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PubMed1993

[3H]phorbol ester binding sites and neuronal plasticity in the hippocampus following entorhinal cortex lesions.

Entorhinal cortex lesioning (ECL) produces a loss of more than 80% of the synapses in the outer molecular layer of the hippocampus. However, the loss of synapses is transient. Beginning a few days after denervation, new synapses are formed, virtually replacing the lost inputs within 2 months. Synaptic remodelling induced by ECL is associated with specific modifications of neurotransmitters, hormones and growth factors. Particularly, protein kinase C (PKC) plays important functional roles in receptor-mediated transmembrane signal transduction. PKC is also involved in various aspects of synaptic plasticity, such as cellular growth and differentiation. To investigate further the potential roles of PKC in synaptic plasticity observed in the ECL model, [3H]phorbol 12,13-dibutyrate ([3H]PDBu) binding, a putative marker of PKC, was examined at different times post-lesion. [3H]PDBu binding sites transiently decreased bilaterally at 2 and 8 days post-lesion (20%) in different laminae and sub-fields of the rostral hippocampus but returned to control values at 14 and 30 days post-lesion. In caudal portion of the hippocampus, [3H]PDBu binding was also decreased at 2 days post-lesion but only on the contralateral side. Interestingly, [3H]PDBu binding sites in the cortex increased by up to 30% in the contralateral side while no significant change was observed in the ipsilateral side at any time post-lesion. It is known that PKC can be regulated by different systems following alterations of neuronal and glial activity. We suggest that these could be involved in the response of PKC and [3H]PDBu binding sites following ECL. Moreover, PKC seemed to be modified in different brain areas in neuronal inputs from the entorhinal cortex and the subsequent reinnervation process.

Acetylcholinesterase↗
PubMed2003

Persistent activity and memory in the entorhinal cortex.

The entorhinal cortex (EC) is an essential component of the medial temporal lobe long-term-memory system. Recently, Egorov et al. demonstrated that neurons in layer 5 of the EC show graded persistent activity: each neuron could maintain a constant rate firing over several minutes, even in the absence of input from other neurons. These findings suggest that layer-5 EC neurons could play a central role in the formation of associations among stimuli that occur at different times.

Action Potentials↗
PubMed2006

Dopaminergic regulation of neuronal excitability through modulation of Ih in layer V entorhinal cortex.

The entorhinal cortex (EC) is a significant component of the systems that underlie certain forms of memory formation and recall. Evidence has been emerging that the dopaminergic system in the EC facilitates these and other functions of the EC. The effects of dopamine (DA) on membrane properties and excitability of EC neurons, however, are not known. We used in vitro whole-cell patch-clamp recordings from layer V pyramidal neuronal somata and dendrites of the adult rat lateral EC to investigate the effects of DA on the excitability of these neurons. We found that brief application of DA caused a reduction in the excitability of layer V EC pyramidal neurons. This effect was attributable to voltage-dependent modification of membrane properties that can best be explained by an increase in a hyperpolarization-activated conductance. Furthermore, the effects of DA were blocked by pharmacological blockade of h-channels, but not by any of a number of other ion channels. These actions were produced by a D1 receptor-mediated increase of cAMP but were independent of protein kinase A. A portion of the actions of DA can be attributed to effects in the apical dendrites. The data suggest that DA can directly influence the membrane properties of layer V EC pyramidal neurons by modulation of h-channels. These actions may underlie some of the effects of DA on memory formation.

Animals↗
PubMed2006

Long-term depression in identified stellate neurons of juvenile rat entorhinal cortex.

