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PubMed1992

Tyrosine hydroxylase-like (TH) immunoreactivity in Parkinson's disease and Alzheimer's disease.

We used tyrosine hydroxylase immunoreactivity (TH) to mark dopaminergic fibers in cerebral tissue from adult persons with Parkinson's disease (PD) or Alzheimer's disease (AD). In the PD cases we found a loss of dopaminergic neurons in the ventral tegmental area (VTA), severely reduced TH fibers in dopaminergic terminal fields (particularly in the hippocampal perforant pathway) and neurofibrillary tangles (NFT), that occurred only in the perforant pathway. In contrast, AD cases were characterized by a lack of significant neuron loss in the VTA and by mild loss of TH fibers. A decreased dopaminergic innervation of the perforant pathway in cases of PD appears to be associated with the occurrence of NFT in these structures.

Alzheimer Disease↗
PubMed1996

Tiagabine prevents seizures, neuronal damage and memory impairment in experimental status epilepticus.

A novel antiepileptic drug, tiagabine ((R)-N-[4,4-di-(3-methylthien-2-yl) but-3-enyl] nipecotic acid hydrochloride), was studied in rats in order to determine its efficacy in preventing seizures, seizure-induced neuronal damage and impairment of spatial memory in the perforant pathway stimulation model of status epilepticus. In pilot experiments, administration of tiagabine (50, 100 or 200 mg/kg/day) with subcutaneously implanted Alzet osmotic pumps led to a dose-dependent increase in tiagabine concentrations in the serum and brain. Two days of tiagabine treatment at a dose range of 50-200 mg/kg/day did not change the levels of gamma-aminobutyric acid (GABA), glutamate or aspartate in cisternal cerebrospinal fluid (CSF) compared to the controls. In the pentylenetetrazol test, the maximal anticonvulsive effect of tiagabine administered via osmotic pumps was achieved already with a dose of 50 mg/kg/day. In the perforant pathway model of status epilepticus, subchronic treatment with tiagabine (Alzet pumps, 50 mg/kg/day) completely prevented the appearance of generalized clonic seizures during stimulation (P < 0.001). In the same rats, tiagabine treatment reduced the loss of pyramidal cells in the CA3c and CA1 fields of the hippocampus (P < 0.05) but not the loss of somatostatin immunoreactive neurons in the hilus. Two weeks after perforant pathway stimulation, the tiagabine-treated rats performed better in the Morris water-maze test than the vehicle-treated rats did (P < 0.001). Our results show that tiagabine treatment reduces the severity of seizures in the perforant pathway stimulation model of status epilepticus. Possibly associated with the reduction in seizure number and severity, tiagabine treatment also reduced seizure-induced damage to pyramidal cells in the hippocampus as well as the impairment of the spatial memory associated with hippocampal damage.

Animals↗
PubMed1975

Some connections of the entorhinal (area 28) and perirhinal (area 35) cortices of the rhesus monkey. III. Efferent connections.

In this investigation the efferent projections of the entorhinal and prorhinal cortices relative to their sites of termination in the hippocampus and fascia dentata were investigated in the rhesus monkey using experimental silver impregnation methods. Contrary to the often cited observations of Lorente de No, all entorhinal areas, including the laterally lying prorhinal cortex, were found to give rise to the perforant pathway, and furthermore, each cytoarchitectonically defined subarea was found to contribute a unique component. These perforant pathway components terminate in distinct regions of the dendritic zones of the fascia dentata granule cell and the hippocampal pyramidal cell. A previously undescribed projection to the prosubiculum and hippocampus has been found to originate from the prorhinal cortex which forms the medial wall of the rhinal sulcus along the lateral-most portion of the entorhinal cortex in the rhesus monkey. These results, in conjunction with our previous observations regarding differential afferents to the entorhinal cortex, indicate that specific afferent and efferent connections characterize each cytoarchitectonically definable subareas of this periallocortical region. Additionally, they indicate that the perforant pathway might be conceptualized as the final link in a multisynaptic series of connections instrumental in providing the hippocampus with potential modality specific and multimodal input.

Animals↗
PubMed1998

Finasteride blocks the reduction in ictal activity produced by exogenous estrous cyclicity.

