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PubMed1995

Electron microscopy of cell islands in layer II of the primate entorhinal cortex.

An electron microscopic analysis of cell islands in layer II of the entorhinal cortex from rhesus monkeys was made to determine the ultrastructural features of these unique neuronal clusters. The rostral, intermediate, and caudal divisions of the entorhinal cortex were selected for electron microscopic examination. In the rostral division, neurons were grouped together in prominent clusters, often with 10 or more contiguous somata. Somatic and dendrosomatic appositions were frequent, without intervening cellular processes or specialized junctions. Somata were relatively small, typically 10-15 microns in diameter, with oval or circular nuclei that were euchromatic and contained nucleoli. Small nuclear infoldings were commonly seen. A thin shell of perikaryal cytoplasm contained numerous organelles. Axosomatic synapses were infrequent, with a mean of only 1.0 synapse per neuron per thin section. The neuropil contained numerous synapses, and myelinated axons were seen infrequently. In the intermediate division, somatic appositions were rarely observed. Somata were relatively large, typically 15-20 microns in diameter, and displayed a moderate amount of cytoplasm. Axosomatic synapses were relatively common, with a mean of 3.3 synapses per neuron per thin section. In the caudal division, neurons were typically grouped in clusters of two to three contiguous somata. Neurons were about 15 microns in diameter and displayed a moderate amount of cytoplasm. Axosomatic synapses were of moderate frequency, with a mean of 2.5 synapses per neuron per thin section. The neuropil in the caudal division displayed a relatively high frequency of myelinated axons. Our analysis of three regions of the entorhinal cortex revealed significant differences in the frequency of somatic appositions and axosomatic synapses, and in certain ultrastructural features of the somata and neuropil. These results showed that cell islands in layer II of the entorhinal cortex display regional morphologic differences. The paucity of symmetric axosomatic synapses in the rostral division may correlate with this region's vulnerability in certain diseases.

Animals↗

PubMed2006

Functional interactions between entorhinal cortex and posterior cingulate cortex at the very early stage of Alzheimer's disease using brain perfusion single-photon emission computed tomography.

OBJECTIVE: The cause of the reduced regional cerebral blood flow (rCBF) in the posterior cingulate cortex in the early stage of Alzheimer's disease has not been clarified. In Alzheimer's disease, the posterior cingulate cortex itself shows little neuropathologic degeneration, and a hypothesis explaining such a discrepancy is that the functional impairment in the posterior cingulate cortex reflects remote effects caused by degeneration in distant but connected areas, such as the entorhinal cortex. To test the hypothesis, we investigated the functional connectivity between the entorhinal cortex and posterior cingulate cortex. METHODS: Sixty-one patients with probable Alzheimer's disease at a very early stage and 61 age-matched healthy controls underwent both brain structural magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT). Voxel-based morphometry was performed on MRI data to identify clusters of significantly reduced grey matter concentration in patients with Alzheimer's disease relative to controls, which were set as volumes of interest (VOIs) for correlation analyses of SPECT images. We then used adjusted rCBF values in the VOIs as covariates of interest in statistical parametric mapping. RESULTS: Voxel-based morphometry demonstrated a significant reduction in grey matter concentration in the bilateral entorhinal cortex in Alzheimer's disease. A positive correlation between rCBF in the entorhinal cortex as VOI and that in the limbic and paralimbic systems, including the posterior cingulate cortex, anterior cingulate cortex, lingual gyri and left middle temporal gyrus (P<0.001), was observed in Alzheimer's disease. Control subjects also showed a similar correlation in the limbic and paralimbic systems, but not in the posterior cingulate cortex. CONCLUSION: These results indicate that rCBF changes in the posterior cingulate cortex may be closely related to those in the entorhinal cortex in patients with Alzheimer's disease, thereby supporting the 'remote effect' hypothesis.

Aged↗

PubMed1998

Spatial memory, habituation, and reactions to spatial and nonspatial changes in rats with selective lesions of the hippocampus, the entorhinal cortex or the subiculum.

