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PubMed2006

CaMKII activation in the entorhinal cortex disrupts previously encoded spatial memory.

To investigate the role of the entorhinal cortex in memory at a molecular level, we developed transgenic mice in which transgene expression was inducible and limited to the superficial layers of the medial entorhinal cortex, pre- and parasubiculum. We found that expression of a constitutively active mutant form of CaMKII in these structures disrupted spatial memory formation. Immediate post-training activation of the transgene disrupted previously established memory while transgene activation 3 weeks following the training was ineffective. These results demonstrate that, similar to the hippocampus, the entorhinal cortex plays a time-limited role in spatial memory formation but is not a final cortical repository of long-term memory. Moreover, these results suggest that the indiscriminate activation of CaMKII is able to disrupt preexisting memories, possibly by altering the pattern of synaptic weight changes that are thought to form the basis of the memory trace.

Animals↗

PubMed2005

Effects of pre- or post-training entorhinal cortex AP5 injection on fear conditioning.

Fear conditioning is one of the most studied paradigms to assess the neural basis of emotional memory. The circuitry involves NMDA receptor activation in the amygdala and, in the case of contextual conditioning, in the hippocampus. Entorhinal cortex is one of the major input/output structures to the hippocampus and also projects to the amygdala, both through glutamatergic transmission. Other learning tasks involving hippocampus and amygdala, such as inhibitory avoidance, require entorhinal cortex during acquisition and consolidation. However, the involvement of NMDA receptors mediated transmission in entorhinal cortex in fear conditioning acquisition and consolidation is not clear. To investigate that issue, rats were trained in fear conditioning to both contextual and tone conditioned stimulus. Immediately before, immediately, 30 or 90 min after training they received NMDA antagonist AP5 or saline injections bilaterally in the entorhinal cortex (AP-6.8 mm, L +/-5.0 mm DV-6.8 mm). Contextual fear conditioning was measured 24 h after training, and tone fear conditioning 48 h after training. AP5 injections selectively impaired contextual fear conditioning only when injected pre-training. Post-training injections had no effect. These findings suggest that entorhinal cortex NMDA receptors are necessary for acquisition, but not for consolidation, of contextual fear conditioning. On the other hand, both acquisition and consolidation of tone fear conditioning seem to be independent of NMDA receptors in the entorhinal cortex.

2-Amino-5-phosphonovalerate↗

PubMed1986

Neurophysiology of limbic system pathways in the rat: projections from the amygdala to the entorhinal cortex.

We studied the responses of rat entorhinal neurons to electrical stimulation of the amygdala. Four main results were obtained: (1) excitatory postsynaptic potentials were recorded in entorhinal neurons in response to electrical stimulation of the amygdala. Cells in layers II, III and V of the entorhinal cortex were responsive. (2) Excitatory responses were followed by inhibitory postsynaptic potentials. (3) Frequency potentiation of both excitatory and inhibitory responses was observed when 10/s stimulation was used. (4) Three amygdala neurons were antidromically activated by entorhinal stimulation; and two layer II entorhinal cells that were excited by amygdala stimulation were also antidromically activated by dentate gyrus stimulation. These results provide evidence for a monosynaptic, excitatory projection from the amygdala to the entorhinal cortex. In addition, the data indicate that amygdala neurons are only one synapse removed from the excitation of dentate gyrus granule cells.

Action Potentials↗

PubMed1994

Distribution of calbindin D28k immunoreactive cells and fibers in the monkey hippocampus, subicular complex and entorhinal cortex. A light and electron microscopic study.

