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PubMed1997

Pathway specificity of l-isoproterenol indicates beta-adrenergic modulation of the Schaffer collateral pathway in field CA1 in the rat hippocampal slice.

Behavioral relevance of norepinephrine is associated with neuronal processing underlying arousal, affect, attention, learning and memory, and is associated with beta-adrenergic modifications of neuronal activation in the hippocampal formation. This study utilized l-isoproterenol to initiate pathway-specific activation of afferents to hippocampal CA1 pyramidal cells. The consistent effects of l-isoproterenol on the initiation of action potentials to field CA1 pyramidal neurons to single-pulse stimulation was repeatedly associated with the activation of the Schaffer collateral pathway. In contrast, l-isoproterenol plus single-pulse stimulation never elicited action potential initiation of the perforant pathway to CA1. We interpret these results as indicating that beta-adrenergic modification underlies the augmentation of information processing via the Schaffer collateral pathway in the trisynaptic circuit vs the direct perforant pathway.

Action Potentials↗

PubMed2006

Modeling of context-dependent retrieval in hippocampal region CA1: implications for cognitive function in schizophrenia.

The symptoms of schizophrenia may be associated with reductions in NMDA receptor (NMDAR) function. This is suggested by the psychotomimetic effects of NMDA antagonists, the ameliorative effects of NMDAR indirect agonists, elevated levels of the NMDA antagonist N-acetyl-aspartyl-glutamate (NAAG) in schizophrenic brain, and findings from recent genetic studies. However, the link between reduced NMDAR function and the behavioral features of schizophrenics has not been made explicit. Here we present a network simulation of hippocampal function, focused on retrieval of verbal stimuli in human memory tasks. Specifically, we trained a computational model of the hippocampal complex to perform a context-dependent paired associate task, a free recall task with category clustering, and the transitive inference (TI) task. In this network, direct perforant pathway input from entorhinal cortex to region CA1 provides the basis for semantic context cueing during initial encoding and retrieval, allowing selective retrieval on the basis of category cues. Alterations in the magnitude of this direct perforant pathway input to region CA1 causes impairments in use of organizational strategies for memory, accounting for specific features of memory dysfunction in schizophrenics and in normals treated with ketamine. This model provides a theoretical link between cellular physiological changes and specific cognitive symptoms. As such, it can shed light on the etiology of schizophrenia in a fundamental way, and also holds the promise of pointing the way to more effective treatments.

Brain Mapping↗

PubMed1987

Modulation of the excitability of septohippocampal terminals in the rat: relation to neuronal discharge rate.

The excitability of the axonal terminals of medial septal neurons projecting to the dentate gyrus has been studied in the anesthetized rat under various experimental conditions: spontaneous or drug-induced variations in neuronal soma discharge rate, conditioning stimulation of afferent pathways (perforant path, commissural pathway, fimbria-fornix). It has been observed that terminals excitability is inversely correlated to the level of neuronal ongoing activity. These effects were observed on virtually all septal neurons projecting to the dentate gyrus. Since about one half of the septohippocampal neurons are likely to be cholinergic, it follows that such a phenomenon is not transmitter specific.

Action Potentials↗

PubMed1990

Hippocampal adenosine A1 receptors are decreased in Alzheimer's disease.

Previous studies showed that adenosine receptors of the temporal and frontal cortices were not affected in Alzheimer's disease (AD). Here, we assessed the specific binding of [3H]cyclohexyladenosine to adenosine1 (A1) receptors in hippocampus from AD subjects and age-matched controls. By both particulate membrane and in vitro autoradiographic receptor binding methods we demonstrate that A1 receptors are significantly reduced by 40-60% in AD subjects. Scatchard analysis showed that maximum binding capacity (Bmax) was affected and there was no evidence for a change in the affinity of the receptor for the ligand (Kd). Receptor autoradiography revealed that although several regions including CA1, CA3 and deep layer of the subiculum were affected, the loss in A1 receptors was most prominent in the molecular layer of the dentate gyrus. In view of previous evidence indicating that these receptors are associated with the perforant pathway and dendritic fields of the CA1 and CA3 regions, our findings suggest loss of the presynaptic A1 receptors on axon terminals of extrinsic pathways including the perforant path and intrinsic pyramidal neurons which release glutamate.

