonovalerate↗
PubMed1999

Assessment of inhibition and epileptiform activity in the septal dentate gyrus of freely behaving rats during the first week after kainate treatment.

Mossy fiber reorganization has been hypothesized to restore inhibition months after kainate-induced status epilepticus. The time course of recovery of inhibition after kainate treatment, however, is not well established. We tested the hypothesis that if inhibition is decreased after kainate treatment, it is restored within the first week when little or no mossy fiber reorganization has occurred. Chronic in vivo recordings of the septal dentate gyrus were performed in rats before and 1, 4, and 7-8 d after kainate (multiple injections of 5 mg/kg, i.p.; n = 17) or saline (n = 11) treatment. Single and paired-pulse stimuli were used to assess synaptic inhibition. The first day after kainate treatment, only a fraction of rats showed multiple population spikes (35%), prolonged field postsynaptic potentials (76%), and loss of paired-pulse inhibition (29%) to perforant path stimulation. Thus, inhibition was reduced in only some of the kainate-treated rats. By 7-8 d after treatment, nearly all kainate-treated rats showed partial or full recovery in these response characteristics. Histological analysis indicated that kainate-treated rats had a significant decrease in the number of hilar neurons compared to controls, but Timm staining showed little to no mossy fiber reorganization. These results suggest that a decrease in synaptic inhibition in the septal dentate gyrus is not a prerequisite for epileptogenesis and that most of the recovery of inhibition occurs before robust Timm staining in the inner molecular layer.

Animals↗
PubMed1999

Biphasic modulation of hippocampal plasticity by behavioral stress and basolateral amygdala stimulation in the rat.

Explicit memory may depend on the hippocampus, whereas the amygdala may be part of an emotional memory system. Priming stimulation of the basolateral group of the amygdala (BLA) resulted in an enhanced long-term potentiation (LTP) in the dentate gyrus (DG) to perforant path (PP) stimulation 30, 90, 150, and 180 min after high-frequency stimulation (HFS). Exposure of rats to a behavioral stress is reported to inhibit DG LTP. Because the amygdala is thought to mediate emotional responses, we examined the apparent discrepancy between the effects of behavioral stress induced 1 hr before HFS to the PP and of amygdala priming on hippocampal plasticity by stimulating the BLA 1 hr before HFS to the PP. The two delayed protocols inhibited the expression of LTP to PP stimulation, whereas priming the BLA immediately before HFS to the PP enhanced DG LTP. Moreover, exposure to the behavioral stress blocked the enhancing effects of BLA priming on LTP. We propose that the activation of the BLA (either by behavioral stress or by direct electrical stimulation) has a biphasic effect on hippocampal plasticity: an immediate excitatory effect and a longer-lasting inhibitory effect.

Amygdala↗
PubMed2000

Protein phosphatase-1 regulation in the induction of long-term potentiation: heterogeneous molecular mechanisms.

Protein phosphatase inhibitor-1 (I-1) has been proposed as a regulatory element in the signal transduction cascade that couples postsynaptic calcium influx to long-term changes in synaptic strength. We have evaluated this model using mice lacking I-1. Recordings made in slices prepared from mutant animals and also in anesthetized mutant animals indicated that long-term potentiation (LTP) is deficient at perforant path-dentate granule cell synapses. In vitro, this deficit was restricted to synapses of the lateral perforant path. LTP at Schaffer collateral-CA1 pyramidal cell synapses remained normal. Thus, protein phosphatase-1-mediated regulation of NMDA receptor-dependent synaptic plasticity involves heterogeneous molecular mechanisms, in both different dendritic subregions and different neuronal subtypes. Examination of the performance of I-1 mutants in spatial learning tests indicated that intact LTP at lateral perforant path-granule cell synapses is either redundant or is not involved in this form of learning.

Animals↗
PubMed2000

IFNgamma enhances microglial reactions to hippocampal axonal degeneration.