Calbindin D28k (CB)-containing neurons and axon terminals in the hippocampus, subicular complex and entorhinal cortex of the African green monkey (Cercopithecus aethiops) were studied by light and electron microscopic immunocytochemistry. CB was present in granule cells of the dentate gyrus, pyramidal neurons of hippocampal fields CA1 and CA2, and in pyramidal neurons of the prosubiculum and entorhinal cortex. In contrast, pyramidal neurons in the CA3, subiculum and presubiculum were not labeled. A subpopulation of non-principal neurons (non-granule and non-pyramidal cells) was also stained for CB. These cells were rare in the hippocampus and subiculum, but were more frequently observed in the presubiculum, parasubiculum, and in the entorhinal cortex. In the electron microscope, these non-principal cells displayed fine-structural characteristics of GABAergig neurons. Strongly stained CB-immunoreactive bundles of myelinated axons were found in the molecular layer of the subiculum and in various layers of the presubiculum. The CB-positive, unmyelinated axons of the granule cells, the mossy fibers, gave rise to distinct fiber bundles. Mossy fiber terminals formed asymmetric synapses on large spines in the hilus and CA3. In addition to the giant mossy fiber boutons, there were large CB-positive terminals that formed asymmetric synapses with dentritic spines throughout the hippocampal formation. These boutons also formed axo-dendritic synapses in the entorhinal cortex. Axon terminals that formed symmetric synapses and might, thus, be derived from non-principal neurons, were rarely found in the hippocampus and subicular complex. They were more frequent in the parasubiculum and entorhinal cortex. These CB-positive terminals were small, heavily immunostained, and formed symmetric axo-dendritic synapses. Our results demonstrate a great diversity of CB-containing neurons, axons, and terminals in the monkey hippocampal formation. In general, regions that received a dense innervation of CB-positive terminals displayed pyramidal neurons that all lacked this calcium-binding protein. Further studies are required to understand the functional significance of these findings.

Animals↗

PubMed2001

Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease.

OBJECTIVES: To determine whether nondemented subjects with pathological evidence of preclinical Alzheimer disease (AD) demonstrate neuronal loss in the entorhinal cortex and hippocampus, and whether the onset of cognitive deficits in AD coincides with the onset of neuronal degeneration. METHODS: Preclinical AD cases have been defined by the absence of cognitive decline but with neuropathological evidence of AD. The hippocampus and entorhinal cortex were examined in 13 nondemented cases (Clinical Dementia Rating [CDR] 0) with healthy brains, 4 cases with preclinical AD, 8 cases with very mild symptomatic AD (CDR 0.5), and 4 cases with severe AD (CDR 3, hippocampus only). The volume and number of neurons were determined stereologically in 2 areas that are vulnerable to AD--the entorhinal cortex (as a whole and layer II alone) and hippocampal field CA1. RESULTS: There was no significant decrease in neuron number or volume with age in the healthy nondemented group and little or none between the healthy and preclinical AD groups. Substantial decreases were found in the very mild AD group in neuron number (35% in the entorhinal cortex, 50% in layer II, and 46% in CA1) and volume (28% in the entorhinal cortex, 21% in layer II, and 29% in CA1). Greater decrements were observed in CA1 in the severe AD group. CONCLUSIONS: There is little or no neuronal loss in aging or preclinical AD but substantial loss in very mild AD. The findings indicate that AD results in clinical deficits only when it produces significant neuronal loss.

Aged↗

PubMed1998

Major decrease in the volume of the entorhinal cortex in patients with Alzheimer's disease carrying the apolipoprotein E epsilon4 allele.

OBJECTIVE: Recent evidence indicates that the apolipoprotein E (ApoE) epsilon4 allele is a risk factor for developing Alzheimer's disease. It has also been proposed that it is associated with increased counts of amyloid plaques and neurofibrillary tangles that in turn are neuropathological hallmarks initially appearing in the medial temporal lobe structures in Alzheimer's disease. In this study, the effect of the ApoE epsilon4 allele on the volume of the entorhinal cortex was evaluated in vivo. METHODS: The volume of the entorhinal cortex was measured on MR images using a recently designed histology based protocol in 16 patients with Alzheimer's disease with ApoE epsilon4 (mean age 70.4 (SD 9.9)), 11 patients with Alzheimer's disease without ApoE epsilon4 (mean age 69.1 (SD7.1)), and in 31 healthy age and sex matched normal controls (72.2 (SD 3.9)). The patients met the NINCDS-ADRDA criteria for probable Alzheimer's disease and were in mild to moderate stages of the disease. MRI was performed with a 1.5 Tesla Magnetom and a 3D technique permitting the reconstruction of 2.0 mm thick contiguous slices perpendicular to the axis of the anterior-posterior commissure. RESULTS: The patients with Alzheimer's disease without the ApoE epsilon4 allele had atrophy in the entorhinal cortex, the volume was reduced by 27% compared with control subjects. However, the most prominent shrinkage (45%) in the entorhinal cortex was seen in patients with Alzheimer's disease with the ApoE epsilon4 allele (p=0.0001). The effect of epsilon4 on the entorhinal cortex volume was especially prominent in female patients with Alzheimer's disease compared to male patients with Alzheimer's disease (p=0.014). Additionally, patients with the ApoE epsilon4 allele had inferior performance in verbal and visual memory functions than those without the allele CONCLUSIONS: Volumetric MRI measurements disclose that ApoE epsilon4 is associated with the degree of atrophy in the entorhinal cortex in early Alzheimer's disease, this effect being especially prominent in female patients with Alzheimer's disease.

