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PubMed2003

Differential subcellular localization of phosphorylated neurofilament and tau proteins in degenerating neurons of the human entorhinal cortex.

A panel of novel monoclonal antibodies was tested on the human entorhinal cortex for the recognition of age- and disease-related changes of neurofilament proteins (NF). Several antibodies identified phosphorylated NF-H subunit, which occurred preferentially in those aged between 60 and 80 years and were localized in degenerating neurons. Such neurons also contained neurofibrillary tangles, but neurofilament aggregates did not co-localize with tangles, nor did the quantity nor the number of NF-positive neurons correlate with the severity of Alzheimer's disease. This points to a susceptibility of NF in a subset of neurons for phosphorylation- and metabolically related morphological changes during neurodegeneration.

Aged↗
PubMed1996

Facilitation of conditioned odor aversion by entorhinal cortex lesions in the rat.

This study examined the role of the entorhinal cortex (EC) in conditioned odor aversion learning (COA). Lateral EC lesions did not impair but rather facilitated COA. In the experiments the delay separating the odor cue presentation from the subsequent toxicosis was varied during acquisition. EC-lesioned rats demonstrated COA for delays up to 2 hr, whereas sham-operated rats displayed COA only if toxicosis immediately followed the odor cue. This facilitation was not dependent on the intensity of the odor and corresponded to a facilitated long-delay learning. EC lesion did not affect conditioned taste aversion, confirming that the facilitation effect does not correspond to a general facilitation of conditioned aversion learning. Taken together, these results indicate that the removal of the EC may allow odor-toxicosis associations across longer delays by extending the duration of the olfactory trace.

Animals↗
PubMed2000

Hippocampus and entorhinal cortex in frontotemporal dementia and Alzheimer's disease: a morphometric MRI study.

BACKGROUND: Magnetic resonance imaging (MRI) of hippocampal atrophy is a sensitive but not specific method to support the clinical diagnosis of early Alzheimer's disease (AD). We recently described our findings that atrophy of the entorhinal cortex (ERC) in frontotemporal dementia (FTD) is equal to that found in AD but that hippocampal atrophy in FTD is less than that found in AD. The MRI volumes of these structures provide a topographic representation of the region of interest. We hypothesized that two different dementias with distinct histopathologic and clinical features might, in addition to quantitative patterns, display topographically different patterns of atrophy. METHODS: We adopted a morphometric approach to monitor the pattern of atrophy of the hippocampus and the ERC by computing two-dimensional profiles from MRI volumes of the structures in control subjects and patients with FTD and AD. RESULTS: Compared with control subjects, atrophy of the hippocampus in patients with AD was diffuse. In patients with FTD, atrophy of the hippocampus was localized predominantly in the anterior hippocampus, suggesting a different pattern of hippocampal atrophy in FTD compared with AD. The amount and pattern of atrophy of the entorhinal cortex was virtually equal in both demented groups. CONCLUSIONS: This study provides novel data on the nature of medial temporal lobe atrophy in FTD. Morphometric MRI may be a useful technique for characterizing different patterns of atrophy in primary degenerative dementias in vivo.

Aged↗
PubMed1977

Modulation of memory processes induced by stimulation of the entorhinal cortex.

This study investigated the effects of posttrial electrical stimulation of the entorhinal cortex in rats (3 mA or 300 microA; 60 sec, 3 hr or 6 hr after training) on retention of inhibitory or active avoidance responses. In the inhibitory avoidance task 3 mA, but not 300 microA, 60 sec after training produced retrograde amnesia. The 300 microA stimulation produced amnesia when given 3 hr after training, but 3 mA was without effect. Neither level of stimulation affected retention if given 6 hr after training. In the active avoidance task 300 microA given 60 sec and 3 hr after training significantly facilitated acquisition in comparison with unoperated, but not operated control rats. The 3 mA stimulation had no effect in the active avoidance task. Cortical afterdischarge activity occurred 64%, 23%, and 77% of the time when the 300 microA stimulation was given 60 sec, 3 hr, or 6 hr after inhibitory avoidance training, and 54%, 69%, and 92% for 3 mA. In the two conditions where amnesia was observed (3 mA at 60 sec and 300 microA at 3 hr) the lowest proportion of animals exhibited afterdischarge activity. Afterdischarge activity was not related to active avoidance performance.

