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PubMed1999

Differential induction of c-Fos, c-Jun and Jun B in the rat central nervous system following unilateral entorhinal cortex lesion.

In order to identify some of the molecular mechanisms that occur after a central nervous system trauma, the immediate early gene encoded proteins c-Fos, c-Jun and Jun B were analysed by immunocytochemistry following unilateral entorhinal cortex lesion (controls, 30 min, 2, 5, 12 and 24 h, two, six, 10 and 14 days, four weeks and six months postlesion). In the dentate gyrus, c-Fos was induced in some supragranular neurons (30 min), massively expressed in granule cells ipsilaterally to the lesion (2 h), expressed in hilar neurons (5 h and two days) and was absent at all later stages. A basal expression of c-Jun was found in dentate granule cells of controls, which was strongly increased on the lesion side (2 h) and on the side contralateral to the lesion (12 h). c-Jun expression returned to control levels by 24 h. Jun B was induced in granule cells ipsilateral to the lesion within 2 h and was back to control levels by 5 h. In the lateral septal area, c-Fos and c-Jun were induced 30 min postlesion and decreased rapidly thereafter. In the cerebral cortex, a widespread induction of c-Fos and c-Jun occurred within 30 min after entorhinal cortex lesion and this up-regulation lasted until two days postlesion. These data indicate that electrolytic lesion of the entorhinal cortex leads to a rapid and widespread induction of c-Fos, c-Jun and Jun B. Within the denervated fascia dentata, some of these changes may be linked to the reorganization processes following the lesion. Alternatively, the alterations in immediate early gene expression reported here may be due to changes in synaptic activity or postlesional seizures which occur in this lesioning paradigm.

Animals↗
PubMed2003

Analysis of glial acidic fibrillary protein in the human entorhinal cortex during aging and in Alzheimer's disease.

Glial fibrillary acidic protein, GFAP, is a major intermediate filament protein of glial cells and major cytoskeletal structure in astrocytes. The entorhinal cortex has a key role in memory function and is one of the first brain areas to reveal hallmark structures of Alzheimer's disease and therefore provides an ideal tissue to investigate incipient neurodegenerative changes. Here we have analyzed age- and disease-related occurrence and composition of GFAP in the human entorhinal cortex by using one- and two-dimensional electrophoresis, Western blots and immunocytochemistry combined with confocal microscopy. A novel monoclonal antibody, GF-02, was characterized that mainly reacted with intact GFAP molecules and indicated that more acidic and soluble GFAP forms were also more susceptible to degradation. GFAP and vimentin increased with aging and in Alzheimer's disease (AD). Two-dimensional electrophoresis and Western blots revealed a complex GFAP pattern, both in aging and AD with different modification and degradation forms. Immunohistochemistry indicated that reactive astrocytes mainly accumulated in relation to neurofibrillary tangles and senile plaques in deeper entorhinal cortex layers. GFAP may be used as an additional but not exclusive diagnostic tool in the evaluation of neurodegenerative diseases because its levels change with age and respond to senile plaque and tangle formation.

Aged↗
PubMed1997

Effects of D-cycloserine and aniracetam on spatial learning in rats with entorhinal cortex lesions.