Aged↗

PubMed1993

A heart-like Na+ current in the medial entorhinal cortex.

Acutely dissociated neurons from the superficial layers of the medial entorhinal cortex of the rat were studied under voltage clamp using the whole-cell patch-clamp configuration. Neurons from the medial entorhinal cortex exhibit a tetrodotoxin (TTX)-resistant Na+ current (ITTX-R; IC50 approximately 146 nM), in addition to the normal TTX-sensitive Na+ current (ITTX-S; IC50 approximately 6 nM). ITTX-R was found in both putative stellate and putative pyramidal neurons from the medial entorhinal cortex. ITTX-R is kinetically indistinguishable from ITTX-S, but can be distinguished from ITTX-S based on its enhanced sensitivity to block by Cd2+, La3+, and Zn2+. ITTX-R is kinetically and pharmacologically similar to the TTX-resistant Na+ current found in cardiac muscle.

Animals↗

PubMed1993

Extended temporal gradient for the retrograde and anterograde amnesia produced by ibotenate entorhinal cortex lesions in mice.

Effects of ibotenic entorhinal cortex (EC) lesions on both retrograde and anterograde amnesia in mice were assessed using two-choice discrimination tasks learned at different intervals before surgery in two eight-arm radial mazes. The results indicated that EC-lesioned mice were severely impaired in postoperative retention of discrimination problems learned 3 d or 2 weeks prior to surgery, but showed no deficit on problems learned between 4, and up to 6 weeks before surgery, as compared to sham-operated controls. When trained on a novel two-choice discrimination problem (not acquired preoperatively), experimental subjects demonstrated quite normal rates of acquisition, but were impaired in learning its reversal. Furthermore, they exhibited a faster rate of forgetting (anterograde amnesia) relative to controls over a 2-week retention interval. These results indicate that approximately 4 weeks is required before memory for a two-choice spatial discrimination problem no longer depends on the integrity of the entorhinal cortex, and suggests that, beyond this time, an EC-independent memory storage system is capable of supporting the retrieval of information. The data, together with complementary behavioral results, are discussed in the context of current theories of memory storage.

Amnesia↗

PubMed2000

Physiological patterns in the hippocampo-entorhinal cortex system.

The anatomical connectivity and intrinsic properties of entorhinal cortical neurons give rise to ordered patterns of ensemble activity. How entorhinal ensembles form, interact, and accomplish emergent processes such as memory formation is not well-understood. We lack sufficient understanding of how neuronal ensembles in general can function transiently and distinctively from other neuronal ensembles. Ensemble interactions are bound, foremost, by anatomical connectivity and temporal constraints on neuronal discharge. We present an overview of the structure of neuronal interactions within the entorhinal cortex and the rest of the hippocampal formation. We wish to highlight two principle features of entorhinal-hippocampal interactions. First, large numbers of entorhinal neurons are organized into at least two distinct high-frequency population patterns: gamma (40-100 Hz) frequency volleys and ripple (140-200 Hz) frequency volleys. These patterns occur coincident with other well-defined electrophysiological patterns. Gamma frequency volleys are modulated by the theta cycle. Ripple frequency volleys occur on each sharp wave event. Second, these patterns occur dominantly in specific layers of the entorhinal cortex. Theta/gamma frequency volleys are the principle pattern observed in layers I-III, in the neurons that receive cortical inputs and project to the hippocampus. Ripple frequency volleys are the principle population pattern observed in layers V-VI, in the neurons that receive hippocampal output and project primarily to the neocortex. Further, we will highlight how these ensemble patterns organize interactions within distributed forebrain structures and support memory formation.