Animals↗
PubMed1999

Epileptiform activity induced by 4-aminopyridine in entorhinal cortex hippocampal slices of rats with a genetically determined absence epilepsy (GAERS).

Patients with absence epilepsy frequently develop convulsions later in life. We were therefore interested whether tissue from rats with a genetic absence epilepsy is more prone to seizure generation than normal animals. We compared the epileptiform activities induced by 4-aminopyridine (4-AP) induced in hippocampal-entorhinal cortex slices from genetic absence epilepsy rats of Strasbourg (GAERS, age 6 months) in which absence seizures have been present for about 4 months and from control non epileptic rats (NE). 4-AP induced short recurrent discharges in area CA1 of rat hippocampus, seizure-like events and interictal discharges in the entorhinal cortex. The various epileptiform discharges did not differ between the two strains in amplitude, duration and frequency. However, the latency for induction of different epileptiform activities by 50 microM 4-AP was significantly shorter in GAERS (about 16 min) than in NE rats (about 25 min). We also analysed differences in evoked field potentials (fp) in hippocampal area CA1 before, during and after application of 4-AP. Before application of 4-AP, responses to stimulation of Schaffer collateral were smaller in GAERS than in NE rats. Paired pulse potentiation was significantly larger in GAERS than in NE rats. 4-AP in the bath augmented the size of the evoked field potentials and this increase was larger in GAERS than in NE rats. Our findings show a greater excitability of hippocampal area CA1 in GAERS rats and a greater ability to develop 4-AP-induced epileptiform activity in combined hippocampal-enthorhinal cortex slices in GAERS than in NE rats.

4-Aminopyridine↗
PubMed1997

Expression of fetal ALZ-50 reactive clone 1 (FAC1) in dentate gyrus following entorhinal cortex lesion.

The Fetal ALZ-50 Reactive Clone 1 (FAC1) gene is expressed at high levels during brain development and is re-expressed in some neurodegenerative diseases. It is hypothesized that FAC1 functions during neuronal differentiation and may play an active role in neuritic re-organization following brain injury. We have previously employed the entorhinal cortex lesion model to examine reactive synaptogenesis and plasticity in the hippocampal dentate molecular layer following denervating lesion. We now report re-expression of FAC1 in the molecular layer (ML) of the dentate gyrus following entorhinal cortex (ERC) lesion. Denervated hippocampi (2,6,15, and 30 days post ERC lesion) were stained with anti-FAC1 antibody and processed for both light and electron microscopy. FAC1 was rapidly re-expressed (by 2 days) following ERC lesion, paralleling our previous observations with embryonic neural cell adhesion molecule (eN-CAM). Like eN-CAM, FAC1 expression was restricted to the denervated outer ML (OML) at 2 days post lesion. Analysis of later time points revealed an elimination of FAC1 immunostaining at the inner ML (IML)/(OML) interface as IML sprouts into the denervated zone. Image analysis confirmed the diminution of FAC1 staining in the OML as the IML sprouted into the denervated zone and revealed that FAC1 expression paralleled the temporal and spatial expression of eN-CAM following ERC lesion. Ultrastructural analysis of FAC1 staining at 6 and 30 days post lesion revealed immunoreactive profiles with the morphological characteristics of dendrites and cytoplasmic staining of granule cell perikarya. Dendritic staining was localized to the denervated OML and was not associated with any other neuropil profiles within this zone; IML staining was rare and restricted to large apical dendrites proximal to granule cell perikarya. These findings suggest that re-expression of FAC1 in the denervated OML is a rapid response to brain injury and may be important in synaptic plasticity and sprouting.