Adenosine↗

PubMed2002

Evidence that synaptically released beta-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice.

A neuropathological hallmark of Alzheimer's disease is the deposition of amyloid-beta (Abeta) peptides in senile plaques in the hippocampus and cerebral cortex. Abeta is derived from larger integral membrane proteins termed amyloid precursor proteins (APP). We demonstrated previously that APP, synthesized by neurons in the entorhinal cortex, is transported via the perforant pathway to presynaptic terminals in the dentate gyrus. We reported that, although full-length APP and membrane-tethered, C-terminal APP derivatives (APP-CTFs) accumulate at terminal fields, the production of Abeta peptides at these sites was indeterminate. To test the hypothesis that APP-CTFs, generated from axonally transported APP, are further metabolized to Abeta peptides that are subsequently released and deposited proximal to nerve terminals, we created unilateral knife lesions of the perforant pathway of transgenic mice that exhibit hippocampal amyloid deposits. We observed pronounced reductions in amyloid burden in the ipsilateral dentate gyrus, findings that lead us to conclude that axonally transported APP gives rise to Abeta peptides that are released from presynaptic sites in the dentate gyrus and deposited in extracellular plaques. Moreover, our findings are consistent with the view that Abeta deposits are dynamic structures and that the perforant path lesion alters the equilibrium between Abeta production-deposition toward clearance as a consequence of blocked axonal transport of APP from the entorhinal cortex to terminal fields in the hippocampus.

Alzheimer Disease↗

PubMed2004

Translamellar disinhibition in the rat hippocampal dentate gyrus after seizure-induced degeneration of vulnerable hilar neurons.

Longitudinally restricted axonal projections of hippocampal granule cells suggest that transverse segments of the granule cell layer may operate independently (the "lamellar" hypothesis). Longitudinal projections of excitatory hilar mossy cells could be viewed as antithetical to lamellar function, but only if longitudinal impulse flow effectively excites distant granule cells. We, therefore, determined the effect of focal granule cell discharges on granule cells located >2 mm along the longitudinal axis. During perforant pathway stimulation in urethane-anesthetized rats, passive diffusion of the GABA(A) receptor antagonist bicuculline methiodide from the tip of a glass recording electrode evoked granule cell discharges and c-Fos expression in granule cells, mossy cells, and inhibitory interneurons, within a approximately 400 microm radius. This focally evoked activity powerfully suppressed distant granule cell-evoked responses recorded simultaneously approximately 2.5-4.5 mm longitudinally. Three days after kainic acid-induced status epilepticus or prolonged perforant pathway stimulation, translamellar inhibition was intact in rats with <40% hilar neuron loss but was consistently abolished after extensive (>85%) hilar cell loss. Retrograde transport of Fluoro-Gold (FG) from the rostral dentate gyrus revealed that few inhibitory interneurons were among the many retrogradely labeled hilar neurons 2.5-4.5 mm longitudinally. Although many somatostatin-positive hilar interneurons effectively transported FG from the distant septum, few of these neurons transported detectable FG from much closer hippocampal injection sites. Inhibitory basket and chandelier cells also exhibited minimal longitudinal FG transport. These findings suggest that translamellar disinhibition may result from the loss of vulnerable, longitudinally projecting mossy cells and may represent a network-level mechanism underlying postinjury hippocampal dysfunction and epileptic network hyperexcitability.

Animals↗

PubMed2005

Group II and III mGluRs-mediated presynaptic inhibition of EPSCs recorded from hippocampal interneurons of CA1 stratum lacunosum moleculare.

