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PubMed1995

The perforant path projection to hippocampal area CA1 in the rat hippocampal-entorhinal cortex combined slice.

1. The perforant path projection from layer III of the entorhinal cortex to CA1 of the hippocampus was studied within a hippocampal-entorhinal combined slice preparation. We prevented contamination from the other main hippocampal pathways by removal of CA3 and the dentate gyrus. 2. Initially the projection was mapped using field potential recordings that suggested an excitatory sink in stratum lacunosum moleculare with an associated source in stratum pyramidale. 3. However, recording intracellularly from CA1 cells, stimulation of the perforant path produced prominent fast GABAA and slow GABAB IPSPs often preceded by small EPSPs. In a small number of cells we observed EPSPs only. 4. CNQX blocked excitatory and inhibitory responses. This indicated the presence of an intervening excitatory synapse between the inhibitory interneurone and the pyramidal cell. 5. Focal bicuculline applications revealed that the major site of GABAA inhibitory input was to stratum radiatum of CA1. 6. The inhibition activated by the perforant path was very effective at reducing simultaneously activated Schaffer collateral mediated EPSPs and suprathreshold-stimulated action potentials. 7. Blockade of fast inhibition increased excitability and enhanced slow inhibition. Both increases relied upon the activation of NMDA receptors. 8. Perforant path inputs activated prominent and effective disynaptic inhibition of CA1 cells. This has significance for the output of hippocampal processing during normal behaviour and also under pathological conditions.

2-Amino-5-phosphonovalerate↗
PubMed2001

Properties of entorhinal cortex deep layer neurons projecting to the rat dentate gyrus.

Medial entorhinal cortex (EC) deep layer neurons projecting to the dentate gyrus (DG) were studied. Neurons, retrogradely-labelled with rhodamine-dextran-amine were characterized electrophysiologically with the patch clamp technique and finally labelled with biocytin. Pyramidal and nonpyramidal neurons form projections from the deep layers of the EC to the molecular layer of the DG. In addition, both classes of projection neurons send ascending axon collaterals to the superficial layers of the EC. Both classes of neurons were characterized physiologically by regular action potential firing upon depolarizing current injection. While a substantial number of pyramidal projection cells showed intrinsic membrane potential oscillations, none of the studied nonpyramidal cells exhibited oscillations. Despite the morphological similarity of bipolar and multipolar cells to those of GABAergic interneurons in the EC, their electrophysiological characteristics were similar to those of principal neurons and immunocytochemistry for GABA was negative. We conclude, that neurons of the deep layers of the medial EC projecting to the DG may function as both local circuit and projecting neurons thereby contributing to synchronization between deep layers of the EC, superficial layers of the EC and the DG.

Animals↗
PubMed1995

Neurophysiology and neuropharmacology of projections from entorhinal cortex to striatum in the rat.

We studied projections from the entorhinal cortex (Ent) to the striatum in anesthetized rats using extra- and intracellular recording and multibarrel iontophoresis. The majority of recording were from the caudate-putamen (CPu) and core of the nucleus accumbens (AcbC). Electrical stimulation of the Ent evoked synaptic responses in 77% of tests with AcbC neurons and 48% of tests with CPu neurons. In the case of AcbC neurons, 61% of these tests proved to be excitatory and were often followed by inhibitory phases. In contrast to this, only 18% of tests from CPu neurons were excitatory. Intracellular HRP labeling showed that responsive cells were medium spiny neurons. During iontophoretic experiments, application of the glutamatergic AMPA antagonist DNQX could selectively decrease or block excitatory responses. The GABAA antagonist bicuculline methiodide increased cellular firing rates and could reveal excitatory responses, suggesting block of a short-latency, short-duration inhibitory component. Ejection of the GABAB antagonist CGP-35348 could attenuate a later, longer-duration component of inhibition. The results indicate that the Ent excites striatal neurons at least in part by glutamatergic receptors and suggest that this excitation is followed by secondary prolonged GABAergic inhibition.