Animals↗
PubMed2001

A quantitative immunohistochemical study of astrocytes in the entorhinal cortex in schizophrenia, bipolar disorder and major depression: absence of significant astrocytosis.

A number of macroscopic changes have been reported in the temporal lobe in schizophrenia. We have evaluated the density of glial fibrillary acidic protein (GFAP)-positive astrocytes in cortical layers 2 through 6 in the intermediate subarea of entorhinal cortex in two cohorts: the first, 15 cases, made up of schizophrenic (n = 7) and normal nonpsychiatric control subjects (n = 8), and the second, 56 cases, composed of schizophrenic (n = 14), bipolar disorder (n = 13), major depressive (n = 14) and normal control subjects (n = 15). No significant difference in density of GFAP-positive astrocytes was detected between the psychiatric diagnostic groups and the normal controls in either of the two cohorts. In both cohorts there was a positive correlation between increasing age and astrocytic density which reached statistical significance in only the larger cohort (r = 0.38, p = 0.004). Our results find no evidence for astrocytosis in the entorhinal cortex in several mental illnesses. Although other studies have reported macroscopic and other structural abnormalities in this region, we have not detected astrocytic proliferation, which is a typical hallmark of atrophy and/or progressive neuronal loss.

Adult↗
PubMed1998

nNOS expressing neurons in the entorhinal cortex and hippocampus are affected in patients with Alzheimer's disease.

Nitric oxide is a multifunctional molecule that acts as messenger/modulator in synaptogenesis and potential neurotoxin and is synthesized by three isozymes of Nitric oxide synthase (NOS). The role of NOS in Alzheimer's disease (AD) is unclear. For example, neurons in the entorhinal cortex (EC) that are highly vulnerable to neurodegeneration in AD express low levels of NOS and while it has been suggested that the inducible form of NOS is upregulated in AD, it is still not clear if the constitutive expressed isozyme (nNOS) is involved in the process of neurodegeneration. In order to better understand the role of nNOS in the pathogenesis of AD, sections from the EC and hippocampus (HC) of AD and control cases were immunohistochemically analyzed by single- and double-immunolabeling using antibodies against nNOS and PHF-tau. Semiquantitative assessment of numbers of nNOS expressing neurons in different areas of the HC and EC showed a remarkable loss of nNOS expressing neurons in the entorhinal cortex layer II and--less severe--CA1 and CA3 of the hippocampus in patients with AD. In addition, double-immunolabeling studies revealed that nNOS is strongly associated with neurofibrillary tangles and plaques. These findings indicate that nNOS expressing neurons are highly susceptible to neurodegeneration and that nNOS might contribute to the pathogenesis of AD.

Aged↗
PubMed2003

LTP in cultured hippocampal-entorhinal cortex slices from young adult (P25-30) rats.

Cultured hippocampal neurons and immature organotypic slice cultures overcome temporal limitations of acute hippocampal slices and have been useful for investigating long-lasting plasticity. Difficulties with culturing adult neurons have restricted such studies to preparations from embryonic, perinatal, and juvenile tissue. By improving the methods for culturing and maintaining hippocampal-entorhinal cortex slices obtained from mature rats (P25-30), we show that their use in long-term electrophysiological investigations is feasible. Our cultured slices maintained an intact and functional trisynaptic cascade, normal synaptic function, and reliable long-term recording stability for at least 14 days in vitro. The electrophysiological properties and, in particular, the induction of long-term potentiation (LTP) in our mature organotypic slices were highly sensitive to dissection and tissue culture techniques. We present data describing the extracellular stimulation requirements for LTP-induction and its long-lasting maintenance (>4 h) at the Schaffer-collateral-CA1 synapse, and show that such changes in synaptic efficiency are NMDA receptor dependent. Our hippocampal-entorhinal cortex cultures from mature tissue can retain the electrophysiological properties required for long-term plasticity for several weeks in vitro.