A great body of behavioural and neurophysiological evidence suggests that excitatory amino acids are involved in mechanisms of learning and memory. Moreover, degeneration of glutamatergic pathways may underlie the cognitive deficits seen in various disorders such as Alzheimer's dementia. As direct stimulation of glutamatergic receptors with agonists may increase the risk of toxicity and accelerate neuropathological changes, a more valid approach seems to be positive modulation of glutamatergic receptors that may reverse the symptoms with a lower risk of excitotoxic effects. Such a possibility offered by partial agonists of the strychnine-insensitive glycine site of the NMDA receptor (Gly-B site) or positive modulators of AMPA receptors, such as aniracetam. In the present study, the effects of d-cycloserine and aniracetam were tested in two animal models of cognitive deficits (entorhinal cortex lesion-induced deficits evaluated in the radial maze and scopolamine-induced amnesia evaluated in passive avoidance test). D-cycloserine (6 mg/kg, for 10 days) had no effect on spatial working memory deficit induced by entorhinal cortex lesions. It did, however, reverse scopolamine-induced deficits in the passive avoidance test when given acutely at the same dose. In contrast, aniracetam (50 mg/kg, for 10 days) produced beneficial effects in the radial maze test in rats with entorhinal cortex lesions, but given at the same dose acutely did not influence scopolamine-induced amnesia. The positive effect of d-cycloserine against scopolamine-induced amnesia may be probably related to the cholinergic-glutamatergic interaction in the hippocampus. The negative data obtained with d-cycloserine in the model of entorhinal cortex lesions-induced cognitive deficits could be taken as a hint that it is probably not suitable for the symptomatological therapy of Alzheimer's disease. The mechanism of positive action of aniracetam cannot be explained on the basis of AMPA receptor modulation, as the dose used (50 mg/kg) is well below that required for the effect at AMPA receptors. Other actions such as peripheral effects or modulation of metabotropic receptors seem more likely.

Animals↗
PubMed1985

Knife cuts of entorhinal cortex: effects on development of amygdaloid kindling and seizure-induced decrease of muscarinic cholinergic receptors.

This report examines the effect of transection of the entorhinal hippocampal projection on amygdaloid kindling. We found that: bilateral knife cuts of entorhinal cortex but not of dorsal neocortex antagonize the development of amygdaloid kindling; and bilateral knife cuts of entorhinal cortex eliminate the seizure-induced decrease in number of muscarinic receptors of dentate granule cells. We suggest the following interpretations of these data: the hippocampal formation circuitry facilitates the development of amygdaloid kindling; and the decline of muscarinic receptors after kindled seizures is due to excessive activation of granule cells by axons from entorhinal cortex, a noncholinergic afferent.

Amygdala↗
PubMed1997

Involvement of the hippocampus, amygdala, entorhinal cortex and posterior parietal cortex in memory consolidation.

A total of 182 young adult male Wistar rats were bilaterally implanted with cannulae into the CA1 region of the dorsal hippocampus and into the amygdaloid nucleus, the entorhinal cortex, and the posterior parietal cortex. After recovery, the animals were trained in a step-down inhibitory avoidance task. At various times after training (0, 30, 60 or 90 min) the animals received a 0.5-microliter microinfusion of vehicle (saline) or 0.5 microgram of muscimol dissolved in the vehicle. A retention test was carried out 24 h after training. Retention test performance was hindered by muscimol administered into both the hippocampus and amygdala at 0 but not at 30 min posttraining. The drug was amnestic when given into the entorhinal cortex 30, 60 or 90 min after training, or into the parietal cortex 60 or 90 min after training, but not before. These findings suggest a sequential entry in operation, during the posttraining period, of the hippocampus and amygdala, the entorhinal cortex, and the posterior parietal cortex in memory processing.

Amygdala↗
PubMed2006

Spatial representation and the architecture of the entorhinal cortex.

It has recently been recognized that the entorhinal cortex has a crucial role in spatial representation and navigation. How the position of an animal is computed within the entorhinal circuitry remains to be determined, but the architectural organization of this brain area might provide some clues. Here, we review three organizational principles--recurrent connectivity, interlaminar connectivity and modular organization--and propose how each of them might contribute to the emergence and maintenance of positional representations in entorhinal neural networks.

Animals↗
PubMed1988

Lesions of entorhinal cortex produce a calpain-mediated degradation of brain spectrin in dentate gyrus. II. Anatomical studies.