We have studied the effects of groups II and III metabotropic glutamate receptor (mGluR) activation on excitatory responses recorded from hippocampal interneurons of CA1 stratum lacunosum moleculare (SLM). Excitatory postsynaptic currents (EPSCs) evoked by stimulation of the perforant pathway were reduced either by the group II mGluR agonist LY354740 (50-100 nM, 49.1+/-5.7% of control) or by the group III mGluR agonist l-2-amino-4-phosphonobutyric acid (l-AP4) (50 microM, 36.8+/-4.4% of control). Both drugs significantly enhanced paired-pulse facilitation of the EPSCs. Furthermore, both 100 nM LY354740 and 50 microM l-AP4 reduced the frequency, but not the amplitude, of miniature excitatory synaptic currents (mEPSCs), recorded in the presence of 1 microM TTX and 50 microM picrotoxin, or EPSCs evoked by perforant pathway stimulation in the presence of 2.5 mM Sr2+. The broad-spectrum mGluR antagonist LY341495 (10-50 microM) did not affect test EPSCs elicited 210 ms after stimulation at 100 Hz. At network level, 1-5 microM LY354740 significantly reduced the power of gamma frequency oscillations induced by 20 microM carbachol, 600 nM kainate and 5 mM K+ in hippocampal CA1 area. Our results show powerful modulation of excitatory transmission impinging on interneurons of CA1 SLM by presynaptic group II or III mGluRs.

Amino Acids↗

PubMed1999

A role for the Eph ligand ephrin-A3 in entorhino-hippocampal axon targeting.

Neurons of layers II and III of the entorhinal cortex constitute the major afferent connection of the hippocampus. The molecular mechanisms that target the entorhinal axons to specific layers in the hippocampus are not known. EphA5, a member of the Eph receptor family, which has been shown to play critical roles in axon guidance, is expressed in the entorhinal cortex, the origin of the perforant pathway. In addition, ligands that interact with EphA5 are expressed in distinct hippocampal regions during development of the entorhino-hippocampal projection. Of these ligands, ephrin-A3 mRNA is localized both in the granular cell layer of the dentate gyrus and in the pyramidal cell layer of the cornu ammonis, whereas ephrin-A5 mRNA is only expressed in the pyramidal cell layer of the cornu ammonis. In the dentate gyrus, the ligand protein is not present in the termination zone of the entorhinal efferents (the outer molecular layer of the dentate gyrus) but is concentrated in the inner molecular layer into which entorhinal efferents do not grow. We used outgrowth and stripe assays to test the effects of ephrin-A3 and ephrin-A5 on the outgrowth behavior of entorhinal axons. This functional analysis revealed that entorhinal neurites were repelled by ephrin-A3 but not by ephrin-A5. These observations suggest that ephrin-A3 plays an important role in the layer-specific termination of the perforant pathway and that this ligand may interact with the EphA5 receptor to restrict entorhinal axon terminals in the outer molecular layer of the dentate gyrus.

3T3 Cells↗

PubMed2000

Outgrowth-promoting molecules in the adult hippocampus after perforant path lesion.

Lesion-induced neuronal plasticity in the adult central nervous system of higher vertebrates appears to be controlled by region- and layer-specific molecules. In this study we demonstrate that membrane-bound hippocampal outgrowth-promoting molecules, as present during the development of the entorhino-hippocampal system and absent or masked in the adult hippocampus, appear 10 days after transection of the perforant pathway. We used an outgrowth preference assay to analyse the outgrowth preference of axons from postnatal entorhinal explants on alternating membrane lanes obtained from hippocampus deafferented from its entorhinal input taken 4, 10, 20, 30 and 80 days post-lesion and from adult control hippocampus. Neurites from the entorhinal cortex preferred to extend axons on hippocampal membranes disconnected from their entorhinal input for 10 days in comparison with membranes obtained from unlesioned adult animals. Membranes obtained from hippocampi disconnected from their entorhinal input for 10 days were equally as attractive for growing entorhinal cortex (EC) axons as membranes from early postnatal hippocampi. Further analysis of membrane properties in an outgrowth length assay showed that entorhinal axons extended significantly longer on stripes of lesioned hippocampal membranes in comparison with unlesioned hippocampal membranes. This effect was most prominent 10 days after lesion, a time point at which axonal sprouting and reactive synaptogenesis are at their peak. Phospholipase treatment of membranes obtained from unlesioned hippocampi of adult animals strongly promoted the outgrowth length of entorhinal axons on these membranes but did not affect their outgrowth preference for deafferented hippocampal membranes. Our results indicate that membrane-bound outgrowth-promoting molecules are reactivated in the adult hippocampus following transection of the perforant pathway, and that neonatal entorhinal axons are able to respond to these molecules. These findings support the hypothesis of a temporal accessibility of membrane-bound factors governing the layer-specific sprouting of remaining axons following perforant path lesion in vivo.