Afferent Pathways↗

PubMed2001

Dendrotoxin sensitive potassium channels modulate GABA but not glutamate release in the rat entorhinal cortex in vitro.

We have previously shown that the anticonvulsant drug, phenytoin, increases the frequency and amplitude of spontaneous inhibitory postsynaptic currents at GABA synapses on principal neurones in the rat entorhinal cortex. This effect is similar to that seen at other GABA synapses following blockade of voltage-gated potassium channels (Kv1.1, 1.2 and 1.6) with alpha-dendrotoxin. In the present study we examined whether dendrotoxins can alter GABA release at synapses in the entorhinal cortex. We recorded spontaneous inhibitory postsynaptic currents using whole cell voltage clamp techniques in slices of rat entorhinal cortex in vitro. alpha-Dendrotoxin evoked an increase in frequency and amplitude of spontaneous inhibitory postsynaptic currents, an effect that was blocked by prior perfusion with tetrodotoxin. The effect of the toxin did not occlude the increase in spontaneous inhibitory postsynaptic currents seen with phenytoin. Indeed, the effect of the two drugs together was, at least, additive on GABA release. Perfusion with the specific Kv1.1 blocker, dendrotoxin-K had no effect on GABA release. In addition, alpha-dendrotoxin had no effect on frequency or amplitude of spontaneous excitatory postsynaptic currents at glutamate synapses on entorhinal cortex neurones. We conclude that K-channels containing the Kv1.2 and/or 1.6 subunits modulate the release of GABA, but not glutamate in the entorhinal cortex. The modulation of GABA release by phenytoin is unlikely to be due to an effect on these channels.

Animals↗

PubMed1995

Parvalbumin-immunoreactive neurons in the entorhinal cortex of the rat: localization, morphology, connectivity and ultrastructure.

We studied the distribution, morphology, ultrastructure and connectivity of parvalbumin-immunoreactive neurons in the entorhinal cortex of the rat. Immunoreactive cell bodies were found in all layers of the entorhinal cortex except layer I. The highest numbers were observed in layers II and III of the dorsal division of the lateral entorhinal area whereas the lowest numbers occurred in the ventral division of the lateral entorhinal area. Most such neurons displayed multipolar configurations with smooth dendrites. We distinguished a type with long dendrites and a type with short dendrites. We also observed pyramidal immunoreactive neurons. A dense plexus of immunoreactive dendrites and axons was prominent in layers II and III of the dorsal division of the lateral entorhinal area and the medial entorhinal area. None of the parvalbumin-immunoreactive cells became retrogradely labelled after injection of horseradish peroxidase into the hippocampal formation. By electron microscopy, immunoreactivity was observed in cell bodies, dendrites, myelinated and unmyelinated axons and axon terminals. Immunoreactive dendrites and axons occurred in all cortical layers. We noted many myelinated immunoreactive axons. Immunoreactive axon terminals were medium sized, contained pleomorphic synaptic vesicles, and established symmetrical synapses. Both horseradish peroxidase labelled and unlabelled immunonegative cell bodies often received synapses from immunopositive axon terminals arranged in baskets. Synapses between immunoreactive axon terminals and unlabelled dendritic shafts and spines were abundant. Synapses with initial axon segments occurred less frequently. In addition, synaptic contacts were present between immunopositive axon terminals and cell bodies and dendrites. Thus, the several types of parvalbumin-containing neuron in the entorhinal cortex are interneurons, connected to one another and to immunonegative neurons through a network of synaptic contacts. Immunonegative cells projecting to the hippocampal formation receive axo-somatic basket synapses from immunopositive terminals. This connectivity may form the morphological substrate underlying the reported strong inhibition of cells in layers II and III of the entorhinal cortex projecting to the hippocampal formation.