Various spatial memory deficits have been described in rats with damage to the hippocampal formation (including the subiculum and the entorhinal cortex) and particularly in rats with selective lesions of the hippocampus proper. So far, the involvement of the entorhinal cortex in spatial memory is still controversial and the role of the subiculum is poorly documented. The aim of the present study was to compare the behavioural effects of selective lesions of the hippocampus, the entorhinal cortex or the subiculum in (a) a water-maze task using testing procedures sensitive to the disruption of reference or working memory and (b) in an object exploration task designed to evaluate habituation and subsequently reactions to changes of the spatial layout of objects (spatial change) or to the substitution of a familiar object by a new one (nonspatial change). Our results showed several similarities between the behavioural consequences of damage to each of the three structures. A few differences were also noted. Hippocampal rats were impaired in all spatial tasks, but they reacted like controls to a nonspatial change. The rats sustaining lesions of the entorhinal cortex or the subiculum were not impaired in the reference-memory procedure of the water-maze task and showed a deficit in reacting to a nonspatial change. Overall, our results confirm the central role of the hippocampus in spatial memory and also suggest a role for the entorhinal cortex and the subiculum in processing spatial informations. In addition, they indicate that the entorhinal cortex and the subiculum may have a hippocampal-independent role in memory.

Animals↗

PubMed2000

Morphological and electrophysiological characteristics of layer V neurons of the rat medial entorhinal cortex.

This study aimed to characterize the morphological and electrophysiological properties of neurons in layer V of the entorhinal cortex in the rat brain. Using the in vitro slice preparation and sharp electrode techniques, we recorded from layer V neurons located in the medial entorhinal cortex. Recorded cells were also labeled with biocytin. Based on morphological criteria, layer V of the entorhinal cortex is comprised of three categories of neurons: pyramidal cells, horizontal cells, and polymorphic cells. Horizontal cells could be easily distinguished from the pyramidal cells because the bulk of their dendritic plexus extended horizontally within layer V. Polymorphic cells vary in size and shape. Interestingly, they typically do not have apical dendrites, and some of them have dendrites that extend into the subiculum. Based on electrophysiological criteria alone, it was not possible to unequivocally distinguish the morphological cell types because they were somewhat heterogeneous with respect to several parameters including inward rectification, spike-frequency adaptation, and intrinsic oscillations. Nevertheless, although most horizontal cells displayed time-dependent inward rectification, most pyramidal cells displayed fast inward rectification exclusively. None of the entorhinal cortex layer V cells displayed oscillatory activity like that of neocortical layer V "bursting" cells, although neurons from all groups displayed rhythmic subthreshold membrane potential oscillations. In summary, we have found that layer V of the rat medial entorhinal cortex consists of three morphologically distinct neuronal subtypes that cannot be clearly distinguished from each other by traditional electrophysiological measures.

Animals↗

PubMed2003

Long-term synaptic depression in the adult entorhinal cortex in vivo.

The piriform cortex provides a major input to the entorhinal cortex. Mechanisms of long-term depression (LTD) of synaptic transmission in this pathway may affect olfactory and mnemonic processing. We have investigated stimulation parameters for the induction of homosynaptic LTD and depotentiation in this pathway using evoked synaptic field potential recordings in the awake rat. In this study, 15 min of 1-Hz stimulation induced a transient (< 5 min) depression of evoked responses but did not induce LTD or depotentiation. To determine whether inhibitory and/or facilitatory mechanisms contribute to LTD induction, repetitive delivery of pairs of stimulation pulses was also assessed. Repetitive paired-pulse stimulation with a 10-ms interval between pulses, which activates inhibitory mechanisms during the second response, did not reliably induce LTD. However, repetitive paired-pulse stimulation using a 30-ms interval, which evokes marked paired-pulse facilitation, resulted in synaptic depression that lasted > or = 1 day, and which was reversible by tetanization. The selective induction of LTD by stimulation that evokes paired-pulse facilitation suggests that strong synaptic activation is required for LTD induction. The N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (0.1 mg/kg) blocked the induction of LTD, indicating that NMDA receptor activation is required for LTD induction in this pathway. These results indicate that LTD in piriform cortex inputs to the entorhinal cortex in the awake rat is effectively induced by strong repetitive synaptic stimulation, and that this form of LTD is dependent on activation of NMDA receptors.