The purpose of the present study was to examine seizure activity during reduced 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) production. Ovariectomized Long-Evans rats were stereotaxically implanted with bipolar electrodes above the perforant pathway; silastic implants filled with estradiol-17-benzoate (EB) and progesterone were inserted subcutaneously to mimic diestrus. Estrus was then induced in half of these animals by injection of EB (30 microg) and progesterone (2.5 mg), 48 and 4 h, respectively, prior to perforant pathway stimulation. Half of the estrous and diestrous rats also received a 5alpha-reductase inhibitor, finasteride (50 mg/kg), 6 h prior to perforant pathway stimulation. The estrous condition was associated with reduced number and duration of partial seizures, improved performance on a Morris water maze recovery of function test, reduced neuronal loss in the hilar region of the hippocampus, and elevated central and plasma 3alpha,5alpha-THP, compared to estrus+finasteride, diestrus+vehicle and diestrus+finasteride conditions, which did not differ from each another. These data suggest antiseizure effects of estrus may be caused, in part, by the action of 3alpha,5alpha-THP and that the precipitous decline in 3alpha,5alpha-THP may restore seizure threshold to control levels.

5-alpha Reductase Inhibitors↗
PubMed2002

Relationship in the formation process between neurofibrillary tangles and Lewy bodies in the hippocampus of dementia with Lewy bodies brains.

Using tau immunohistochemistry and alpha-synuclein immunohistochemistry, we quantitatively investigated the most frequent sites and the formation process of neurofibrillary tangles (NFT) and Lewy bodies (LB) in the hippocampus from 20 patients with dementia with Lewy bodies (DLB). NFT were most frequently found in the CA2 and the subiculum-pre-CA1, while LB were most frequently found in the CA3-4 and the subiculum-pre-CA1. In the intrahippocampal routes of the perforant pathway, tau immunoelectron microscopy demonstrated distal axons containing aggregated tau-positive microtubules, while alpha-synuclein immunoelectron microscopy revealed terminal axons containing aggregated alpha-synuclein-positive tubular or filamentous components. These findings suggest that NFT and LB are first formed in the CA2 and the CA3-4 related to degeneration of the nonperforating route of the perforant pathway, respectively, and subsequently in the subiculum-pre-CA1 chiefly related to degeneration of the perforating route. Coexistence of NFT and LB in the same neurons was found most frequently in the subiculum-pre-CA1. In addition, coexistence of tau and alpha-synuclein was found in terminal axons of the perforant pathway, and tau accumulated not in paired helical filaments but in the periphery of alpha-synuclein-positive components immunoelectron-microscopically, suggesting that alpha-synuclein stimulates the accumulation of phosphorylated tau in terminal axons.

Aged↗
PubMed1998

Differential presynaptic and postsynaptic expression of m1-m4 muscarinic acetylcholine receptors at the perforant pathway/granule cell synapse.

A family of muscarinic acetylcholine receptor proteins mediates diverse pre- and postsynaptic functions in the hippocampus. However the roles of individual receptors are not understood. The present study identified the pre- and postsynaptic muscarinic acetylcholine receptors at the perforant pathway synapses in rat brain using a combination of lesioning, immunocytochemistry and electron microscopic techniques. Entorhinal cortex lesions resulted in lamina-specific reductions of m2, m3, and m4 immunoreactivity in parallel with the degeneration of the medial and lateral perforant pathway terminals in the middle and outer thirds of the molecular layer, respectively. In contrast, granule cell lesions selectively reduced m1 and m3 receptors consistent with degeneration of postsynaptic dendrites. Direct visualization of m1-m4 by electron microscopic immunocytochemistry confirmed their differential pre- and postsynaptic localizations. Together, these findings provide strong evidence for both redundancy and spatial selectivity of presynaptic (m2, m3 and m4) and postsynaptic (m1 and m3) muscarinic acetylcholine receptors at the perforant pathway synapse.

Animals↗
PubMed1988

Development of intersecting CNS fiber tracts: the corpus callosum and its perforating fiber pathway.