Animals↗

PubMed2003

Connections between the anterior inferotemporal cortex (area TE) and CA1 of the hippocampus in monkey.

In addition to the trisynaptic perforant pathway from entorhinal cortex to CA1, there are multiple direct parallel pathways between several cortical regions and CA1. These may be supposed to function cooperatively, in conjunction with the perforant pathway; but neither the functional nor anatomical organization of the extended network is well understood. In this report, we further investigate the connections between anterior inferotemporal cortex (area TE) and CA1. Injections of tracer substances demonstrate that part of the dorsal subdivision of TE sends projections to CA1, but does not receive reciprocating projections back. This contrasts with the bi-directional connections between the more ventral subdivision, TEav, and CA1, as reported by previous studies (and corroborated by tracer injections in this report). The corticohippocampal projections from dorsal TE are likely to be unimodal visual. They partially converge in the posterior portion of CA1 with connections from posterior TE and from the inferior parietal lobule, perhaps constituting a network related to visual or visuospatial processes.

Animals↗

PubMed1996

Differential involvement of group II and group III mGluRs as autoreceptors at lateral and medial perforant path synapses.

1. Previous reports have shown that group III metabotropic glutamate receptors (mGluRs) serve as autoreceptors at the lateral perforant path, but to date there has been no rigorous determination of the roles of other mGluRs as autoreceptors at this synapse. Furthermore, it is not known which of the mGluR subtypes serve as autoreceptors at the medial perforant path synapse. With the use of whole cell patch-clamp and field excitatory postsynaptic potential (fEPSP) recording techniques, we examined the groups of mGluRs that act as autoreceptors at lateral and medial perforant path synapses in adult rat hippocampal slices. 2. Consistent with previous reports, the group III mGluR agonist (D,L)-2-amino-4-phosphonobutyric acid reduced fEPSPs and excitatory postsynaptic currents (EPSCs) in the dentate gyrus. However, the group-II-selective agonist (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) also reduced fEPSPs and EPSCs, suggesting that multiple mGluR subtypes may serve as autoreceptors at perforant path synapses. 3. Selective activation of either medial or lateral perforant pathways revealed that micromolar concentrations of (L)-2-amino-4-phosphonobutyric acid (L-AP4) reduce fEPSPs in lateral but not medial perforant path, suggesting group III involvement at the lateral perforant pathway. Conversely, DCG-IV and 2R, 4R-4-aminopyrrolidine-2,4-dicarboxylate, another group-II-selective mGluR agonist, potently reduced fEPSPs at the medial but not lateral perforant path, suggesting that a group II mGluR may act as an autoreceptor at the medial perforant path-dentate gyrus synapse. 4. Antagonist studies with group-selective antagonists such as (2S,3S,4S)-2-methyl-2-(carboxycyclpropyl)glycine (MCCG; group II) and alpha-methyl-L-AP4 (MAP4; group III) suggest differential involvement of each group at these synapses. The effect of L-AP4 at the lateral perforant path synapse was blocked by MAP-4, but not MCCG. In contrast, the effect of DCG-IV was blocked by application of MCCG, but not MAP4. 5. Previous studies suggest that the effect of L-AP4 at the lateral perforant path synapse is mediated by a presynaptic mechanism. In the present studies, we found that concentrations of DCG-IV that reduce transmission at the medial perforant path synapse reduce paired-pulse depression and do not reduce kainate-evoked currents recorded from dentate granule cells. This is consistent with the hypothesis that DCG-IV also acts by a presynaptic mechanism.

Animals↗

PubMed1991

The amnesic substance 2-deoxy-D-galactose suppresses the maintenance of hippocampal LTP.