Animals↗
PubMed1988

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

Lesions of the rat entorhinal cortex cause extensive synaptic restructuring and perturbation of calcium regulation in the dentate gyrus of hippocampus. Calpain is a calcium-activated protease which has been implicated in degenerative phenomena in muscles and in peripheral nerves. In addition, calpain degrades several major structural neuronal proteins and has been proposed to play a critical role in the morphological changes observed following deafferentation. In this report we present evidence that lesions of the entorhinal cortex produce a marked increase in the breakdown of brain spectrin, a substrate for calpain, in the dentate gyrus. Two lines of evidence indicate that this effect is due to calpain activation: (i) the spectrin breakdown products observed following the lesion are indistinguishable from calpain-generated spectrin fragments in vitro; and (ii) their appearance can be reduced by prior intraventricular in fusion of leupeptin, a calpain inhibitor. Levels of spectrin breakdown products are increased as early as 4 h post-lesion, reach maximal values at 2 days, and remain above normal to some degree for at least 27 days. In addition, a small but significant increase in spectrin proteolysis is also observed in the hippocampus contralateral to the lesioned side in the first week postlesion. At 2 days postlesion the total spectrin immunoreactivity (native polypeptide plus breakdown products) increases by 40%, suggesting that denervation of the dentate gyrus produces not only an increased rate of spectrin degradation but also an increased rate of spectrin synthesis. These results indicate that calpain activation and spectrin degradation are early biochemical events following deafferentation and might well participate in the remodelling of postsynaptic structures. Finally, the magnitude of the observed effects as well as the stable nature of the breakdown products provide a sensitive assay for neuronal pathology.

Animals↗
PubMed2002

Frequency selectivity of layer II stellate cells in the medial entorhinal cortex.

Electrophysiologically, stellate cells (SCs) from layer II of the medial entorhinal cortex (MEC) are distinguished by intrinsic 4- to 12-Hz subthreshold oscillations. These oscillations are thought to impose a pattern of slow periodic firing that may contribute to the parahippocampal theta rhythm in vivo. Using stimuli with systematically differing frequency content, we examined supra- and subthreshold responses in SCs with the goal of understanding how their distinctive characteristics shape these responses. In reaction to repeated presentations of identical, pseudo-random stimuli, the reliability (repeatability) of the spiking response in SCs depends critically on the frequency content of the stimulus. Reliability is optimal for stimuli with a greater proportion of power in the 4- to 12-Hz range. The simplest mechanistic explanation of these results is that rhythmogenic subthreshold membrane mechanisms resonate with inputs containing significant power in the 4- to 12-Hz band, leading to larger subthreshold excursions and thus enhanced reliability. However, close examination of responses rules out this explanation: SCs do show clear subthreshold resonance (i.e., selective amplification of inputs with particular frequency content) in response to sinusoidal stimuli, while simultaneously showing a lack of subthreshold resonance in response to the pseudo-random stimuli used in reliability experiments. Our results support a model with distinctive input-output relationships under subthreshold and suprathreshold conditions. For suprathreshold stimuli, SC spiking seems to best reflect the amount of input power in the theta (4-12 Hz) frequency band. For subthreshold stimuli, we hypothesize that the magnitude of subthreshold theta-range oscillations in SCs reflects the total power, across all frequencies, of the input.

Algorithms↗
PubMed1999

Entorhinal cortex in temporal lobe epilepsy: a quantitative MRI study.

BACKGROUND: The entorhinal cortex (EC) is a distinct anatomic and functional region of the anterior parahippocampal gyrus, which plays a role in seizure generation and propagation in temporal lobe epilepsy (TLE). In tissue resected from TLE patients, cell loss in the EC has been described. OBJECTIVES: To develop a standardized protocol for identifying the anatomic boundaries of the EC using high-resolution MRI and to examine morphologic changes of the EC in TLE. METHODS: We performed T1-weighted MRIs in 20 patients (7 males) with TLE (mean age 34 years) and 18 normal controls (mean age 26 years). Eleven patients had a left and 9 a right epileptic focus as defined by history, video-EEG, and surgical outcome. The volumes of the EC, the hippocampus, and the amygdala were measured using a standardized MRI protocol. Analysis of variance (ANOVA) was used to examine the effect of seizure focus lateralization and hemisphere on these volumes. An asymmetry ratio [A (%) = 100 x (R-L)/(R+L)/2] was also compared between groups using ANOVA. RESULTS: In normal controls the volume of the right EC was 1,247 +/- 127 mm3 (mean +/- standard deviation), and that of the left EC was 1,215 +/- 135 mm3 (p > 0.05). We found a bilateral reduction in the volume of the EC in TLE patients compared with controls (p < 0.05). Examination of the asymmetry ratios showed that the reduction in volume of the EC was greater ipsilateral to the epileptic focus (p < 0.05). The volumes of the hippocampus and the amygdala were smaller on the side of the focus in TLE patients compared with controls (p < 0.05). CONCLUSIONS: With a standardized protocol for the quantitative assessment of the EC, patients with unilateral TLE show bilateral reduction in the volume of the EC. However, this reduction is more severe ipsilateral to the epileptic focus.