Glial reactivity is implicated in CNS repair and regenerative responses. Microglia, the cells responding earliest to axonal injury, produce tumor necrosis factor-alpha (TNFalpha), a cytokine with both cytopathic and neuroprotective effects. We have studied activation of hippocampal microglia to produce TNFalpha in response to transection of perforant path axons in SJL/J mice. TNFalpha mRNA was produced in a transient manner, peaking at 2 d and falling again by 5 d after lesioning. This was unlike other markers of glial reactivity, such as Mac-1 upregulation, which were sustained over longer time periods. Message for the immune cytokine interferon-gamma (IFNgamma) was undetectable, and glial reactivity to axonal lesions occurred as normal in IFNgamma-deficient mice. Microglial responses to lesion-induced neuronal injury were markedly enhanced in myelin basic protein promoter-driven transgenic mice, in which IFNgamma was endogenously produced in hippocampus. The kinetics of TNFalpha downregulation 5 d after lesion was not affected by transgenic IFNgamma, indicating that IFNgamma acts as an amplifier and not an inducer of response. These results are discussed in the context of a regenerative role for TNFalpha in the CNS, which is innately regulated and potentiated by IFNgamma.

Animals↗
PubMed2000

cAMP-dependent protein kinase inhibits mGluR2 coupling to G-proteins by direct receptor phosphorylation.

One of the primary physiological roles of group II and group III metabotropic glutamate receptors (mGluRs) is to presynaptically reduce synaptic transmission at glutamatergic synapses. Interestingly, previous studies suggest that presynaptic mGluRs are tightly regulated by protein kinases. cAMP analogs and the adenylyl cyclase activator forskolin inhibit the function of presynaptic group II mGluRs in area CA3 of the hippocampus. We now report that forskolin has a similar inhibitory effect on putative mGluR2-mediated responses at the medial perforant path synapse and that this effect of forskolin is blocked by a selective inhibitor of cAMP-dependent protein kinase (PKA). A series of biochemical and molecular studies was used to determine the precise mechanism by which PKA inhibits mGluR2 function. Our studies reveal that PKA directly phosphorylates mGluR2 at a single serine residue (Ser(843)) on the C-terminal tail region of the receptor. Site-directed mutagenesis combined with biochemical measures of mGluR2 function reveal that phosphorylation of this site inhibits coupling of mGluR2 from GTP-binding proteins

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2000

Synaptic plasticity in the human dentate gyrus.

Activity-dependent plasticity is a fundamental feature of most CNS synapses and is thought to be a synaptic correlate of memory in rodents. In humans, NMDA receptors have been linked to verbal memory processes, but it is unclear whether NMDA receptor-dependent synaptic plasticity can be recruited for information storage in the human CNS. Here we have for the first time analyzed different forms of synaptic plasticity in human hippocampus. In human subjects who show a morphologically intact hippocampus that is not the primary seizure focus, NMDA receptor-dependent long-term potentiation (LTP) and forskolin-induced long-lasting potentiation are readily induced at the perforant path-dentate gyrus synapse. In this group, long-term potentiation could be partially depotentiated by low-frequency stimulation. Because patients with a hippocampal seizure focus showed a marked reduction in verbal memory performance in previous studies, we asked whether synaptic plasticity is similarly affected by the presence of a hippocampal primary seizure focus. We found that the amount of potentiation induced by high-frequency stimulation or perfusion of forskolin is dramatically reduced in this patient group. In addition, low-frequency stimulation is not effective in inducing synaptic depression. In summary, we show that activity-dependent synaptic plasticity with properties similar to the rodent is available for information storage in the human hippocampus. Because both verbal memory processes and synaptic plasticity are impaired by a hippocampal seizure focus, we suggest that impaired synaptic plasticity may contribute to deficient declarative memory in human temporal lobe epilepsy.

1-Methyl-3-isobutylxanthine↗
PubMed2000

The involvement of recurrent connections in area CA3 in establishing the properties of place fields: a model.