Male Wistar rats were intraventricularly injected with 2-deoxy-D-galactose (do-gal), a substance interfering with the fucosylation of glycomacromolecules and impairing memory consolidation in various learning tasks. Do-gal was found to have no influence on the monosynaptically evoked field potential (MEFP) recorded in the dentate gyrus upon stimulation of the perforant pathway. However, hippocampal long-term potentiation (LTP) induced in do-gal-pretreated animals by fractionated tetanization of the perforant pathway declined to control levels 2 h after tetanization, whereas it remained constant for 24 h in saline-treated rats. Similar effects were observed in the CA1 region of hippocampal slices. The results indicate a participation of fucosylated macromolecules in the maintenance of LTP. The possible significance of processes involved in LTP for memory formation is discussed.

Amnesia↗

PubMed1990

Hippocampal formation: anatomy and the patterns of pathology in Alzheimer's disease.

Anatomical studies of the primate brain have shown that the subicular and CA1 allocortices give rise to hippocampal efferents that course to numerous telencephalic and diencephalic targets including other parts of the cortex. The hippocampal formation is damaged heavily in Alzheimer's disease, and is a focal point for pathology. We examined the anteroposterior extent of the hippocampal formation in 52 cases of Alzheimer's disease, 6 cases of other types of dementia and 10 age-compatible controls, to determine the patterns of pathology. We have observed that only certain subfields of the hippocampal formation are affected by cell loss, neurofibrillary tangles and neuritic plaques, while adjacent, anatomically distinct subfields are relatively spared. The portions of the hippocampal formation most crucial for both cortical and subcortical efferent projections are severely affected by Alzheimer pathological changes. Most notable are neurofibrillary tangles in the subicular and CA1 subfields. Layer IV of entorhinal cortex, specifically affected by neurofibrillary tangles. Hippocampal input is also compromised. For example, layer II of entorhinal cortex, which gives rise to perforant pathway hippocampal afferents, also undergoes severe neurofibrillary changes. Neuritic plaques appear in a distinct layer in the terminal zone of the perforant pathway, which carries the majority of corticohippocampal afferents. Plaques are also common in a zone that receives serotoninergic projections from the raphe complex, thus compromising another hippocampal afferent. In sum, these changes disrupt intrinsic and extrinsic hippocampal circuitry at multiple levels, and the pathological dissection deprives the hippocampal formation of many of its efferent and afferent connections with cortical and subcortical structures important in memory-related neural systems. These changes likely contribute to the memory impairment that characterizes Alzheimer's disease and the devastating intellectual decline that ensues.

Aged↗

PubMed1992

Hippocampal opioid peptides and seizures.

We have employed a molecular biological approach to study the dynamic status of hippocampal opioid peptides in response to seizures elicited by different experimental models, such as electroconvulsive shocks (ECS) and amygdaloid kindling. Both ECS- and kindling-induced seizures triggered an initial large release of enkephalin and dynorphin, but produced opposite long-term effects on the biosynthesis of these two peptides, an increase of enkephalin, and a drastic decrease of dynorphin. Electrical stimulation of the perforant pathway produced differential changes of enkephalin and dynorphin, which were identical to those of ECS and kindling. This finding confirmed our hypothesis that the perforant pathway was responsible for the mediation of ECS- and kindling-induced changes in opioid peptide turnover. Strongest evidence indicating a role for opioid peptides in mediating the expression of seizure-related behaviors was found using the kainic acid model, where we saw that hippocampal enkephalin was essential to the expression of kainic acid-induced wet dog shakes (a preconvulsive shaking behavior). Furthermore, it was found that the granular-mossy fiber pathway of the ventral, but not the dorsal, hippocampus was essential for the expression of this shaking behavior. However, destruction of the granular-mossy fiber pathway potentiated the seizures and hippocampal cell loss induced by kainic acid. This unexpected, yet extremely interesting, finding not only distinguished the roles of the granular-mossy fiber pathway in mediating wet dog shakes vs. convulsive seizures, but also challenged the dogma that this granular-mossy fiber pathway is essential for the expression of limbic seizures.