Adolescent↗
PubMed1994

Perforant path damage results in progressive neuronal death and somal atrophy in layer II of entorhinal cortex and functional impairment with increasing postdamage age.

In vivo model systems that can evaluate neuronal death, survival, and regeneration are critical to revealing basic mechanisms of neuronal response and developing strategies for CNS repair. We propose a distinct experimental model of CNS degeneration following lesions to the perforant path connecting the hippocampus and the entorhinal cortex. Within 2 weeks of a unilateral aspirative perforant path lesion, 30% of the ipsilateral entorhinal cortex layer II (ECL II) projection neurons had died with no change in the contralateral ECL II population. Although there was no loss of ECL II neurons with normal aging, animals that survived for 15 months postlesion experienced an almost 50% loss of ipsilateral neurons compared to unlesioned controls. This progressive neuronal death was bilateral, with the contralateral ECL II experiencing a 30% decline in neuronal number relative to unlesioned controls. The use of unbiased stereology ensured that estimates of total number were not distorted by changes in the reference volume. The documented progressive neuronal death resulted in delayed behavioral impairment in spatial learning and performance (latency nearly 200% of controls). We propose, therefore, that the perforant path model is suitable for experimental investigation of neuronal survival and regeneration following CNS trauma.

Aging↗
PubMed2006

Odor increases [3H]phorbol dibutyrate binding to protein kinase C in olfactory structures of rat brain. Effect of entorhinal cortex lesion.

Since protein kinase C (PKC) is known to be activated in the olfactory bulb and in several limbic areas related to odor processing, we determined whether an olfactory stimulus was able to modulate the activity of PKC in animals with bilateral entorhinal cortex lesion. The translocation of PKC from the cytosol to the membrane was studied using the phorbol ester 12,13-dibutyrate ([3H]PDBu) binding in control and bilateral entorhinal cortex (EC) lesioned rats. The lesion of EC per se did not significantly affect [3H]PDBu binding in any of the brain structures analyzed, while odor stimulation induced it in both control and EC-lesioned groups in the external plexiform layer of the olfactory bulb. In contrast, an odor-induced increase of [3H]PDBu binding in internal glomerular layer of the olfactory bulb was only observed in EC lesioned animals. Similar results were obtained in the piriform cortex. In both CA1 and CA3 hippocampal subfields, odor stimulation induced an increase of [3H]PDBu binding in both control and EC-lesioned animals, the increase being potentiated only in CA1 of lesioned rats. The dentate gyrus and the amygdala exhibited a similar pattern of [3H]PDBu binding, showing a significant increase exclusively in EC-lesioned animals after odor stimulation. The results strongly suggest that the EC plays a key role in odor processing. PKC appears to play an important role in responding to the activation of lipid second messengers, which have been described to be involved in the processing of odor stimuli in several structures of the olfactory pathway.

Amygdala↗
PubMed1997

Asymmetrical increases in dopamine turn-over in the nucleus accumbens and lack of changes in locomotor responses following unilateral dopaminergic depletions in the entorhinal cortex.

Functional interdependence between mesencephalic dopaminergic pathways is an emerging concept. Using in vivo voltammetry and acute manipulation of dopaminergic transmission with pharmacological agents, we have previously reported the existence of a preferentially left lateralized functional interdependence between the entorhinal cortex and the nucleus accumbens. The aim of the present work was to test if this phenomenon is only a dynamic process or if compensation occurs when interdependent functioning is considered in a more long-term perspective. In this study 6-OHDA lesions of the dopamine terminals of the entorhinal cortex were performed separately in the left and right hemispheres. Spontaneous and (+)-amphetamine stimulated locomotor activity were recorded 3 weeks after unilateral interventions in the Ent. Variations in DA and DOPAC levels were measured in the nucleus accumbens 5 weeks after the lesion. The following results were obtained. After unilateral 6-OHDA in the left Ent, DA and DOPAC tissue contents as well as the DOPAC/DA ratio were found significantly changed in nucleus accumbens in the two hemispheres. After dopaminergic destruction in the right Ent only the DOPAC/DA ratio in the left Acc was found statistically elevated. No differences in spontaneous or (+)-amphetamine-stimulated locomotor activity were observed after either left or right lesions. These data confirm those previously obtained with the voltammetric approach and further support the existence of an asymmetrical functional interdependence between mesencephalic DAergic pathways reaching the Ent and the Acc. These results may provide new insights in the pathophysiology of schizophrenic psychoses.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Hippocampal N-methyl-D-aspartate and kainate binding in response to entorhinal cortex aspiration or 192 IgG-saporin lesions of the basal forebrain.