Strong constraints on the neural mechanisms underlying the formation of place fields in the rodent hippocampus come from the systematic changes in spatial activity patterns that are consequent on systematic environmental manipulations. We describe an attractor network model of area CA3 in which local, recurrent, excitatory, and inhibitory interactions generate appropriate place cell representations from location- and direction-specific activity in the entorhinal cortex. In the model, familiarity with the environment, as reflected by activity in neuromodulatory systems, influences the efficacy and plasticity of the recurrent and feedforward inputs to CA3. In unfamiliar, novel, environments, mossy fiber inputs impose activity patterns on CA3, and the recurrent collaterals and the perforant path inputs are subject to graded Hebbian plasticity. This sculpts CA3 attractors and associates them with activity patterns in the entorhinal cortex. In familiar environments, place fields are controlled by the way that perforant path inputs select among the attractors. Depending on the training experience provided, the model generates place fields that are either directional or nondirectional and whose changes when the environment undergoes simple geometric transformations are in accordance with experimental data. Representations of multiple environments can be stored and recalled with little interference, and these have the appropriate degrees of similarity in visually similar environments.

Animals↗
PubMed2000

Identification of the kainate receptor subunits underlying modulation of excitatory synaptic transmission in the CA3 region of the hippocampus.

To understand the physiological role of kainate receptors and their participation in seizure induction in animal models of epilepsy, it will be necessary to develop a comprehensive description of their action in the CA3 region of the hippocampus. Activation of presynaptic kainate receptors depresses excitatory synaptic transmission at mossy fiber and associational-commissural inputs to CA3 pyramidal neurons (Vignes et al., 1998; Bortolotto et al., 1999; Kamiya and Ozawa, 2000). In this study, we use gene-targeted mice lacking glutamate receptor 5 (GluR5) or GluR6 kainate receptor subunits to identify the receptor subunits that comprise the kainate receptors responsible for presynaptic modulation of CA3 transmission. We found that bath application of kainate (3 microm) profoundly reduced EPSCs at mossy fiber and collateral synapses in neurons from wild-type and GluR5(-/-) mice but had no effect on EPSCs in neurons from GluR6(-/-) mice. These results therefore contrast with previous studies that supported a role for GluR5-containing receptors at mossy fiber and associational-commissural synapses (Vignes et al., 1998; Bortolotto et al., 1999). Surprisingly, at perforant path synapses kainate receptor activation enhanced transmission; this potentiation was abolished in both GluR5 and GluR6 knock-out mice. Kainate receptors thus play multiple and complex roles to modulate excitatory synaptic transmission in the CA3 region of the hippocampus.

Animals↗
PubMed2001

Behavior-dependent states of the hippocampal network affect functional clustering of neurons.

Local versus distant coherence of hippocampal CA1 pyramidal cells was investigated in the behaving rat. Temporal cross-correlation of pyramidal cells revealed a significantly stronger relationship among local (<140 microm) pyramidal neurons compared with distant (>300 microm) neurons during non-theta-associated immobility and sleep but not during theta-associated running and walking. In contrast, cross-correlation between local pyramidal cell-interneuron pairs was significantly stronger than between distant pairs during theta oscillations but were similar during non-theta-associated behaviors. We suggest that network state-dependent functional clustering of neuronal activity emerges because of the differential contribution of the main excitatory inputs, the perforant path, and Schaffer collaterals during theta and non-theta behaviors.

Action Potentials↗
PubMed2001

Reinforcement of early long-term potentiation (early-LTP) in dentate gyrus by stimulation of the basolateral amygdala: heterosynaptic induction mechanisms of late-LTP.

The basolateral amygdala (BLA) can influence distinct learning and memory formation. Hippocampal long-term potentiation (LTP), the most prominent cellular model of memory formation, can be modulated by stimulation of the BLA in its induction and early maintenance. However, it is not known how the late maintenance of LTP beyond its initial phases might be affected. Behavioral stimuli have been shown to result in a reinforcement of a transient early-LTP into a lasting potentiation. Here we show that BLA stimulation mimics the behavioral effects on early-LTP in freely moving rats when the BLA is activated within a time window of 30 min before or after tetanization of the perforant path. The reinforcement of LTP was blocked by inhibitors of muscarinergic and beta-adrenergic but not dopaminergic receptors and was dependent on translation. Through these heterosynaptic associative interactions, hippocampal sensory information can be stabilized by amygdaloidal influences.

Adrenergic beta-Antagonists↗
PubMed2001

Physiological and structural evidence for hippocampal involvement in persistent seizure susceptibility after traumatic brain injury.