Lesions of the various afferents to the hippocampus have been widely used to investigate the mechanisms underlying growth and degeneration in adult mammalian CNS. It has been proposed that disturbances in intracellular calcium and activation of calcium-dependent proteases represent key steps in producing come of the consequences of the lesions. In this study, we show that lesions of the entorhinal cortex or of the commissural pathway result in profound changes in the distribution of brain spectrin. At 2 days after lesions of the entorhinal cortex, immunoreactivity to spectrin is markedly increased in the outer molecular layer (OML) of the dentate gyrus; conversely at 2 days after commissural lesions, immunoreactivity to the same antigen is increased in the inner molecular layer. The increase in immunoreactivity to spectrin varies with survival time after lesions of the entorhinal cortex. By 24 h post lesion, the increase is homogeneous across the OML, and becomes more intense by 48 h. Between 1 and 3 weeks the increase is much less than at 48 h and is concentrated at the inner border of the OML. Pretreatment of the animals with the calpain inhibitor leupeptin reduces the increase in spectrin immunoreactivity normally seen 48 h after the lesion of the entorhinal cortex. Changes in the pattern of immunoreactivity to GFAP are very different to that seen with spectrin antibodies and are consistent with the known modifications in astrocytes that follow lesions of hippocampal afferents.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Neuropeptide Y inhibits in vitro epileptiform activity in the entorhinal cortex of mice.

Previous studies show that neuropeptide Y (NPY) inhibits in vitro seizures in rodent hippocampus. Here, we explored the effect of NPY application on epileptiform discharges induced by perfusion with magnesium-free solution in slices of entorhinal cortex from two different mouse strains. NPY significantly reduced the duration of epileptiform discharges with a peak effect of 36-50%. This is the first study showing anti-epileptiform effect of NPY in the entorhinal cortex and also the first evidence that NPY inhibits seizures in a cortical region in mice. The entorhinal cortex has a central role in transferring information between the hippocampus and the rest of the brain. Therefore our data further strengthen the concept of NPY and its receptors as widespread regulators of epileptiform activity and as a potential future target for antiepileptic therapy.

Action Potentials↗
PubMed1996

Potassium currents in acutely isolated neurons from superficial and deep layers of the juvenile rat entorhinal cortex.

Using the whole-cell configuration of the patch-clamp technique, outward K+ currents were recorded from acutely isolated stellate cells from superficial layers, and pyramidal cells from deep layers, of the entorhinal cortex of juvenile rats. In both cell types a fast transient and a slowly inactivating outward K+ current were obtained. Whereas the fast transient current (IA) activated at potentials beyond -50 mV, the activation threshold of the slowly inactivating current (IK) was measured at -40 mV in stellate and pyramidal cells. In stellate cells a half-maximal inactivation was estimated for IA at -80.4 mV and for IK at -74.6 mV, and in pyramidal cells at -81.1 mV and -71.8 mV, respectively. IK of both cell types were reduced by tetraethylammonium (TEA) in a concentration-dependent manner. IC50 values were 0.8 mM TEA for stellate cells and 1.1 mM TEA for pyramidal cells. Superfusion of 4-aminopyridine resulted in a reduction of the amplitudes of IA and IK as well as in an acceleration of the inactivation time constants of IA. Extracellularly applied dendrotoxin did not have any effect on entorhinal cortex K+ currents. In summary, kinetic and pharmacological properties of IA as well as of IK are rather similar in superficial-layer stellate and deep-layer pyramidal cells acutely isolated from the entorhinal cortex of juvenile rats.

4-Aminopyridine↗
PubMedDate not supplied

Increasing acetylcholine levels in the hippocampus or entorhinal cortex reverses the impairing effects of septal GABA receptor activation on spontaneous alternation.

Intra-septal infusions of the gamma-aminobutyric acid (GABA) agonist muscimol impair learning and memory in a variety of tasks. This experiment determined whether hippocampal or entorhinal infusions of the acetylcholinesterase inhibitor physostigmine would reverse such impairing effects on spontaneous alternation performance, a measure of spatial working memory. Male Sprague-Dawley rats were given intra-septal infusions of vehicle or muscimol (1 nmole/0.5 microL) combined with unilateral intra-hippocampal or intra-entorhinal infusions of vehicle or physostigmine (10 microg/microL for the hippocampus; 7.5 microg/microL or 1.875 microg/0.25 microL for the entorhinal cortex). Fifteen minutes later, spontaneous alternation performance was assessed. The results indicated that intra-septal infusions of muscimol significantly decreased percentage-of-alternation scores, whereas intra-hippocampal or intra-entorhinal infusions of physostigmine had no effect. More importantly, intra-hippocampal or intra-entorhinal infusions of physostigmine, at doses that did not influence performance when administered alone, completely reversed the impairing effects of the muscimol infusions. These findings indicate that increasing cholinergic levels in the hippocampus or entorhinal cortex is sufficient to reverse the impairing effects of septal GABA receptor activation and support the hypothesis that the impairing effects of septal GABAergic activity involve cholinergic processes in the hippocampus and the entorhinal cortex.