2-Amino-5-phosphonovalerate↗
PubMed2003

Increased persistent sodium currents in rat entorhinal cortex layer V neurons in a post-status epilepticus model of temporal lobe epilepsy.

PURPOSE: Spontaneous seizures in rats emerge several weeks after induction of status epilepticus with pharmacologic treatment or electrical stimulation, providing an animal model for human temporal lobe epilepsy. In this study, we investigated whether status epilepticus caused changes in the function of voltage-gated sodium channels in entorhinal cortex layer V neurons, a cellular group important for the genesis of limbic seizures. METHODS: We induced status epilepticus in rats, by using lithium-pilocarpine, and then 2-12 weeks later, used whole-cell voltage-clamp to examine voltage-activated sodium currents of acutely dissociated layer V neurons. RESULTS: Transient sodium currents of entorhinal cortex layer V neurons isolated from 9- to 12-week post-status epilepticus rats were similar to currents in age-matched controls; however, low-threshold persistent sodium currents were significantly larger. This increase in persistent activity was not seen 2-3 weeks after pilocarpine treatment; thus it occurred after a delay comparable to the delay in the appearance of spontaneous seizures. CONCLUSIONS: Increased persistent currents are expected to accentuate neuronal excitability and thus may contribute to the genesis of spontaneous seizures after status epilepticus.

Animals↗
PubMed1989

Angiotensin II inhibits the release of [3H]acetylcholine from rat entorhinal cortex in vitro.

The effects of angiotensin I and II on basal potassium-induced release of [3H]acetylcholine were investigated in slices of rat entorhinal cortex. Potassium (10-25 mM) produced a concentration-dependent increase in the release of [3H]acetylcholine in the presence of extracellular calcium. Angiotensin II (10(-9)-10(-5) M) (but not angiotensin I) reduced the potassium-induced release of [3H]acetylcholine in a concentration-related manner to 60% of control levels, but did not effect basal tritium release. The effect of angiotensin II was antagonised by [1-sarcosine, 8-threonine] angiotensin II, an angiotensin II receptor antagonist, but not by agents acting on alpha- and beta-adrenoceptors, muscarinic, nicotinic, histamine or 5-hydroxytryptamine receptors nor by the angiotensin converting enzyme (ACE) inhibitor SQ 29852. The results indicate that angiotensin II acting via an angiotensin II receptor can inhibit the release of [3H]acetylcholine in slices of the rat entorhinal cortex. It is hypothesised that the ability of ACE inhibitors to facilitate cognitive processes may be related to a reduced availability of angiotensin II.

Acetylcholine↗
PubMed1997

GABAergic presubicular projections to the medial entorhinal cortex of the rat.

We characterized presubicular neurons giving rise to bilateral projections to the medial entorhinal cortex (MEA) of the rat. Retrograde labeling of presubiculo-entorhinal projections with horseradish peroxidase and subsequent GABA immunocytochemistry revealed that 20-30% of the ipsilaterally projecting neurons are GABAergic. No GABAergic projections to the contralateral MEA were observed. GABAergic projection neurons were observed only in the dorsal part of the presubiculum, which, when taking into account the topography of presubicular projections to MEA, indicates that only the dorsal part of MEA receives GABAergic input. The GABAergic projection neurons constitute approximately 30-40% of all GABAergic neurons present in the superficial layers of the dorsal presubiculum. Using double-label fluorescent retrograde tracing, we found that the ipsilateral and contralateral presubiculo-entorhinal projections originate from different populations of neurons. Anterograde labeling of presubiculo-entorhinal projections and electron microscopical analysis of labeled terminals substantiated the presence of a restricted GABAergic presubiculo-entorhinal projection. A small fraction of afferents to only ipsilateral dorsal MEA formed symmetrical synapses with dendritic shafts. No symmetrical synapses on spines were noted. Most afferents to the dorsal part of ipsilateral MEA, as well as all afferents to the remaining ipsilateral and contralateral MEA, formed asymmetrical synapses with both spines and dendritic shafts in an almost equal ratio. Thus, we conclude that the majority of the presubiculo-entorhinal projections exert an excitatory effect on both principal neurons and interneurons. The projections from the dorsal part of the presubiculum comprise a small inhibitory component that originates from GABAergic neurons and targets entorhinal interneurons.