Epilepsy is a common outcome of traumatic brain injury (TBI), but the mechanisms of posttraumatic epileptogenesis are poorly understood. One clue is the occurrence of selective hippocampal cell death after fluid-percussion TBI in rats, consistent with the reported reduction of hippocampal volume bilaterally in humans after TBI and resembling hippocampal sclerosis, a hallmark of temporal-lobe epilepsy. Other features of temporal-lobe epilepsy, such as long-term seizure susceptibility, persistent hyperexcitability in the dentate gyrus (DG), and mossy fiber synaptic reorganization, however, have not been examined after TBI. To determine whether TBI induces these changes, we used a well studied model of TBI by weight drop on somatosensory cortex in adult rats. First, we confirmed an early and selective cell loss in the hilus of the DG and area CA3 of hippocampus, ipsilateral to the impact. Second, we found persistently enhanced susceptibility to pentylenetetrazole-induced convulsions 15 weeks after TBI. Third, by applying GABA(A) antagonists during field-potential and optical recordings in hippocampal slices 3 and 15 weeks after TBI, we unmasked a persistent, abnormal APV-sensitive hyperexcitability that was bilateral and localized to the granule cell and molecular layers of the DG. Finally, using Timm histochemistry, we detected progressive sprouting of mossy fibers into the inner molecular layers of the DG bilaterally 2-27 weeks after TBI. These findings are consistent with the development of posttraumatic epilepsy in an animal model of impact head injury, showing a striking similarity to the enduring behavioral, functional, and structural alterations associated with temporal-lobe epilepsy.

2-Amino-5-phosphonovalerate↗
PubMed2001

Conditioning hypoxia in vivo alters neuronal excitability of hippocampal neurones of rats in vitro and in vivo.

PURPOSE: Moderate normobaric hypoxia causes long-lasting protection against damage induced by a second ischemic or traumatic insult. The changes induced by such conditioning hypoxia are not yet fully understood. The protective effect has been described in various publications but other effects seem possible. METHODS: In order to search for effects of conditioning normobaric hypoxia yet unknown, we measured O-Mg++ potentiation and classical long-term potentiation (LTP) in the CA, region of hippocampal slices seven days after the conditioning procedure. Furthermore, tests were also carried out in chronically implanted rats as to whether LTP was changed in the dentate gyrus after conditioning hypoxia. RESULTS: In slices taken from animals which received conditioning hypoxia, O-Mg++ potentiation and classical LTP of the population spike were significantly enhanced, when compared to population in two control groups. Anoxic LTP, i.e. increase in the population spike of the field potential in the dentate gyrus immediately after finishing the procedure, and a tendency to elevation of LTP seven days after conditioning were also found in chronically implanted animals which were subjected to conditioning hypoxia. CONCLUSIONS: lt. may be hypothesized that elevated Ca++ transport in the neurons during conditioning hypoxia is responsible for both long- lasting increases in plastic reactions and the protective effect.

Animals↗
PubMed2002

Local generation of fast ripples in epileptic brain.

Aperiodic high-frequency oscillations (>100 Hz) reflect a short-term synchronization of neuronal electrical activity. It has been shown in the epileptic brain that spontaneous oscillations in the frequency range of 250-600 Hz reflect action potential population bursts of synchronously discharging neuronal clusters. These oscillations occur in the early stages of epileptogenesis in areas adjacent to the brain lesion and may trigger the formation of seizure-generating neuronal networks. We studied the extent of the area generating oscillations in the frequency range of 250-600 Hz [fast ripples (FRs)] in intrahippocampal kainic acid-treated rats with spontaneous seizures, by analyzing voltage versus depth profiles of FRs in hippocampal and parahippocampal areas in freely moving animals and by spatial mapping in hippocampal slice preparations in vitro. The strength of inhibition was compared in areas with and without FRs using a paired-pulse paradigm. The extent of the areas generating FRs did not exceed 1 mm(3). The areas generating FRs became broader after the application of the GABA(A) receptor antagonist bicuculline. Paired-pulse fast inhibition at 15-30 msec intervals was similar in areas generating FRs and areas not generating FRs. Our data illustrate that hypothesized clusters of highly interconnected neurons are capable of overcoming interneuron feedback inhibition, resulting in generation of epileptiform bursts, eventually leading to seizure activity.