The entorhinal cortex (EC) serves as a gateway to the hippocampus and plays a pivotal role in memory processing in the brain. Superficial layers of the EC convey the cortical input projections to the hippocampus, whereas deep layers of the EC relay hippocampal output projections back to the superficial layers of the EC or to other cortical regions. Whereas the EC expresses long-term potentiation (LTP) and depression (LTD), the underlying cellular and molecular mechanisms have not been determined. Because the axons of the stellate neurons in layer II of the EC form the perforant path that innervates the dentate gyrus granule cells of the hippocampus, we studied the mechanisms underlying the long-term plasticity in identified stellate neurons. Application of high-frequency stimulation (100 Hz for 1 s, repeated 3 times at an interval of 10 s) or forskolin (50 microM) failed to induce significant changes in synaptic strength, whereas application of pairing (presynaptic stimulation at 0.33 Hz paired with postsynaptic depolarization from -60 to -10 mV for 5 min) or low-frequency stimulation (LFS, 1 Hz for 15 min) paradigm-induced LTD. Pairing- or LFS-induced LTDs were N-methyl-D-aspartate receptor-dependent and occluded each other suggesting that they have the similar cellular mechanism. Pairing-induced LTD required the activity of calcineurin and involved AMPA receptor endocytosis that required the function of ubiquitin-proteasome system. Our study provides a cellular mechanism that might in part explain the role of the EC in memory.

Aging↗
PubMed2002

D-amphetamine-induced behavioral sensitization: effect of lesioning dopaminergic terminals in the medial prefrontal cortex, the amygdala and the entorhinal cortex.

The behavioral sensitization produced by the repeated administration of D-amphetamine is known to involve dopaminergic neurons in the mesoaccumbens pathway. Induction of this process is dependent on action of the drug in the ventral tegmental area while its expression involves action in the nucleus accumbens. We studied here the putative involvement of dopaminergic projections other than the mesoaccumbens in this phenomenon. We examined the influence of dopaminergic lesion of the medial prefrontal cortex, the amygdala and the entorhinal cortex in the behavioral sensitization produced by repeated injections of amphetamine either peripherally or directly into the ventral tegmental area of the brain. The repeated administration of amphetamine induced a behavioral sensitization, with the ventral tegmental area a critical site for induction of the process. This sensitization to amphetamine cross-reacted with morphine and was still observed 2 weeks after cessation of the treatment. Bilateral 6-hydroxydopamine lesion of dopaminergic terminals in either the medial prefrontal cortex or the amygdala, but not in the entorhinal cortex, prevented the development of behavioral sensitization to amphetamine and the cross-sensitization with morphine, whether the amphetamine pretreatment was administered peripherally or directly into the ventral tegmental area. In conclusion, these results indicated that behavioral sensitization to amphetamine, which involves dopaminergic neurons of the ventral tegmental area, is also dependent on dopaminergic neurotransmission of the medial prefrontal cortex and amygdala but not of the entorhinal cortex.

Amygdala↗
PubMed2001

Long-term synaptic alteration in the rat hippocampal CA3 field following an entorhinal cortex lesion.

The entorhinal cortex is a key initial relay for cortical input to the hippocampus. To better understand hippocampal dysfunction resulting from early entorhinal cortex involvement in Alzheimer's disease, we stereotaxically injected ibotenic acid to produce unilateral entorhinal cortex lesions in rats. We then serially examined the CA3 hippocampal region by neuronal counts, histochemistry for acetylcholinesterase, and synaptophysin immunohistochemistry. Over 12 months, the neuronal counts did not change. Acetylcholinesterase-positive fibers were persistently but non-progressively beginning at 3 months. Synaptophysin immunoreactivity progressively declined over 12 months. Since much of the entorhinal cortex output proceeds to CA3 via the dentate gyrus, transsynaptic degeneration is suspected.

Acetylcholinesterase↗
PubMed1993

Relationships between stress protein induction and NMDA-mediated neuronal death in the entorhinal cortex.