Animals↗

PubMed1998

Total number of neurons in the layers of the human entorhinal cortex.

The total number of neurons in the major laminae of the human entorhinal cortex were estimated with a design-based stereological technique, the optical fractionator. Detailed descriptions of the laminar organization and the cortical limits of the region required for the analysis are provided, along with detailed descriptions of the sampling scheme employed. The individual, mean values, and variances for estimates made in layers II, III, V, and VI are presented and discussed in terms of the precision of the estimation procedure and the results of other studies. Neuron numbers were estimated to be about 1 million layer II cells, 5 million layer III cells, 2 million layer V cells, and 4 million layer VI cells, for a total of slightly more that 13 million neurons in the entorhinal cortex. Combined with data from a similar study carried out in the human hippocampus, the data presented represent the first rigorous stereological evidence of the divergence of entorhinal projections to the hippocampus. The data presented also indicate that projections from layer II of the entorhinal cortex to the dentate gyrus and CA2/3 and projections from layer III of the entorhinal cortex to CA1 differ in the degrees of their divergence.

Adult↗

PubMed1999

Quantitative evidence for increase in galanin-immunoreactive terminals in the hippocampal formation following entorhinal cortex lesions in the adult rat.

The projection from the entorhinal cortex to the dentate gyrus and hippocampus is severely affected in Alzheimer's disease and there is a depletion of cholinergic terminals but an upregulation of the neuropeptide galanin, which inhibits the release of acetylcholine. Evidence for changes to galanin-immunoreactive terminals in the hippocampal formation was therefore examined after unilateral entorhinal cortex lesions in the adult rat. An increase in the density of galanin-immunoreactive terminals on the lesioned side was evident in the stratum lacunosum moleculare of the hippocampus and the outer molecular layer of the dentate gyrus at 17 days post-lesion, and it increased gradually until the last time point examined, at 40 days post-lesion. Thus we demonstrate that there is an increase in galanin-immunoreactive terminals in the hippocampal formation following entorhinal cortex lesions.

Acetylcholinesterase↗

PubMed2004

Co-expression of calretinin and gamma-aminobutyric acid in neurons of the entorhinal cortex of the common marmoset monkey.

The gamma-aminobutyric acid (GABA)-containing interneuron population in the entorhinal cortex has been shown to consist of several subpopulations. In addition to GABA, these neurons contain another neurochemical substance, such as a neuropeptide or a calcium binding protein. In the present study, we examined the co-localization of calretinin and GABA in the entorhinal cortex of the common marmoset Callithrix jacchus, a New World monkey. Although the function of calretinin remains unclear, there are indications that it might have a protective role against cell death in a number of neuropathological diseases. Furthermore, it might have a regulatory role in the neurotransmission of GABAergic neurons. In contrast to the rat brain, sparse data exist regarding the degree of co-expression of these two markers in the monkey brain. Using immunofluorescence and confocal laser scanning microscopy, we found that an average of 56% of the calretinin-positive neurons in the monkey entorhinal cortex contained GABA, whereas about 27% of the GABA-positive neurons co-expressed calretinin. Interestingly, these numbers were higher in the superficial layers of the entorhinal cortex in comparison with the deep layers. However, no differences were found in co-localization percentages between the different entorhinal subfields. In general, the degree of co-localization was higher in comparison to findings in the rat entorhinal cortex. The higher amount of co-localization observed in the present study might reflect species differences between the primate and the non-primate brain.

Animals↗

PubMed1992

NMDA-receptor-dependent, muscimol-sensitive role of the entorhinal cortex in post-training memory processing.