Action Potentials↗
PubMed2002

The AMPA receptor subunit GluR1 regulates dendritic architecture of motor neurons.

The morphology of the mature motor neuron dendritic arbor is determined by activity-dependent processes occurring during a critical period in early postnatal life. The abundance of the AMPA receptor subunit GluR1 in motor neurons is very high during this period and subsequently falls to a negligible level. To test the role of GluR1 in dendrite morphogenesis, we reintroduced GluR1 into rat motor neurons at the end of the critical period and quantitatively studied the effects on dendrite architecture. Two versions of GluR1 were studied that differed by the amino acid in the "Q/R" editing site. The amino acid occupying this site determines single-channel conductance, ionic permeability, and other essential electrophysiologic properties of the resulting receptor channels. We found large-scale remodeling of dendritic architectures in a manner depending on the amino acid occupying the Q/R editing site. Alterations in the distribution of dendritic arbor were not prevented by blocking NMDA receptors. These observations suggest that the expression of GluR1 in motor neurons modulates a component of the molecular substrate of activity-dependent dendrite morphogenesis. The control of these events relies on subunit-specific properties of AMPA receptors.

Action Potentials↗
PubMed2002

Induction and experience-dependent consolidation of stable long-term potentiation lasting months in the hippocampus.

Long-term potentiation (LTP) is widely regarded as a memory mechanism, but it is not known whether it can last long enough to underlie very long-term memory. We report that high-frequency stimulation (HFS) paradigms applied to the rat dentate gyrus can elicit stable LTP lasting months and up to at least 1 year. The induction of stable LTP was sensitive to stimulation variables on the day of HFS and was associated with phosphorylation of cAMP response element-binding protein. The maintenance of stable LTP was also experience-dependent, because it was reversed when animals were exposed repeatedly to an enriched environment beginning 14 d post-HFS. However, stable LTP eventually consolidated over time and became resistant to reversal, because exposure to enriched environments 90 d post-HFS failed to influence stable LTP maintenance. Thus, LTP can be shown to meet one of the principal criteria for a very long-term memory storage mechanism. However, under naturalistic environmental conditions, LTP may normally be retained in the hippocampus for only short periods of time.

Animals↗
PubMed2002

Mechanisms of amygdala modulation of hippocampal plasticity.

Basolateral amygdala (BLA) activation by emotional arousal modulates memory-related processes in the hippocampus. We have shown (Akirav and Richter-Levin, 1999b) that activating the BLA before perforant path (PP) tetanization has a biphasic effect on hippocampal plasticity; priming the BLA immediately before PP tetanization results in the enhancement of dentate gyrus (DG) long-term potentiation (LTP) (an "emotional tag"), whereas stimulation in a spaced interval results in the suppression of DG-LTP. Here, we aimed to elucidate the mechanisms underlying BLA modulation of DG-LTP and specifically to examine whether the stress hormones norepinephrine (NE) and corticosterone (CORT) are main mediators of the BLA biphasic effects. We found that the BLA affects hippocampal plasticity in a complex manner; BLA priming enhanced DG-LTP, and both NE and CORT mediated this effect. Furthermore, we found that ipsilateral BLA spaced activation (2 hr before PP tetanization) suppressed DG-LTP and that this suppressive effect was also mediated by NE and CORT. Priming the contralateral BLA enhanced DG-LTP similarly to the ipsilateral enhancement, but neither NE nor CORT mediated this effect. The spaced activation of the contralateral BLA did not suppress DG-LTP. Taken together, these results suggest that differential mechanisms underlie the ipsilateral and contralateral BLA effects on hippocampal plasticity. Hence, the BLA modulates hippocampal memory processes, presumably via the mediation of the stress hormones NE and CORT, to establish a diverse memory of the experience. Possibly, at the onset of an emotional event the stress hormones permissively mediate plasticity. However, their prolonged presence in the system may suppress the cognitive response to stress.

Adrenergic Agents↗