The entorhinal cortex (EC) appears to be one of the earliest regions to express cellular pathology in aging and Alzheimer's disease. The relationships between cellular stress protein responses and the temporal and spatial aspects of cell death induced by N-methyl-D-aspartate (NMDA) was investigated in this anatomical region. Low doses of NMDA were infused stereotactically into the medial EC of the rat. At intervals starting from 0.5 h up to 7 days after a 1.25-microliters EC infusion of 15 mM NMDA, 30 mM NMDA, or saline, the expression of ubiquitin (Ub), 72-kDa heat shock protein (HSP 72), and c-Fos was determined in relation to neuronal death. Volumes of entorhinal Ub- and HSP 72-like immunoreactivity peaked between 18 and 48 h after either 15 or 30 mM NMDA infusions. After 15 mM NMDA infusions, maximal volumes of HSP 72- and Ub-like immunoreactivity in the EC at 48 h were similar to the subsequent maximal volume of neuronal loss in the EC seen after 96 hours. After infusion of 30 mM NMDA, the final EC volume of neuronal loss seen at 7 days after NMDA corresponded to 70-80% of the maximal HSP-Ub stress protein response seen at 2 days, implying that a population of HSP 72- and Ub-immunopositive cells survived the NMDA insult. C-Fos expression as determined by immunoreactivity for the nuclear phosphoprotein (Fos) indicated neuronal activation at NMDA infusion sites, in the perirhinal cortex, hippocampus, and other sites throughout the injected hemisphere. In the EC, c-Fos immunoreactivity returned to baseline levels by 8 h, well before the dramatic increases in HSP 72 and Ub volumes. Our results demonstrate that HSP 72 and Ub expression in vivo precedes and correlates with, but does not necessarily lead to, neuronal death following glutamate receptor-mediated toxicity in the EC.

Analysis of Variance↗
PubMed1991

Astrocytic apolipoprotein E mRNA and GFAP mRNA in hippocampus after entorhinal cortex lesioning.

Entorhinal cortex lesions (ECL) that damage the perforant path to the hippocampus induce rapid increases of apolipoprotein E (apo E) mRNA in the hippocampus. Apo E mRNA was localized in astrocytes by in situ hybridization in combination with immunocytochemistry for glial fibrillary acidic protein (GFAP). Unilateral ECL also increased hippocampal GFAP mRNA, with increases preceding those of apo E mRNA. The apo E mRNA and GFAP mRNA responses were transiently bilateral in non-denervated zones. The timing of response in apo E mRNA to deafferentation supports suggestions that apo E has roles in membrane remodelling during responses to neuron injury.

Animals↗
PubMed1990

Functional reciprocal connections of the rat entorhinal cortex and subicular complex with the medial frontal cortex: an in vivo intracellular study.

We used in vivo intracellular recording techniques in the rat in order to determine the properties of projections from the medial frontal cortex to the entorhinal cortex and subicular complex. Three main results were obtained. (1) A high proportion (65%) of neurons within the medial frontal cortex were antidromically activated at short latency (0.4-1.9 ms) by electrical stimulation of the entorhinal cortex or subicular complex. This provided physiological evidence for fast direct projections from the medial frontal cortex to the entorhinal cortex and subicular complex. (2) Clear excitatory postsynaptic potentials (EPSPs) were evoked in 8% of the cells within the entorhinal cortex, subicular complex, or adjacent cortices after electrical stimulation of the medial frontal cortex. (3) The most salient synaptic response was inhibition, as shown by the presence of inhibitory postsynaptic potentials (IPSPs) in 50% of the cells sampled. Similar results were obtained for the reciprocal pathway: 56% of the sampled cells in the entorhinal cortex or subicular complex responded with antidromic spikes to stimulation of the medial cortex; 4% of medial frontal neurons responded to stimulation of the entorhinal cortex or subicular complex with clear EPSPs, and 48% with IPSPs. The latencies of most synaptic responses, 15-25 ms, were inconsistent with monosynaptic activation. This suggests that oligosynaptic relays amplified the signal within or en route to their targets, and/or that cells with more slowly propagating axons were also present but not sampled by the intracellular electrodes. Finally, responsive fast-spiking cells (candidate inhibitory neurons) were encountered within target structures. The results provide evidence that these distant cortical regions are functionally connected in a reciprocal manner, and that both principal and inhibitory neurons are excited by this projection system.

Animals↗
PubMed1997

Morphological and electrophysiological characterization of layer III cells of the medial entorhinal cortex of the rat.