The bilateral infusion into the entorhinal cortex of the NMDA receptor antagonist, AP5 (5.0µg) or of the GABA(A) agonist, muscimol (0.03µg) 90min after training but not 30min before training, 0min after training or 10min before testing, hindered retention test performance 24h after inhibitory avoidance in rats. Glutamate (5.0µg) or picrotoxin (0.08µg) infused 90min after training had no effect. In animals trained with a low level footshock a second training session, 120min after the first, was needed in order to obtain a good retention test performance. This was taken to reflect summation of the consecutive memory traces left by the two training sessions. In these animals, the infusion of AP5 or muscimol into the entorhinal cortex between the two training sessions impeded their summation. The present results suggest that the entorhinal cortex plays a late role in memory processing, that this role does not need a hyperactivation of the entorhinal cortex, and that it is important for the interaction between consecutive memory traces.

Journal Article↗

PubMed1996

Long-lasting transneuronal changes in rat dentate granule cell dendrites after entorhinal cortex lesion. A combined intracellular injection and electron microscopy study.

Following entorhinal cortex lesion, inhibitory hippocampal neurons show a persistent rarefication of those dendrites formally receiving entorhinal input. Physiological data indicate a long lasting disequilibrium of inhibition and excitation in the de-entorhinated hippocampus. We analyzed the intracellularly-stained dendritic tree of de-entorhinated excitatory rat granule cells. Granule cells of controls and animals surviving 2, 8, 60 and 270 days after unilateral entorhinal cortex lesion were impaled. Dendrites of control cells were of typical shape, traced to the hippocampal fissure and a complete dye filling of dendrites was ascertained by EM-analysis. Conversely, 60 and 270 days following lesioning, dendrites were only rarely seen to extend into the outer portions of the molecular layer and the dendritic architecture became significantly rarefied. Sixty days post-lesion, intracellularly filled dendrites extending to the middle molecular layer were surrounded by cell clusters resembling glia. Some of these contained the neuronally applied dye, suggesting a close association of the cytosolic compartments with the altered dendrites. These observed alterations exceed the process of sprouting and de novo synaptogenesis of remaining afference for long periods of time. The dendritic morphology of both inhibitory and excitatory neurons seems to require specific input from the entorhinal cortex. Moreover, sprouting of remaining afferents is apparently not sufficient to compensate for this loss of input.

Animals↗

PubMed2005

The entorhinal cortex plays a role in extinction.

In this study, we analyzed the participation of the entorhinal cortex in extinction of a learned aversive response. Rats with infusion cannulae aimed to the entorhinal cortex were trained in a one-trial step-down inhibitory avoidance task (IA) and submitted to four consecutive daily test sessions without the footshock, a procedure that induced extinction of the conditioned response in control animals. When infused into the entorhinal cortex immediately after the first extinction session at doses able to block consolidation of IA memory, the NMDA receptor antagonist, AP5 (25 nmol/side), the inhibitor of protein synthesis anisomycin (300 nmol/side) and the inhibitor of CaMKII, KN-93 (10 nmol/side), but not the MEK1/2 inhibitor PD-98059 (5 nmol/side) hindered extinction of the IA response. The same results were obtained when the interval between the first and second test session was 48 instead of 24h. The data indicate that normal functionality of the NMDA receptors, together with CaMKII activity and protein synthesis are necessary in the entorhinal cortex at the time of the first test session to generate extinction. Our results also suggest that the ERK1/2 pathway does not play a role in this process.

Amygdala↗

PubMed2002

Induction of STAT3 signaling in activated astrocytes and sprouting septal neurons following entorhinal cortex lesion in adult rats.

Entorhinal cortex lesion (ECL) leads to the activation of astrocytes and reactive axonal sprouting in the denervated fascia dentata. Previous studies indicated that CNTF or related cytokines are involved in the regulation of these processes. Therefore, we studied (1). whether the cytokine-associated STAT3 signaling pathway is activated in response to ECL and (2). which CNTF/cytokine receptor components are available for signal transduction. Lesion-induced STAT3 phosphorylation was found in reactive astrocytes of the fascia dentata. Intriguingly, rapid and transient activation of STAT3 signaling was also observed in sprouting neurons of the medial septum. Messenger RNAs for the three components of the CNTF/cytokine receptor complex were expressed and differentially regulated following ECL both in septal neurons and in reactive astrocytes of the fascia dentata. These data indicate that CNTF or related gp130-associated cytokines play a dual role after brain lesion: (1). regulation of astrocytic responses to deafferentation and (2). regulation or modulation of axonal sprouting.