What are the mechanisms acting during development at points of intersection of central nervous system fiber tracts which influence the direction taken by a population of growing axons? In order to address this question, the ontogeny of the intersecting rostral corpus callosum and its perforating fiber pathway (PF), and the microenvironment through which these fiber systems grow, were examined in a series of mouse embryos and early postnates. Our results show that the perforating fibers are identifiable in silver-stained sections between embryonic days (E) 15 and 16, at least 1 day prior to the initial appearance of the callosal projection. Soon after the PF can be identified, a dense accumulation of subventricular cells surrounds the PF at a point just ventral to the location where the callosum and PF will intersect (i.e., at the corticoseptal boundary). Callosal axons, which are present at the point of intersection beginning on E17, do not joint the perforating fibers, nor do they appear to penetrate the underlying population of subventricular cells. Instead, the callosal fibers turn across the PF and enter the contralateral cerebral hemisphere. Thus, the intersection of the callosal and perforating fiber systems during development may be related both to the sequential development of each pathway and to the altered nonneuronal environment at the point of intersection.

Animals↗
PubMed1984

Effects of chemical and surgical lesions on levels of chromatographically identified enkephalin-like peptides in rat hippocampus.

The present study quantitates the content of Met- and Leu-enkephalin in the rat hippocampus, and provides information on the localization of the enkephalins within the hippocampal neuronal circuitry. Several enkephalins were identified in rat hippocampus, two of which are shown to be Met- and Leu-enkephalin. The levels of these enkephalins, and of other unidentified enkephalin-related peptides, were not depleted by intrahippocampal colchicine, which destroyed the great majority of the hippocampal granule cells and the associated mossy fiber pathway. Entorhinal cortical lesions ablating the perforant pathway input to the hippocampus also did not significantly lower enkephalin levels in the hippocampus. Unilateral fimbrial transection caused a significant bilateral increase in both Met- and Leu-enkephalin levels. This may result from loss of a stimulatory input to putative enkephalin containing interneurons within the hippocampus. The extents of all lesions were verified histologically in hippocampi used for biochemical analysis. No evidence was seen for the presence of enkephalins in the perforant pathway, nor in nerve fibers in the fimbria/fornix, which provide the other main source of hippocampal efferents. The enkephalins are likely to be intrinsic to the hippocampus, in which neuronal cell bodies containing enkephalin-like immunoreactivity have been extensively reported.

Animals↗
PubMed2006

Neuronal hyperactivity induces astrocytic expression of neurocan in the adult rat hippocampus.

Extracellular matrix molecules are involved in the cellular functions of proliferation, migration, morphological differentiation, and synaptic plasticity. One candidate molecule of the extracellular matrix is the chondroitin sulfate proteoglycan neurocan. To determine whether neurocan expression is regulated by neuronal activity in the adult rat brain, we studied changes in hippocampal neurocan mRNA and protein expression following electrical stimulation of the perforant pathway in urethane-anesthetized rats. After 24 h of intermittent, unilateral 20 Hz stimulation, in situ hybridization revealed increased neurocan mRNA in glial fibrillary acidic protein (GFAP)-positive astrocytes bilaterally in all hippocampal subfields. These changes were quantified in the dentate molecular layer, the termination zone of the perforant pathway, using laser microdissection in combination with quantitative reverse transcription-polymerase chain reaction (RT-PCR). Immediately after 24 h stimulation, a six-fold upregulation was detected, which returned to control levels by 3 days post-stimulation. Neurocan immunoreactivity was similarly upregulated bilaterally. Immunostaining intensity reached a maximum by 4 days and returned to control levels by 14 days. The pattern of neurocan expression in the hippocampus depended on the intensity and duration of electrical stimulation. Under conditions of less intense afferent stimulation (4-24 h of 2.0 Hz paired-pulse stimulation, interpulse interval 40 ms), increases in neurocan mRNA and immunoreactivity were restricted to the ipsilateral termination zone of the stimulated perforant pathway. This layer-specific neurocan upregulation was not affected by intraperitoneal application of the NMDA-receptor antagonist MK-801. In conclusion, our data indicate that synaptic activity regulates the astrocytic expression of neurocan in a graded manner.