Acetylcholine↗
PubMed2005

Cholinergic deafferentation of the entorhinal cortex in rats impairs encoding of novel but not familiar stimuli in a delayed nonmatch-to-sample task.

Acetylcholine may regulate working memory for novel stimuli by activating intrinsic mechanisms for sustained spiking in entorhinal cortical neurons, which have been demonstrated in slice preparations of the entorhinal cortex. Computational modeling demonstrates that loss of the cholinergic activation of intrinsic mechanisms for sustained activity could selectively impair working memory for novel stimuli, whereas working memory for familiar stimuli could be maintained because of previously modified synapses. Blockade of muscarinic cholinergic receptors and selective cholinergic lesions has been shown to impair encoding in delayed matching tasks. However, previous studies have not compared explicitly the role of cholinergic modulation in working memory for novel versus familiar stimuli. Here, we show that lesions of the cholinergic innervation of the entorhinal cortex selectively impair delayed nonmatch to sample performance for novel odors, whereas delayed nonmatch to sample for familiar odors is spared. This indicates an important role for cholinergic innervation of the entorhinal cortex in working memory for novel stimuli.

Afferent Pathways↗
PubMed1992

The human entorhinal cortex: normal morphology and lamina-specific pathology in various diseases.

The entorhinal territory consists of the entorhinal and transentorhinal regions spreading over the ambient gyrus and anterior portions of the parahippocampal gyrus. The transentorhinal region mediates between the adjoining temporal isocortex laterally and the entorhinal region medially. The entorhinal cortex consists of a molecular layer, followed by an external principal stratum, a cell-sparse lamina dissecans, an internal principal stratum and--within the underlying white matter--a profound cellular layer. The principal strata can each be divided into three layers Pre alpha, beta, gamma, and Pri alpha, beta, gamma. Data obtained from experimental investigations in monkeys reveal that the entorhinal territory serves as a relay station for information from both isocortical association areas and centers of the limbic system. After processing within the entorhinal cortex, this information is transferred to the hippocampal formation via the perforant path. Pathological changes within the entorhinal territory impair this continuous data transfer and contribute to a decline of cognitive functions. Entorhinal involvement associated with impaired cognitive functions is described in cases of Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, dementia with argyrophilic grains and Huntington's disease.

Central Nervous System Diseases↗
PubMed1992

Lesion-induced synapse reorganization in the hippocampus of cats: sprouting of entorhinal, commissural/associational, and mossy fiber projections after unilateral entorhinal cortex lesions, with comments on the normal organization of these pathways.