Animals↗

PubMed2003

Involvement of the entorhinal cortex in the stress response to immobilization, but not to insulin-induced hypoglycaemia.

Although the involvement of the limbic system in the neuroendocrine responses to some stressors has been documented, the specific role of the entorhinal cortex has not been elucidated. In this study, we investigated the involvement of the entorhinal cortex in stress responses. Fos immunoreactivity, a widely used marker for neuronal activation, was detected in the entorhinal cortex of rats subjected to immobilization stress, whereas no marked staining was observed in the entorhinal cortex of the control and insulin-induced hypoglycaemia groups. Lesion of the entorhinal cortex produced by ibotenic acid significantly attenuated the adrenocorticotropic hormone (ACTH) release evoked by immobilization; however, no significant change in ACTH release was observed in insulin-induced hypoglycaemia. No significant difference between entorhinal-lesioned rats and control rats was observed in blood glucose concentrations when subjected to either immobilization or to insulin-induced hypoglycaemia. Together, these results indicate that the entorhinal cortex is closely involved in the stress response to immobilization but not to insulin-induced hypoglycaemia.

Adrenocorticotropic Hormone↗

PubMed1997

Synapse alteration in hippocampal CA3 field following entorhinal cortex lesion.

To model one aspect of the neurodegeneration observed in Alzheimer's disease and to investigate the synaptic alteration of the hippocampus associated with entorhinal cortex lesion, ibotenic acid was used to produce selective unilateral neuronal loss in rat entorhinal cortex. Immunohistological and microdensitometrical analyses confirmed ibotenic acid lesion of the entorhinal cortex after 3 months and showed a decrease of synaptophysin-immunoreactive substances in the stratum lucidum of the CA3 field. This study demonstrates that entorhinal cortex lesion can lead to synaptic alterations and cause damage to presynaptic terminals with projecting area in the disruption of the entorhinal cortex hippocampus relay passage.

Alzheimer Disease↗

PubMed2002

Differential excitability and voltage-dependent Ca2+ signalling in two types of medial entorhinal cortex layer V neurons.

The entorhinal cortex (EC) is a key structure in memory formation, relaying sensory information to the hippocampal formation and processed information to the neocortex. EC neurons in the deep layers modulate the transfer of sensory information by the superficial layers and the dentate gyrus, and form the output to the neocortex. Here we characterize two types of EC layer V neurons by their fluorescence morphology, electrophysiology and intracellular Ca2+ signalling using intracellular recording and Ca2+ imaging. Pyramidal neurons show, in response to depolarizing current pulses, regular firing with strong adaptation and a fast and medium afterhyperpolarization (AHP) which are separated by a depolarizing notch and, with hyperpolarizing current injection, a transient sag. Multipolar cells respond to depolarization with delayed firing with very weak adaptation and have no depolarizing notch between fast and medium AHP and no sag with hyperpolarization. The delayed firing was blocked by 30 micro m 4-aminopyridine, indicating mediation by the D-type potassium current. Subthreshold depolarization evoked membrane potential oscillations of 2-5 Hz in both cell types and an increase in [Ca2+]i of 37 nm in pyramidal and 59 nm in multipolar neurons. Repetitive firing at 10 Hz for 30 s increased [Ca2+]i in pyramidal and multipolar neurons by 194 and 295 nm, respectively. Differential temporal firing and Ca2+ signalling suggest specific information processing and synaptic memory storage possibilities in these two layer V cell types of the EC.

4-Aminopyridine↗

PubMed1999

High conductance sustained single-channel activity responsible for the low-threshold persistent Na(+) current in entorhinal cortex neurons.