Animals↗

PubMed1983

Post-trial reticular facilitation of associative changes in multiunit activity; comparison between dentate gyrus and entorhinal cortex.

Multiunit activity recorded in both the dentate gyrus and the entorhinal cortex during classical conditioning was studied in freely moving rats receiving a mild post-trial stimulation of the mesencephalic reticular formation. Dentate multiunit activity progressively increased in response to an auditory signal (conditioned stimulus) after pairing the signal with a footshock (unconditioned stimulus). No such increase was seen in the entorhinal cortex of the same animals during conditioning. Post-trial reticular stimulation facilitated the development of associative changes in dentate multiunit activity, while having no effect in the entorhinal cortex. The results were interpreted as indicating a possible specificity of action of post-trial reticular stimulation on learning-induced plasticity and are discussed in relation to the concept of neural perseverance in memory consolidation.

Animals↗

PubMed1995

Autoradiographic characterization of neurotensin receptors in the entorhinal cortex of schizophrenic patients and control subjects.

Neurotensin, an endogenous peptide and putative neurotransmitter, exhibits a wide range of interactions with dopaminergic neurons and displays some actions akin to neuroleptics. Moreover, neurotensin receptors are abundant in specific layers of the entorhinal cortex where cytoarchitectural abnormalities have been reported in schizophrenia. We therefore examined the entorhinal cortex from postmortem specimens of five control patients and six schizophrenic patients for alterations in neurotensin receptor quantitation and distribution using receptor autoradiography. Specific 125I- neurotensin binding was concentrated in layer II cell clusters, with a 40% reduction in binding in the schizophrenic group (p < 0.05). Moderate binding was observed in both cohorts in deep layers V/VI, with negligible binding in the hippocampus. There was no statistical difference in quantitative neurotensin binding in other lamina of the entorhinal cortex of schizophrenics compared with controls. The characteristic laminar pattern of binding did not differ between cohorts. The reduction in neurotensin binding in schizophrenics is consistent with an increasing number of reports of structural abnormalities in the medial temporal lobe of schizophrenics in general and the entorhinal cortex in particular. Further studies are required to examine the evidence for neuroanatomic and neurochemical pathology in the entorhinal cortex.

Adult↗

PubMed2000

Computational modeling of entorhinal cortex.

Computational modeling provides a means for linking the physiological and anatomical characteristics of entorhinal cortex at a cellular level to the functional role of this region in behavior. We have developed detailed simulations of entorhinal cortical neurons and networks, with an emphasis on the role of acetylcholine in entorhinal cortical function. Computational modeling suggests that when acetylcholine levels are high, this sets appropriate dynamics for the storage of stimuli during performance of delayed matching tasks. In particular, acetylcholine activates a calcium-sensitive nonspecific cation current which provides an intrinsic cellular mechanism which could maintain neuronal activity across a delay period. Simulations demonstrate how this phenomena could underlie entorhinal cortex delay activity as described in previous unit recordings. Acetylcholine also induces theta rhythm oscillations which may be appropriate for timing of afferent input to be encoded in hippocampus and for extraction of individual stored sequences from multiple stored sequences. Lower levels of acetylcholine may allow sharp wave dynamics which can reactivate associations encoded in hippocampus and drive the formation of additional traces in hippocampus and entorhinal cortex during consolidation.

Acetylcholine↗

PubMed2000

Propagation of synchronous burst discharges from entorhinal cortex to morphologically and electrophysiologically identified neurons of rat lateral amygdala.