Animals↗
PubMed1996

Potentiation effects in the dentate gyrus of pentylenetetrazol-kindled rats.

The study examines changes in the function of perforant pathway dentate granule cell synapses after pentylenetetrazol (PTZ) kindling. Field potentials evoked in the dentate area by test stimuli to the perforant pathway were recorded in freely moving rats at different times after injection of PTZ. In fully kindled animals, but not in sham-kindled controls, subconvulsive test doses of PTZ induced long-lasting potentiation of the population spike. Also, potentiation was not induced in naive controls injected with equieffective doses of the convulsant. The slope function of the field EPSP was depressed 90-120 min after PTZ administration, in both kindled and control animals, indicating that this was an effect of acute-injected PTZ. Later on, only in kindled animals that showed seizure stages 4 or 5 did it increase in parallel with the population spike potentiation. Finally, when compared to controls the kindled animals showed a greater pop spike potentiation induced by moderate tetanization of the perforant pathway. The model offers the possibility of differentiating between acute effects of the convulsant drug and kindling-related changes in neuronal plasticity.

Animals↗
PubMed1995

The neurosteroid 3 alpha, 5 apha-THP has antiseizure and possible neuroprotective effects in an animal model of epilepsy.

Some anticonvulsant drugs may suppress seizures by enhancing activity of GABAergic systems. Progesterone (P)'s anti-convulsant and neuroprotective effects may be due to the steroid's actions on GABAA-benzodiazepine receptor complexes (GBRs) rather than intracellular progestin receptors (PRs), as many P metabolites have a greater effect in vitro on benzodiazepine binding and Cl-flux than P, but poor affinity for PRs. If P's actions are due to metabolism to a progestin more potent at GBRs, then systemic administration of one of those P metabolites should also prevent CNS damage. To test this hypothesis male rats were implanted with a bipolar electrode, aimed above the perforant pathway. Experimental animals received the 5 alpha-reduced P metabolite most effective at GBRs, 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha,5 alpha-THP) 2.5 mg/kg s.c., 3 h prior to perforant pathway stimulation, while control animals received sesame oil vehicle. The duration of chewing and drooling and the incidence of wet dog shakes, partial and full seizures were reduced during perforant pathway stimulation in animals pre-treated with 3 alpha,5 alpha-THP compared to vehicle. Two weeks later, animals pre-treated with 3 alpha,5 alpha-THP had shorter latencies and distances to find a hidden platform in a Morris Water maze task. 3 alpha,5 alpha-THP pre-treatment also reduced damage to CA1 and CA3 layers of the hippocampus and preserved the number of neurons in the hilar region. These data indicate that the neurosteroid metabolite of P, 3 alpha,5 alpha-THP, can have anticonvulsant and may have neuroprotective effects in an animal model of epilepsy. Further, these data suggest that the mechanism of P's protective and anticonvulsant effects may be via GBRs rather than PRs.

Animals↗
PubMed1997

Effect of GABA(B) receptors on synaptic interactions in dentate gyrus granule neurons of the rat.

Dendritic arborization permits convergence of synaptic inputs and their integration in single neurons. The granule neuron in the dentate gyrus represents a relatively simple example where anatomically and functionally distinct medial and lateral perforant pathways terminate on different regions of the dendritic tree. High-frequency stimulation of either pathway alone results in the induction of long-term potentiation. However, whether the potentiated synapses in different parts of the dendrites interact is not known. In this study we have compared long-term potentiation and synaptic interactions in the lateral and medial perforant pathways in the "disinhibited" hippocampal slice preparation in the presence of the GABA(A) receptor blocker bicuculline. The data show that the magnitude of long-term potentiation induced by tetanic stimulation was similar in both pathways, but differences between the two pathways were revealed after two or more tetanizations. A significantly smaller capacity for further long-term potentiation in the lateral, as compared to the medial, perforant pathway was found and can be attributed to stronger postsynaptic GABA(B) inhibition in distal dendrites of granule neurons. Blockade of GABA(B) inhibition with CGP36742 (100 microM) unmasked additional long-term potentiation in the lateral pathway. Presynaptically, GABA(B) receptors produced a short-lasting heterosynaptic depression in the medial pathway, which was reduced by CGP36742. Coincident activation of the two pathways boosted long-term potentiation only in the medial pathway. We propose that the interactions between the two pathways are orchestrated to maximize associative long-term potentiation in the medial pathway; this may be important for types of learning attributed to the hippocampus.