Stellate cells from entorhinal cortex (EC) layer II express both a transient Na(+) current (I(Na)) and a low-threshold persistent Na(+) current (I(NaP)) that helps to generate intrinsic theta-like oscillatory activity. We have used single-channel patch-clamp recording to investigate the Na(+) channels responsible for I(NaP) in EC stellate cells. Macropatch (more than six channels) recordings showed high levels of transient Na(+) channel activity, consisting of brief openings near the beginning of depolarizing pulses, and lower levels of persistent Na(+) channel activity, characterized by prolonged openings throughout 500 msec long depolarizations. The persistent activity contributed a noninactivating component to averaged macropatch recordings that was comparable with whole-cell I(NaP) in both voltage dependence of activation (10 mV negative to the transient current) and amplitude (1% of the transient current at -20 mV). In 14 oligochannel (less than six channels) patches, the ratio of transient to persistent channel activity varied from patch to patch, with 10 patches exhibiting exclusively transient openings and one patch showing exclusively persistent openings. In two patches containing only a single persistent channel, prolonged openings were observed in >50% of test depolarizations. Moreover, persistent openings had a significantly higher single-channel conductance (19.7 pS) than transient openings (15.6 pS). We conclude that this stable high-conductance persistent channel activity is responsible for I(NaP) in EC stellate cells. This persistent channel behavior is more enduring and has a higher conductance than the infrequent and short-lived transitions to persistent gating modes that have been described previously in brain neurons.

Animals↗

PubMed2004

Long-term synaptic plasticity in deep layer-originated associational projections to superficial layers of rat entorhinal cortex.

Superficial layers of the entorhinal cortex (EC) relay the majority of cortical input projections to the hippocampus, whereas deep layers of the EC mediate a large portion of hippocampal output projections back to other cortical areas, suggesting a functional segregation between superficial and deep layers of the EC as input and output structures of the hippocampus, respectively. However, deep layers of the EC send associational projections to superficial layers, suggesting a potential interaction between neocortical input and hippocampus-processed output in superficial layers. This possibility was investigated by examining whether deep to superficial EC projections support long-term synaptic plasticity, and whether they interact with other pathways in superficial layers in rat medial EC slice preparations. Synaptic responses of the deep-to-superficial layer projections were verified based on field potential profiles, paired-pulse facilitation, physical separation between superficial and deep layers, and pharmacological manipulation. Long-term potentiation (LTP) was reliably induced in the deep-to-superficial layer projections by burst stimulations that emulated theta or sharp wave electroencephalogram (EEG),and it was blocked by an N-methyl-d-aspartate receptor antagonist (D-2-amino-5-phosphonopentanoic acid) and a calcium channel blocker (nifedipine). Prolonged low frequency stimulation induced long-term depression. A weak stimulation of deep layers, which induced a small degree of LTP by itself, generated a much larger degree of LTP when paired with a strong stimulation of superficial layers, indicating that the deep-to-superficial layer projections cooperate with other pathways in the superficial EC to enhance synaptic weights. Our results suggest that neocortical input and hippocampal output information are integrated in superficial layers of the EC.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1990

Postsynaptic Hebbian and non-Hebbian long-term potentiation of synaptic efficacy in the entorhinal cortex in slices and in the isolated adult guinea pig brain.

Long-term potentiation (LTP) was investigated in the mammalian entorhinal cortex by using two in vitro preparations, the isolated brain and the entorhinal cortex slice. Hebbian and non-Hebbian types of LTP appear to be present in layer II entorhinal cortex cells as demonstrated using two protocols: (i) tetanic stimulation of the piriform-entorhinal cortex afferent pathway to generate homosynaptic potentiation and (ii) postsynaptic subthreshold rhythmic membrane potential manipulation not paired to presynaptic activation, which gives rise to non-Hebbian LTP. The induction and the expression of both types of LTP were found to be dependent on activation of N-methyl-D-aspartate receptors as shown by their sensitivity to the receptor agonist D-2-amino-5-phosphonovalerate. This is in contrast to LTP in the hippocampus [Zalutsky, R. A. & Nicoll, R. A. (1990) Science 248, 1619-1624], where LTP is expressed by quisqualate receptors. Since, in the entorhinal cortex, LTP is linked to a selective increase of the N-methyl-D-aspartate-receptor-mediated synaptic responses, this enhancement is most likely due to postsynaptic factors.

2-Amino-5-phosphonovalerate↗