Entorhinal cortex layer III cells send their axons into hippocampal area CA1, forming the less well studied branch of the perforant path. Using electrophysiological and morphological techniques within a slice preparation, we can classify medial entorhinal cortex layer III cells into four different types. Type 1 and 2 cells were projection cells. Type 1 cells fired regularly and possessed high input resistances and long membrane time constants. Electrical stimulation of the lateral entorhinal cortex revealed a strong excitation by both N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potentials. Type 2 cells accommodated strongly, had lower input resistances, faster time constants and featured prominent synaptic inhibition. Type 1 and 2 cells responded to repetitive synaptic stimulation with a prolonged hyperpolarization. We identified the two other, presumed local circuit, cell types whose axons remained within the entorhinal cortex. Type 3 cells were regular firing, had high input resistances and slow membrane time constants, while type 4 cells fired at higher frequencies and possessed a faster time constant and lower input resistance than type 3 neurons. Type 3 cells presented long-lasting excitatory synaptic potentials. Type 4 neurons were the only ones with different responses to stimulation from different sites. Upon lateral entorhinal cortex stimulation they responded with an excitatory postsynaptic potential, while a monosynaptic inhibitory postsynaptic potential was evoked from deep layer stimulation. In contrast to type 1 and 2 neurons, none of the local circuit cells could be antidromically activated from deep layers, and prolonged hyperpolarizations following synaptic repetitive stimulation were also absent in these cells. Together, the complementing morphology and the electrophysiological characteristics of all the cells can provide the controlled flexibility required during the transfer of cortical information to the hippocampus.

2-Amino-5-phosphonovalerate↗
PubMed1995

The human entorhinal cortex: a cytoarchitectonic analysis.

The entorhinal cortex of man is in the medial aspect of the temporal lobe. As in other mammalian species, it constitutes an essential component of the hippocampal formation and the route through which the neocortex interacts with the hippocampus. The importance of knowing its architecture in detail arises from the possibility of extrapolating it to experimental findings, notably in the nonhuman primate. We have investigated the cytoarchitectonic features of the human entorhinal cortex by using as a base our previous study (D.G. Amaral, R. Insausti, and W.M. Cowan [1987] J. Comp. Neurol. 264:326-355) of the nonhuman primate entorhinal cortex. We prepared serial sections of the temporal lobe from 35 normal brains. Thionin- and myelin-stained series were made of all cases. Sections spaced 500 microns apart through the full rostrocaudal extent of the entorhinal cortex were analyzed. The human entorhinal cortex is made up of six layers, of which layer IV does not appear throughout all subfields of the entorhinal cortex. The overall appearance resembles that of the adjacent neocortex in lateral and caudal portions. In harmony with general structural principles in the nonhuman primate entorhinal cortex, our analysis supports the partitioning of the human entorhinal cortex into eight different subfields. (1) The olfactory subfield (EO), the rostralmost field, is little laminated. (2) The lateral rostral subfield (ELr), laterally located, merges with the laterally adjacent perirhinal cortex. (3) The rostral subfield (ER) is between EO and ELr, with better differentiation of layers II and III than EO. (4) The medial intermediate subfield (EMI) is located at the medial border. (5) The intermediate field (EI) is a lateral continuation of EMI; lamina dissecans (layer IV) can be best appreciated in this field. (6) The lateral caudal subfield (ELc) laterally borders on EI as a continuation of ELr. (7) The caudal subfield (EC) lies caudal to the beginning of the hippocampal fissure, with a distinctive, clear space (Vc) between layers V and VI. (8) The caudal limiting field (ECL) forms the caudal termination of the entorhinal cortex. Thus our parcellation of the entorhinal cortex in man is largely parallel to that arrived at in the monkey. This close homology provides a rational basis for the application to clinical problems of anatomical and functional information obtained in experimental work in nonhuman primates.

Adolescent↗
PubMed2001

Persistent sodium channel activity mediates subthreshold membrane potential oscillations and low-threshold spikes in rat entorhinal cortex layer V neurons.