Intracellular and field potential recordings were taken from the lateral nucleus of the amygdala in a rat horizontal brain slice preparation that included hippocampal formation. Pyramidal cells comprised the majority of labeled cells (77%). Electrophysiological classification based on hyperpolarizing or depolarizing afterpotentials subdivided both the pyramidal and non-pyramidal cell classes, although pyramidal cells tended to have hyperpolarizing afterpotentials (70%) and non-pyramidal cells tended to have depolarizing afterpotentials (63%). Synchronous population bursts were triggered with single extracellular stimuli in the deep layers of entorhinal cortex. These events propagated from deep layers of entorhinal cortex into the lateral nucleus of the amygdala. Latencies were consistent with a direct entorhinal to amygdala projection. Individual lateral nucleus neurons exhibited responses ranging from a long burst response that included an initial period of 200 Hz firing and a tail of gamma frequency firing lasting over 100 ms (grade 1) to an epsp with no firing (grade 4). Half of pyramidal cells responding to events initiated in entorhinal cortex were found to receive epsps strong enough to trigger firing. Only one stellate neuron fired in response to entorhinal stimulation. Excitatory postsynaptic responses included NMDA and non-NMDA receptor mediated components. We demonstrate that synchronous population events can propagate from entorhinal cortex to the lateral nucleus of the amygdala and that pyramidal neurons of the lateral nucleus are more common targets than stellate neurons. We conclude that other synchronous events such as sharp waves and interictal spikes can spread from entorhinal cortex to amygdala in the same manner.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1995

Chronic alcoholism decreases neuronal nuclear size in the human entorhinal cortex.

The effect of chronic alcoholism in the neuronal nuclear area (karyometry) of the lateral entorhinal cortex at three rostro-caudal levels (rostral, intermediate and caudal) has been studied in 19 alcoholic subjects and in 15 aged-matched controls. Cases were distributed into three groups according to their age (29-44, 45-60 and 61-70 years of age). In the second group (45-60 years), the nuclear size in layers II and III of the caudal entorhinal cortex showed a very significant decrease compared to controls. The first group (29-44 years) also showed a significant reduction in size, while the third group presented the smallest differences. The presence of cirrhosis in the alcoholic group did not vary the observed results. Thus, chronic alcoholism significantly decreases the nuclear size in layers II and III of the lateral entorhinal cortex, and thus the entorhinal output to the hippocampus may be altered in alcoholism.

Adult↗

PubMed2001

Sprouting in the hippocampus after entorhinal cortex lesion is layer- specific but not translaminar: which molecules may be involved?

Entorhinal cortex lesion partially denervates the rat fascia dentata. This is said to induce sprouting of intact fibers from neighboring layers that invade the zone of the degenerating axons. However, recent in vivo and in vitro studies failed to demonstrate sprouting across laminar boundaries. Sprouting does occur, but it mainly involves unlesioned fiber systems terminating within the layer of fiber degeneration. These findings point to laminar cues that promote sprouting of fibers within the denervated zone while repelling other, adjacent fiber systems that try to grow into the denervated zone. A group of molecules that are likely to guide the sprouting process and the formation of borders are extracellular matrix molecules synthesized by reactive astrocytes. These molecules provide boundaries for growing axons during development. Some extracellular matrix molecules (tenascin-C, DSD- 1 -proteoglycan, neurocan, and brevican) were upregulated within the denervated outer molecular layer after lesion of the entorhinal cortex, suggesting a similar role after lesion. These extracellular matrix components forin a sharp molecular border towards the adjacent nondenervated inner molecular layer, and their pattern of distribution correlates precisely with the laminar termination pattern of the sprouting fiber populations. Thus, extracellular matrix molecules could delineate boundaries of axonal growth after entorhinal cortex lesion and could thus contribute to the molecular processes underlying the postlesional re-patterning of the fascia dentata.

Animals↗

PubMed1996

The rhythmic slow activity recorded from entorhinal cortex in freely moving cats.

The relationships between the entorhinal cortex (EC) and the hippocampal formation (Hipp) field potentials were examined in the present study. The detailed analyses of the signal let us group the patterns of theta appearance into three categories: (1) Theta rhythm dominating in both recordings from the EC and from the Hipp (2) Theta rhythm dominating in the Hipp with irregular activity in the EC (3) Theta rhythm dominating in the EC with irregular activity in the Hipp. These findings provide the evidence for the intrinsic generator of theta rhythm to be localized in entorhinal cortex in cats.

Animals↗