Lesion models in the rat were used to examine the effects of removing innervation of the hippocampal formation on glutamate receptor binding in that system. Bilateral aspiration of the entorhinal cortex was used to remove the cortical innervation of the hippocampal formation and the dentate gyrus. The subcortical input to the hippocampus from cholinergic neurons of the basal forebrain was lesioned by microinjection of the immunotoxin 192 IgG-saporin into the medial septum and vertical limb of diagonal band. After a 30-day postlesion survival, the effects of these lesions on N-methyl-D-aspartate-displaceable [3H]glutamate and [3H]kainate binding in the hippocampus were quantified using in vitro autoradiography. The bilateral entorhinal lesion induced a sprouting response in the dentate gyrus, measured by an increase in the width of [3H]kainate binding. It also induced an increase in the density of [3H]kainate binding in CA3 stratum lucidum and an increase in N-methyl-D-aspartate binding throughout the hippocampus proper and the dentate gyrus. The selective lesion of cholinergic septal input did not have any effect on hippocampal [3H]kainate binding and induced only a moderate decrease in N-methyl-D-aspartate binding that was not statistically reliable. The entorhinal and cholinergic lesions were used as in vivo models of the degeneration of hippocampal input that occurs in normal aging and Alzheimer's disease. The results from the present lesion study suggest that some, but not all, of the effects on hippocampal [3H]kainate and N-methyl-D-aspartate binding induced by the lesions are consistent with the status of binding to these receptors in aging and Alzheimer's disease. Consistent with the effects of aging and Alzheimer's disease is an altered topography of [3H]kainate binding after entorhinal cortex lesion and a modest decline in N-methyl-D-aspartate binding after lesions of the cholinergic septal input to the hippocampus.

Acetylcholinesterase↗
PubMed2000

nNOS expression in reactive astrocytes correlates with increased cell death related DNA damage in the hippocampus and entorhinal cortex in Alzheimer's disease.

The immunocytochemical distribution of the neuronal form of nitric oxide synthase (nNOS) was compared with neuropathological changes and with cell death related DNA damage (as revealed by in situ end labeling, ISEL) in the hippocampal formation and entorhinal cortex of 12 age-matched control subjects and 12 Alzheimer's disease (AD) patients. Unlike controls, numerous nNOS-positive reactive astrocytes were found in AD patients around beta-amyloid plaques in CA1 and subiculum and at the places of clear and overt neuron loss, particularly in the entorhinal cortex layer II and CA4. This is the first evidence of nNOS-like immunoreactivity in reactive astrocytes in AD. In contrast to controls, in all but one AD subject, large numbers of ISEL-positive neuronal nuclei and microglial cells were found in the CA1 and CA4 regions and subiculum. Semiquantitative analysis showed that neuronal DNA fragmentation in AD match with the distribution of nNOS-expressing reactive astroglial cells in CA1 (r = 0.74, P < 0.01) and CA4 (r = 0.58, P < 0.05). A portion of the nNOS-positive CA2/CA3 pyramidal neurons was found to be spared even in the most affected hippocampi. A significant inverse correlation between nNOS expression and immunoreactivity to abnormally phosphorylated tau proteins (as revealed by AT8 monoclonal antibody) in perikarya of these CA2/3 neurons (r = -0.85, P < 0.01) suggests that nNOS expression may provide selective resistance to neuronal degeneration in AD. In conclusion, our results imply that an upregulated production of NO by reactive astrocytes may play a key role in the pathogenesis of AD.

Aged↗
PubMed1991

Hippocampus and olfactory discrimination learning: effects of entorhinal cortex lesions on olfactory learning and memory in a successive-cue, go-no-go task.

Three experiments assessed the effect of entorhinal cortex lesions on olfactory learning and memory using a successive-cue olfactory discrimination paradigm. In contrast to the results of other studies that used a simultaneous-cue paradigm, lesions of the entorhinal cortex facilitated rats' acquisition of individual odor discrimination problems, with no impairment in memory for the individual odors across both short (24-hr) and long (65-day) retention intervals and despite limited training. When considered together with previous observations of facilitation or impairment in learning after damage to the hippocampal system, the present data suggest that the hippocampus is preferentially involved in encoding relations among multiple stimuli. By this account, facilitation of performance is due to an interaction between hippocampal system dysfunction and task conditions that hinder direct comparisons among cues.