Entorhinal cortex layer V occupies a critical position in temporal lobe circuitry since, on the one hand, it serves as the main conduit for the flow of information out of the hippocampal formation back to the neocortex and, on the other, it closes a hippocampal-entorhinal loop by projecting upon the superficial cell layers that give rise to the perforant path. Recent in vitro electrophysiological studies have shown that rat entorhinal cortex layer V cells are endowed with the ability to generate subthreshold oscillations and all-or-none, low-threshold depolarizing potentials. In the present study, by applying current-clamp, voltage-clamp and single-channel recording techniques in rat slices and dissociated neurons, we investigated whether entorhinal cortex layer V cells express a persistent sodium current and sustained sodium channel activity to evaluate the contribution of this activity to the subthreshold behavior of the cells. Sharp-electrode recording in slices demonstrated that layer V cells display tetrodotoxin-sensitive inward rectification in the depolarizing direction, suggesting that a persistent sodium current is present in the cells. Subthreshold oscillations and low-threshold regenerative events were also abolished by tetrodotoxin, suggesting that their generation also requires the activation of such a low-threshold sodium current. The presence of a persistent sodium current was confirmed in whole-cell voltage-clamp experiments, which revealed that its activation "threshold" was negative by about 10mV to that of the transient sodium current. Furthermore, stationary noise analysis and cell-attached, patch-clamp recordings indicated that whole-cell persistent sodium currents were mediated by persistent sodium channel activity, consisting of relatively high-conductance ( approximately 18pS) sustained openings. The presence of a persistent sodium current in entorhinal cortex layer V cells can cause the generation of oscillatory behavior, bursting activity and sustained discharge; this might be implicated in the encoding of memories in which the entorhinal cortex participates but, under pathological situations, may also contribute to epileptogenesis and neurodegeneration.

Action Potentials↗
PubMed1976

A quantitative autoradiographic and electrophysiological study of the reinnervation of the dentate gyrus by the contralateral entorhinal cortex following ipsilateral entorhinal lesions.

The post-lesion proliferation of contralateral enthorhinal afferents which occurs in response to ipsilateral entorhinal lesions was quantitatively analyzed with autoradiographic and electrophysiological techniques. In both cases, the extent of the crossed projection to the dentate granule cells was quantified on the basis of a contralateral/ipsilateral (C/I) ratio. Autoradiographic measures of grain density in the entorhinal terminal field indicates that the very sparse crossed entorhinal projection in intact animals proliferates approximately 6-fold following unilateral entorhinal lesions (on the basis of an increased C/I ratio of grain density in animals with long standing unilater entorhinal lesions). Furthermore, the total number of grains in the entorhinal terminal zone (obtained by subtracting background from non-terminal regions) also increases approximately 6-fold, indicating that compression of the neuropil cannot be the factor responsible for the increased grain density. These increases in the anatomical extent of the crossed projection as a consequence of unilateral entorhinal lesions are also reflected electrophysiologically. In operated animals, the C/I ratio of the extracellular population EPSP (a measure of the synaptic current generated by the crossed projections) also increase 5-8 fold. In addition, while in normal animals, no population spikes are observed following stimulation of the contralateral entorhinal area (indicating an absence of synchronous grnaule cell discharge in response to contralateral entorhinal input), such population spikes are quite prominent in the reinnervated dentate gyrus, indicating a large increase in the effective synaptic drive of the proliferated crossed projections.

Animals↗
PubMed2000

Quantitative MRI volumetry of the entorhinal cortex in temporal lobe epilepsy.

The entorhinal cortex (Brodmann's area 28) is located at the anterior aspect of the parahippocampal gyrus ventral to the amygdala and the hippocampus. It is reciprocally interconnected with the hippocampus via glutamatergic pathways. We investigated whether the entorhinal cortex is damaged in human temporal lobe epilepsy (TLE). The volume of the entorhinal cortex was measured using magnetic resonance imaging (MRI) in 36 patients with cryptogenic TLE and in 21 controls. The mean volumes of the entorhinal cortex on the focal side did not differ from controls. In 11 of 36 patients, however, the entorhinal cortex volume was reduced by 25%. Entorhinal volume correlated with hippocampal volume in TLE (ipsilaterally, r= 0.454, P<0.01; contralaterally, r = 0.340, P<0.05). Further, 64% of patients with 25% entorhinal cortex damage had ipsilateral hippocampal atrophy. On the other hand, right focal TLE patients with hippocampal atrophy had a 19% volume reduction of the ipsilateral entorhinal cortex (P<0.05). The volume of the entorhinal cortex correlated with the duration of TLE (r= -0.335, P< 0.05). The present study indicates that the entorhinal cortex might be damaged in a subpopulation of patients with cryptogenic TLE. In most cases, volume reduction was associated with hippocampal damage. These data suggest that entorhinal damage contributes to the symptomatology in TLE.