Afferent Pathways↗
PubMed1988

Feedforward inhibition of the rat entorhinal cortex and subicular complex.

We used in vivo intracellular recording techniques in order to provide evidence about the source of postsynaptic inhibition in the rat entorhinal cortex and subicular complex. Several different structures in the basal forebrain and hippocampus were electrically stimulated in order to activate inhibition by different pathways. This allowed a test of 2 different neuronal circuit models: feedback inhibition, in which recurrent collaterals from principal cell axons excite a local population of inhibitory neurons, and feedforward inhibition, in which excitatory afferents activate the inhibitory neurons. In both models, inhibitory cell axons branch and contribute to the inhibition of a population of principal cells. In the feedback model, a good correlation between antidromic and inhibitory response latencies is predicted. The feedforward model predicts independent antidromic and inhibitory response latencies. In one particular model of feedforward inhibition, afferents excite both local inhibitory cells and principal cells. This model predicts a high correlation between principal cell EPSP and IPSP latencies. The results showed no consistent relationship between the presence of antidromic action potentials and the presence of inhibition in response to stimulation of different sites. In addition, there was no correlation between antidromic and inhibitory response latencies. These results provide no clear support for the feedback model of inhibition. By contrast, there was a highly significant correlation between the latency of principal cell EPSPs and IPSPs, in support of a feedforward model of inhibition. Response latencies of candidate inhibitory neurons were also consistent with the feedforward model. The results provide evidence that an excitatory relay function of the entorhinal cortex and subicular complex is modified temporally by local, extrinsically activated inhibitory circuits.

Animals↗
PubMed2003

Amyloid deposition in the hippocampus and entorhinal cortex: quantitative analysis of a transgenic mouse model.

Various transgenic mouse models of Alzheimer's disease (AD) have been developed that overexpress mutant forms of amyloid precursor protein in an effort to elucidate more fully the potential role of beta-amyloid (A beta) in the etiopathogenesis of the disease. The present study represents the first complete 3D reconstruction of A beta in the hippocampus and entorhinal cortex of PDAPP transgenic mice. A beta deposits were detected by immunostaining and thioflavin fluorescence, and quantified by using high-throughput digital image acquisition and analysis. Quantitative analysis of amyloid load in hippocampal subfields showed a dramatic increase between 12 and 15 months of age, with little or no earlier detectable deposition. Three-dimensional reconstruction in the oldest brains visualized previously unrecognized sheets of A beta coursing through the hippocampus and cerebral cortex. In contrast with previous hypotheses, compact plaques form before significant deposition of diffuse A beta, suggesting that different mechanisms are involved in the deposition of diffuse amyloid and the aggregation into plaques. The dentate gyrus was the hippocampal subfield with the greatest amyloid burden. Sublaminar distribution of A beta in the dentate gyrus correlated most closely with the termination of afferent projections from the lateral entorhinal cortex, mirroring the selective vulnerability of this circuit in human AD. This detailed temporal and spatial analysis of A beta and compact amyloid deposition suggests that specific corticocortical circuits express selective, but late, vulnerability to the pathognomonic markers of amyloid deposition, and can provide a basis for detecting prior vulnerability factors.

Alzheimer Disease↗
PubMed2002

Chronic brain inflammation results in cell loss in the entorhinal cortex and impaired LTP in perforant path-granule cell synapses.