Animals↗
PubMedDate not supplied

[Electrophysiologic study of the functional characteristics of cortical input into the hippocampus of newborn rabbits].

Functional maturation of perforant pathway synapses on neurones of the dorsal hippocampus and fascia dentata was examined in unanaesthetized rabbits 1 to 25 days of age, by means of extracellular recording of fiold potentials and of neuronal responses to electrical stimulation of the cortical afferent input. In the areas CA1 and CA3 of the dorsal hippocampus, field potentials, activating and inhibitory neuronal responses to stimulation of the perforant pathway with single impulses were recorded from the first day of the postnatal life, while short-latency responses of the fascia dentata were revealed later--at the end of the first week or the beginning of the second week of life. The data obtained suggest that in rabbits, the synapses of the perforant pathway are functioning from the first days after birth. The postnatal development of the cortical afferent input to the hippocampus is related to the maturation of the dentate gyrus.

Animals↗
PubMed2002

Disruption of corticocortical connections ameliorates amyloid burden in terminal fields in a transgenic model of Abeta amyloidosis.

We demonstrated previously that amyloid precursor protein (APP) is anterogradely transported from the entorhinal cortex (ERC) to the dentate gyrus via axons of the perforant pathway. In the terminal fields of these inputs, APP undergoes proteolysis to generate C-terminal fragments containing the entire amyloid beta peptide (Abeta) domain. The present study was designed to test the hypothesis that APP derived from ERC neurons is the source of the Abeta peptide deposited in the hippocampal dentate gyrus in Alzheimer's disease (AD) and in transgenic mice with Abeta amyloidosis. We used mice harboring two familial AD-linked genes (human APP Swedish and presenilin1-DeltaE9), in which levels of Abeta (especially Abeta(42)) are elevated, leading to the formation of amyloid plaques, and lesioned the ERC to interrupt the transport of APP from ERC to hippocampus. Our results show that, on the side of ERC lesion, numbers of APP-immunoreactive dystrophic neurites and Abeta burden were significantly reduced by approximately 40 and 45%, respectively, in the dentate gyrus compared with the contralateral side. Reductions in APP and Abeta were more substantial in the molecular layer of the dentate, i.e., a region that contains the ERC terminals, and were associated with a parallel decrease in total APP and Abeta measured by Western blot and ProteinChip immunoassays. Silver and thioflavine staining confirmed the reduction of amyloid plaques on the side of deafferentation. These results are consistent with the hypothesis that ERC may be the primary source of amyloidogenic Abeta in the dentate gyrus, and they suggest an important role of corticocortical and corticolimbic forward connections in determining patterns of amyloid deposition in AD.

Amyloid↗
PubMed1994

Fucose and fucose-containing sugar epitopes enhance hippocampal long-term potentiation in the freely moving rat.

Male Wistar rats were intrahippocampally injected with L-fucose and the sugar epitope 2'-fucosyl-lactose prior to induction of long-term potentiation (LTP). Both substances had only a minimal and short-lasting depressive effect on the monosynaptically evoked field potential recorded in the dorsal blade of the dentate gyrus of freely moving rats upon stimulation of the perforant pathway. However, LTP induced by fractionated tetanization of the perforant pathway, which declined within 24 h in control animals injected with Lactose, remained at the initial level even 48 h after tetanization (difference to the control group significant with P < 0.01). The results support earlier findings which have indicated a participation of fucosylated macromolecules in the maintenance of LTP. Different molecular mechanisms concerning the effect of both substances and the significance of the data in elucidation of the relationship between LTP and memory formation are discussed.

Animals↗
PubMed2006

Semaphorin 6C leads to GSK-3-dependent growth cone collapse and redistributes after entorhino-hippocampal axotomy.