This study evaluates whether three forms of sprouting occur in the hippocampus of the cat following unilateral entorhinal cortex (EC) lesions: (1) sprouting of projections from the EC contralateral to the lesion; (2) sprouting of the commissural/associational system; and (3) sprouting of mossy fibers. Tract tracing techniques were used to define the normal organization of the entorhinal cortical projection system, the commissural/associational (C/A) systems, and the mossy fiber projections in normal cats. The same techniques were then used to evaluate whether there were changes in these projections in animals with long-standing unilateral EC lesions. The projections from the entorhinal cortex were evaluated autoradiographically following injections of 3H proline into the entorhinal area. The projections of the C/A system were traced using the Fink-Heimer technique after lesions of the hippocampal commissures, and by using autoradiographic techniques after injections of 3H proline into the hippocampus. The distribution of mossy fibers was evaluated using the Timm's stain. The results reveal that unilateral lesions of the EC in cats lead to the same sorts of sprouting that have been described in rats. There is: (1) an increase in the density of the crossed projection from the surviving EC to the contralateral dentate gyrus that had been deprived of its normal EC inputs; (2) an expansion of the terminal field of the C/A projection system into portions of the molecular layer of the dentate gyrus normally occupied by EC projections; and (3) an increase in supragranular mossy fibers in some animals. The mossy fiber sprouting was especially prominent when the lesions encroached upon the hippocampus. The studies also reveal additional details about the normal organization of hippocampal pathways in cats. The most important points are: (1) there is a crossed projection from the entorhinal cortex to the contralateral dentate gyrus; and (2) there is a complex laminar organization of the commissural and associational terminal fields in the molecular layer of the dentate gyrus that appears to be related to the point of origin of the projections along the septotemporal axis of the hippocampus. This heretofore unrecognized aspect of the laminar organization of C/A terminations has important implications for the temporal competition hypothesis, which has been advanced to account for the development of these afferent systems.

Animals↗
PubMed2000

Species-specific expression of parvalbumin in the entorhinal cortex of the Mongolian gerbil: dependence on local activity but not extrinsic afferents.

Mongolian gerbils are genetically predisposed to develop epileptic seizures in limbic structures. A species-specific property of the Mongolian gerbil is the expression of the calcium-binding protein parvalbumin in the perforant path where it is predominantly concentrated in nerve terminals. To test the hypothesis that this atypical expression of parvalbumin is induced by seizure-correlated hyperactivity in the entorhinohippocampal loop, we investigated whether it is dependent on extrinsic afferents to the entorhinal cortex. We cultivated organotypic slice cultures of neonate gerbil entorhinal cortex, isolated from all regions it is normally connected with in vivo. In these cultures, parvalbumin-expressing neurons demonstrated their characteristic features like in vivo. Blockade of spontaneous local activity with the sodium-channel blocker tetrodotoxin, however, considerably reduced the number of parvalbumin-expressing neurons in culture. These results indicate that spontaneous local activity, but not activity mediated by extrinsic afferents, is an essential factor for the expression of parvalbumin in the entorhinal cortex of the Mongolian gerbil.

Afferent Pathways↗
PubMed2004

Dendritic morphology, local circuitry, and intrinsic electrophysiology of principal neurons in the entorhinal cortex of macaque monkeys.

Little is known about the neuroanatomical or electrophysiological properties of individual neurons in the primate entorhinal cortex. We have used intracellular recording and biocytin-labeling techniques in the entorhinal slice preparation from macaque monkeys to investigate the morphology and intrinsic electrophysiology of principal neurons. These neurons have previously been studied most extensively in rats. In monkeys, layer II neurons are usually stellate cells, as in rats, but they occasionally have a pyramidal shape. They tend to discharge trains, not bursts, of action potentials, and some display subthreshold membrane potential oscillations. Layer III neurons are pyramidal, and they do not appear to display membrane potential oscillations. The distribution of dendrites and of axon collaterals suggests that neurons in layers II and III are interconnected by a network of associational fibers. Layer V and VI neurons are pyramidal and tend to discharge trains of action potentials. The distribution of dendrites and axon collaterals suggests that there is an associative network of principal neurons in layers V and VI, and they also project axon collaterals toward superficial layers. Importantly, entorhinal cortical neurons in monkeys appear to exhibit significant differences from those in rats. Morphologically, neurons in monkey entorhinal layers II and III have more primary dendrites, more dendritic branches, and greater total dendritic length than in rats. Electrophysiologically, layer II neurons in monkeys exhibit less sag, and subthreshold oscillations are less robust and slower. Some monkey layer III neurons discharge bursts of action potentials that are not found in rats. The interspecies differences revealed by this study may influence information processing and pathophysiological processes in the primate entorhinal cortex. J. Comp. Neurol. 470:317-329, 2004.

Animals↗
PubMed1981

Micromolar L-2-amino-4-phosphonobutyric acid selectively inhibits perforant path synapses from lateral entorhinal cortex.