Alzheimer's disease (AD) is characterized by chronic neuroinflammation, significant temporal lobe cell loss, and dementia. We investigated the influence of chronic neuroinflammation produced by chronic infusion of lipopolysaccharide (LPS) into the fourth ventricle for 4 weeks upon the induction and maintenance of long-term potentiation (LTP) in the dentate gyrus of the hippocampus, a well-characterized model of cellular synaptic plasticity. We also examined for pyramidal cell loss within the entorhinal cortex an area of the brain that contains the cell bodies of the perforant path. The results demonstrate that chronic neuroinflammation results in the loss of pyramidal cells within layers II and III of the entorhinal cortex and a significant attenuation of LTP within the dentate gyrus. Similar changes may underlie the temporal lobe pathology and dementia associated with AD.

Action Potentials↗
PubMed2004

Entorhinal cortex contributes to object-in-place scene memory.

Four rhesus monkeys (Macaca mulatta) were trained preoperatively in a test of object-in-place scene memory. They were presented daily with lists of unique computer-generated scenes each containing a spatial array of multiple individual objects. Within each scene, objects to be discriminated appeared in the foreground, each occupying a unique location, and monkeys were required to correctly discriminate the rewarded object to receive a food reward. Once this preoperative criterion was attained, the monkeys received bilateral entorhinal cortex ablation performed as either one or two surgical operations with a period of testing following each. Postoperatively, they were significantly impaired in learning new object-in-place scene problems. These results show that the entorhinal cortex, like anatomically related structures including the perirhinal cortex and the fornix, contributes to object-in-place scene learning.

Animals↗
PubMedDate not supplied

Galanin receptors in the hippocampus and entorhinal cortex of aged Fischer 344 male rats.

Galanin (GAL) has been proposed to be an inhibitory modulator of cholinergic memory pathways because it acts within the hippocampus to inhibit the release and antagonize the postsynaptic actions of acetylcholine. Here we have used: 1) slice binding and quantitative autoradiography to assess the density and occupancy of GAL receptors; and 2) in situ hybridization histochemistry to assess expression of the GALR1 receptor subtype in the ventral hippocampus of 3-month-old and 21-month-old Fischer 344 male rats. We detected a small but significant (p < or = 0.0003) age-related reduction in 125I-GAL binding-site density in the ventral hippocampus and entorhinal cortex under standard binding conditions. Post-hoc analysis indicated that this reduction with age persisted in the CA1 radiatum and entorhinal cortex following GTP-induced desaturation to unmask pre-existent GAL receptors occupied by endogenous ligand. It was not associated with a significant change in peak GALR1 gene expression in the hippocampus. Because a portion of GAL receptors in this region have been postulated to function as presynaptic auto-receptors on cholinergic fiber terminals, the reduction in GAL binding sites with age may be a consequence of age-related alterations in GAL receptor expression by basal forebrain cholinergic neurons which project to the ventral hippocampus.

Aging↗
PubMed2004

Entorhinal cortex lesions disrupt the relational organization of memory in monkeys.

Recent accounts suggest that the hippocampal system critically supports two central characteristics of episodic memory: the ability to establish and maintain representations for the salient relationships between experienced events (relational representation) and the capacity to flexibly manipulate memory (flexible memory expression). To test this proposal in monkeys, intact controls and subjects with bilateral aspiration lesions of the entorhinal cortex were trained postoperatively on two standard memory tasks, delayed nonmatchingto-sample (DNMS) and two-choice object discrimination (OD) learning, and three procedures intended to emphasize relational representation and flexible memory expression: a paired associate (PA) task, a transitive inference (TI) test of learning and memory for hierarchical stimulus relationships, and a spatial delayed recognition span (SDRS) procedure. The latter assessments each included critical "probe" tests that asked monkeys to evaluate the relationships among previously learned stimuli presented in novel combinations. Subjects with entorhinal cortex lesions scored as accurately as controls on all phases of DNMS and OD, procedures that can be solved on the basis of memory for individual stimuli. In contrast, experimental monkeys displayed deficits relative to controls on all phases of the PA, TI, and SDRS tasks that emphasized the flexible manipulation of memory for the relationships between familiar items. Together, the findings support the conclusion that the primate hippocampal system critically enables the relational organization of declarative memory.

Animals↗