Adolescent↗
PubMed1998

Characterization and localization of galanin receptors in human entorhinal cortex.

The neuropeptide galanin (GAL) has a widespread distribution throughout the human cortex. The entorhinal cortex (ENT) plays a crucial role in the transfer of cortico-cortical information related to memory and displays severe degeneration in Alzheimer's disease (AD). However, very little is known about the pharmacology of the GAL receptor (GALR) in normal human ENT. Therefore, we pharmacologically visualized their distribution and characterized GALRs using in vitro receptor autoradiography and radioligand binding assays. Autoradiograms revealed intense GALR labeling, mainly in the substantia innominata, hypothalamus, the bed nucleus of the stria terminalis and within layers 2 and 4 of the ENT. Kinetic experiments showed that saturation of GALR sites by [125I]GAL (human) (hGAL) occurred within 2 h and that this binding readily reversed in the presence of a GTP analog, but not in the presence of excess unlabeled hGAL. Analysis of [125I]hGAL binding data from saturation experiments gave KD values of 98.6+/-21.6 pM, Bmax values of 52.9+/-32.4 fmol/mg protein and identified a high and low affinity state of the GALR. The presence of 5'-guanylylimidodiphosphate (GppNHp) or NaCl reduced the agonist labeling of hGALR in ENT membranes.

Adult↗
PubMed2002

NMDA receptor-dependent long-term synaptic depression in the entorhinal cortex in vitro.

The entorhinal cortex receives a large projection from the piriform (primary olfactory) cortex and, in turn, provides the hippocampal formation with most of its cortical sensory input. Synaptic plasticity in this pathway may therefore affect the processing of olfactory information and memory encoding. We have recently found that long-term synaptic depression (LTD) can be induced in this pathway in vivo by repetitive paired-pulse stimulation but not by low-frequency (1 Hz) stimulation with single pulses. Here, we have used field potential recordings to investigate the stimulation parameters and transmitter receptors required for the induction of LTD in the rat entorhinal cortex in vitro. The effectiveness of low-frequency stimulation (900 pulses at 1 or 5 Hz) and repeated delivery of pairs of stimulation pulses (30-ms interpulse interval) was assessed. Only repeated paired-pulse stimulation resulted in lasting LTD, and a low-intensity paired-pulse stimulation protocol that induces LTD in vivo was only effective in the presence of the GABA(A) receptor antagonist bicuculline (50 microM). LTD could also be induced in normal ACSF, however, by increasing the number of pulse-pairs delivered and by increasing the stimulation intensity during LTD induction. The induction of LTD was blocked by constant bath application of the N-methyl-d-aspartate (NMDA) glutamate receptor antagonist d-2-amino-5-phosphonovalerate (50 microM), indicating that LTD is dependent on NMDA receptor activation. However, LTD was not blocked by the group I/II mGluR antagonist (RS)-alpha-ethyl-4-carboxyphenylglycine (500 microM) or by bicuculline (50 microM). The induction of LTD in the entorhinal cortex in vitro is therefore dependent on intense stimulation that recruits activation of NMDA receptors, but does not require concurrent activation of mGluRs or inhibitory synaptic inputs.

2-Amino-5-phosphonovalerate↗
PubMed1994

Muscarinic (M1) mediation of carbachol-induced theta in the cat entorhinal cortex in vitro.

Entorhinal cortex slice preparations obtained from the cat exhibited theta rhythm during perfusion with 50 microM carbachol. The effect of carbachol was antagonized by the muscarinic blocker atropine sulphate, but not by hexamethonium and mecamylamine, which are antagonists of the nicotinic receptor. Further analysis of the pharmacological profile of these carbachol-induced theta oscillations showed that M1 receptor subtype to be involved in mediation of this EEG activity: the theta rhythm was antagonized by the M1 receptor blocker pirenzepine, but was unaffected by gallamine, an antagonist of the M2 receptor subtype.

Animals↗