Afferent Pathways↗

PubMed1982

Monosynaptic activation of the hippocampus as a conditioned stimulus: behavioral effects.

The aim of the present study with rats was to show that electrical stimulation of a monosynaptic pathway, whose high plastic potency is well-known, can serve as a conditioned stimulus (CS) in a learning paradigm. Using chronic rats, stimulation of the perforant pathway, which activates the entorhinal cortex input to the dentate gyrus of the hippocampus, was used as the CS in a footshock motivated two-way avoidance task (shuttle box). Among the different stimulation parameters tested, only trains of at least 15 Hz were shown to be effective as a CS, whereas the application of single impulses with a frequency of 1,7 Hz did not result in the establishment of conditioned behavior. Using the 15 Hz-paradigm, in "good learners," the development of reliable conditioned responses started at the end of the first training session (40 trials) and become fairly stable during a further training session, given on the following day. The application of stimulation trains with 100 Hz as a CS led to the development of a high rate of conditioned responses, however, there was also a high level of intertrial reactions. Considering the critical importance of the frequency parameters of the perforant pathway stimulation for the development of conditioned behavior the possible involvement of hippocampal long-term potentiation in behavioral plasticity is discussed. Additionally, it is concluded that this new learning paradigm offers the advantage of concurrent analysis of plastic processes both at the behavioral level and at the level of the synaptic population.

Animals↗

PubMed1988

The association of ventral tegmental area histopathology with adult dementia.

Six cases of adult dementia with mesolimbic pathology are reported. The core clinical syndrome consists of parkinsonism, progressive dementia, and behavioral disturbances (generally depression). The histopathologic findings uniformly include a loss of pigmented neurons in the ventral tegmental area plus neurofibrillary tangles and/or cell loss in the entorhinal cortex and pyramidal cell layer of the hippocampus (perforant pathway). Neuronal depletion in the ventral tegmental area frequently is associated with similar cell loss in the adjacent substantia nigra and in the locus ceruleus. The development of neurofibrillary tangles in the perforant pathway occurs in the absence of senile plaques and is possibly related to diminished dopaminergic input.

Aged↗

PubMed1990

Long-term potentiation and postconditioning potentiation--the same mechanism?

Stimulation of the perforant pathway with different stimulus pattern was used in freely moving rats to elicit classical posttetanic long-term potentiation (LTP), paired-pulse potentiation and postconditioning potentiation which appeared after using the perforant pathway stimulation as a conditioned stimulus in a shuttle-box learning paradigm. The changes in amplitude and latency of the population spike were compared. While in all experimental groups an amplitude potentiation of the population spike occurred, the changes in its latency were different. Only after inducing posttetanic LTP the latency decreased together with the amplitude increase. Postconditioning potentiation in good learners, however, was accompanied by a latency increase. In poor learners, on the other hand, a latency decrease immediately after the training session was the only change. Paired-pulse potentiation which occurred with an interstimulus interval of 50 ms, was also accompanied by a latency increase. The results indicate that the mechanism of learning-related potentiation cannot only be long-term potentiation. Even if assuming an involvement of LTP in the synaptic changes occurring after learning, it seems to be modified or overlapped by another alteration. Considering the similarity to observations after paired-pulse potentiation, a recruiting phenomenon can be assumed to contribute to these differences.

Animals↗

PubMed2001

Expression of type I adenylyl cyclase in intrinsic pathways of the hippocampal formation of the macaque (Macaca nemestrina).

The mossy fiber pathway of the hippocampal formation and type 1 adenylyl cyclase (AC1) have been implicated in long-term potentiation and memory function. Using immunohistochemical labeling and light microscopy we demonstrated intense labeling of AC1 in the mossy fibers and less intense labeling in the molecular layers of both the dentate gyrus and fields CA1, CA2 and CA3 of the hippocampus, i.e. in terminal fields of the perforant pathway. These findings indicate that, in the non-human primate, AC1 is found in the mossy fibers and in terminal fields of the perforant pathway where it may play a role in long term potentiation similar to that demonstrated in the rodent.

Adenylyl Cyclases↗