We studied the changes in the distribution of a specific variant of Semaphorin Y/6C (Sema6C) in mouse forebrain after axotomy of the entorhino-hippocampal perforant pathway. We found this isoform to be widely expressed during development, remaining in the adult and showing variations in distribution when the perforant pathway was axotomized. These changes were detected in both the hippocampal and entorhinal cortices. Sema6C1 immunoreactivity (IR) was high in the stratum radiatum of the hippocampus proper and the inner molecular layer of the dentate gyrus; the entorhinal cortex showed Sema6C1 IR in both cell bodies and in fibers of the II/III and V/VI layers. In axotomized animals, the IR of the ipsilateral, but not the contralateral, hemisphere showed that IR had moved into the stratum lacunosum-moleculare, the medial molecular layer of the dentate gyrus and the fibers, but not the cell bodies, of the entorhinal cortex. These results were not reproduced after lateral axotomy of the fimbria fornix, indicating a specific role for Sema6C variants in the generation and/or stability of entorhino-hippocampal synapses. Growth cone collapse of entorhinal and pyramidal neurons, as well as activation of glycogen synthase kinase-3 (GSK-3) through depletion of the inactive pool, induced by diffusible Sema6C1 further supports this view.

Analysis of Variance↗
PubMed2001

Development of long-lasting potentiation effects in the dentate gyrus during pentylenetetrazol kindling.

In the present study kindling was induced in rats by repeated intraperitoneal injection of pentylenetetrazol (PTZ) once every 48 h. The resulting seizure stages were registered after each PTZ application. The development of PTZ-induced kindling and the time course of possible potentiation effects in the dentate gyrus were examined. The efficacy of perforant pathway transmission to the granule cells was tested in every second kindling session by measuring the monosynaptic evoked field potentials recorded in the dentate gyrus following single test stimuli of the perforant pathway at different times after PTZ injection in freely moving animals. The data suggest that establishment of a PTZ kindling is associated with the development of long-lasting potentiation of the field potentials. After completion of kindling it was demonstrated that kindled rats also show a diminished learning performance. The relationship between the development of potentiation phenomena in hippocampal substructures and learning impairment is discussed.

Animals↗
PubMed1975

Crossed pathways from the entorhinal area to the fascia dentata. II. Provokable in rats.

In the rat thhe perforant pathways from the entorhinal area normally innervate the fascia dentata only ipsilaterally. However, unilateral ablation of the entorhinal area (deentorhination) induces the formation of an anomalous crossed projection from the intact contralateral entorhinal area to the septal portion of the deafferented fascia dentata. After deentorhination of rats aged 1-30 days the organization of this projection was analyzed (a) by producing secondary lesions in the intact entorhinal area of perforant paths and observing the results anterograde degeneration with Fink-Heimer silver impregnation techniques, and (b) by staining with Timm's sulfide silver method whichmakes the terminal fields of afferent systems stand out in different tones of colors. Both methods showed the crossed entorhino-dentate projection to consist of two separable components. They were named the crossed medial perforant path and the crossed lateral perforant path, corresponding to their similarity in origin, dendritic localization of termination and Timm stainability to the ordinary, uncrossed medial and the lateral perforant pathways (MPP and LPP) which arise in the medial and lateral parts of the entorhinal cortex, respectively. Similarly induced crossed projections were demonstrated to the subcallosal continuation of fascia dentata, the fasciola cinerea. The heaviest terminal field of the crossed entorhino-dentate projection which was found in the most rostral and medial parts of the deafferented fascia dentata correlated with a lack of expected aberrant extension into theMPP and LPP terminal zones of commissural and ipsilateral hippocampodentate fibers. In Fink-Heimer preparations there was little variation in the distribution of the aberrant crossed sustems over the range of ages studied although the chronic operations performed earliest postnatally (5 days) tended to produce the heaviest representation. This latter observation appeared consistent with changes in the Timm staining pattern of the deafferented fascia dentata, since with an increase in age at the primary lesion from 5 to 14 days there was no increase in the spread into the fascia dentata of Timm stainable axon ter minals from CA3, interpreted as a sign of fewer crossed entorhinal afferents succeeding in a presumable competition with the CA3-derived system for available terminal space.

Age Factors↗