Transverse slices of the rat hippocampus were used to examine the ability of phosphonate analogues of acidic amino acids to inhibit perforant path synaptic transmission. Micromolar concentrations of L-2-amino-4-phosphonobutyric acid (APB), an analogue of L-glutamic acid, inhibited transmission from the lateral entorhinal cortex. Two other less-sensitive components were detected in projections from the medial entorhinal cortex. The component from the lateral entorhinal cortex showed high stereospecificity for the L-isomer of APB and was relatively insensitive to phosphonate homologues of shorter and longer chain length.

Aminobutyrates↗
PubMed2001

Glutamate transporter expression in astrocytes of the rat dentate gyrus following lesion of the entorhinal cortex.

The glutamate transporters GLT-1 and GLAST localized in astrocytes are essential in limiting transmitter signalling and restricting harmful receptor overstimulation. To show changes in the expression of both transporters following lesion of the entorhinal cortex (and degeneration of the glutamatergic tractus perforans), quantitative microscopic in situ hybridization (ISH) using alkaline-phosphatase-labelled oligonucleotide probes was applied to the outer molecular layer of the hippocampal dentate gyrus of rats (termination field of the tractus perforans). Four groups of rats were studied: sham-operated controls, and animals 3, 14 and 60 days following unilateral electrolytic lesion of the entorhinal cortex. The postlesional shrinkage of the terminal field of the perforant path, ipsilateral to the lesion side, was determined and considered in the evaluation of quantitative ISH data. Statistical analysis revealed that ipsilateral to the lesion side there was a significant decrease of the GLT-1 mRNA at every postlesional time-point and of the GLAST mRNA at 14 and 60 days postlesion. The maximal decrease was approximately 45% for GLT-1 and approximately 35% for GLAST. In the terminal field of the perforant path contralateral to the lesion side, no significant changes of ISH labelling were measured. The results were complemented by immunocytochemical data achieved using antibodies against synthetic GLT-1 and GLAST peptides. In accordance with ISH results, there was an obvious decrease of GLT-1 and GLAST immunostaining in the terminal field of the perforant path ipsilateral to the lesion side. From these data we conclude that, following a lesioning of the entorhinal cortex, the loss of glutamatergic synapses in the terminal field of the perforant path resulted in a strong downregulation of glutamate transporters in astrocytes. The decrease of synaptically released glutamate or of other neuronal factors could be involved in this downregulation.

ATP-Binding Cassette Transporters↗
PubMed1991

Mapping the early development of projections from the entorhinal cortex in the embryonic mouse using prenatal surgery techniques.

The purpose of this work was to study the development of specific projections from the postero-lateral cortex during the third trimester of gestation in the mouse. To do this, we labeled undifferentiated lateral cortex with the fluorescent carbocyanine dye, Dil, in the embryonic day (E) 16 mouse embryo using exo utero surgical techniques (Muneoka, Wanek, and Bryant, 1986). Embryos were allowed to develop to term (postnatal day 0, P0) at which time the fiber patterns emanating from the marked regions were studied. Dye placement in the undifferentiated postero-ventral cortex produced labeled fibers in the hippocampal formation. A robust projection of the angular bundle into the CA1 region of the hippocampus was heavily labeled. In addition, in some animals, cortical tracts, such as the anterior commissure, corpus callosum, and a corticotectal tract, were labeled. These tracts have been described previously as scaffolding pathways in the fetal cat (McConnell, Ghosh, and Shatz, 1989), and other vertebrates (Wilson, Ross, Parrett, and Easter, 1990). Dye placement in adjacent, more anterior or dorsal areas showed strong labeling in cortical structures but no labeling in the hippocampal formation. These data indicate that, by birth, the temporal cortex is subdivided along the rostro-caudal axis as entorhinal cortex and perirhinal cortex, and along the dorso-ventral axis, as entorhinal cortex and neocortex. Also, these earliest connections are similar to adult connections in their specificity of target area selection. Therefore, these early, yet specific, connections may play a role int he formation of future connections during postnatal development.

Animals↗