Animals↗
PubMed1990

Direct projections of non-pyramidal neurons of Ammon's horn to the amygdala and the entorhinal cortex.

When WGA-HRP (wheat germ agglutinin-horseradish peroxidase conjugate) was injected into the amygdala (lateral and basolateral amygdaloid nuclei) or entorhinal cortex of the cat, a number of nonpyramidal neurons in Ammon's horn were retrogradely labeled. The results indicate that some non-pyramidal neurons in Ammon's horn send projection fibers to the amygdala and entorhinal cortex.

Amygdala↗
PubMedDate not supplied

Postnatal development of tyrosine hydroxylase- and dopamine transporter-immunoreactive axons in monkey rostral entorhinal cortex.

Dopamine afferents from the mesencephalon appear to play a critical role in the normal development and cognitive functions of multiple areas of the primate cerebral cortex. In some regions, such as the prefrontal and motor cortices, dopamine innervation changes substantially during postnatal development. However, little is known about the postnatal maturation of dopamine afferents to the primate rostral entorhinal cortex, a periallocortical region that receives a dense dopamine innervation in adults. In this study, we used immunocytochemical techniques and antibodies against tyrosine hydroxylase and the dopamine transporter to examine the postnatal development of dopamine axons in the rostral subdivision of macaque monkey entorhinal cortex. Within animals, the axons labeled with each antibody did not differ in overall density or laminar distribution. Across development, the density of dopamine axons in layers I and VI did not change appreciably. In contrast, the density of labeled axons in layer III significantly increased by a factor of three between birth and 5-7 months of age. The timing of this change differs substantially from that observed in prefrontal cortex, where peak dopamine innervation occurs between 2 and 3 years of age. These findings, in concert with other data, suggest that developmental changes in the dopamine innervation of cortical regions may parallel the functional maturation of those areas.

Aging↗
PubMedDate not supplied

[Sensory characteristics of the cortical input to the hippocampus: the entorhinal cortex].

Sensory reactions of neurones in the medial entorhinal area were investigated in unanaesthetized rabbits. 54% of the units were multimodal. Different stimuli evoked various response patterns with complex on-off components. Differential coding of pure tones was observed in many cells, which were also sensitive to other sensory modalities. Complete habituation of responses was virtually absent; only partial reduction of the late components was observed in some cases. In 71% of units reactions were stable or incremental (gradual development and increase). It may be concluded that from the entorhinal cortex the hippocampus receives highly differentiated signals of "associative" type, which do not habituate and are of a stable or incremental nature.

Animals↗
PubMed2004

Characterization of the inhibitory glycine receptor on entorhinal cortex neurons.

In addition to the well-established functional description of the glycine receptor (GlyR) in the spinal cord, GlyR expression has recently been found in higher brain regions, such as the striatum or hippocampus. In this study we have investigated the electrophysiological response of glycine in the rat entorhinal cortex slice. In all recorded cells we found significant current responses to glycine with an EC(50) value of about 100 micro m. Most importantly, we detected a cross-inhibition of glycine responses by GABA but not vice versa. These findings are in line with recent published data of cross-talks between GABA(A)R and GlyR but indicate a novel type of cross-inhibition of these receptors in the entorhinal cortex.

Animals↗
PubMed2002

A comparison of the effects of fimbria-fornix, hippocampal, or entorhinal cortex lesions on spatial reference and working memory in rats: short versus long postsurgical recovery period.

Using a radial maze task and different postoperative recovery periods, this experiment assessed and compared the reference and working memory performances of adult Long-Evans male rats subjected to entorhinal cortex, fimbria-fornix, and hippocampus lesions. Sham-operated rats were used as controls. In order to see whether the duration of the postsurgical recovery period would influence acquisition of the complex radial maze task, training began 1 month following surgery (Delay 1) for half the rats in each group, while for the other half training was started 6.5 months following surgery (Delay 2). The results indicated that at both recovery periods the entorhinal cortex lesions failed to affect either working or reference memory in the spatial task. Conversely, both fimbria-fornix and hippocampus lesions impaired both reference and working memory. While the reference memory deficit was generally similar in both fimbria-fornix and hippocampal lesion groups, analysis of the results for working memory indicated that at the longer delay rats with fimbria-fornix lesions were still impaired but in animals that had the hippocampus removed, working memory did not differ from that of controls. These results suggest that there was some recovery in those rats with hippocampal lesions (e.g., on the working memory task) but both hippocampal and fimbria-fornix animals were still impaired compared to controls when training was delayed 6.5 months following the operations.

Animals↗
PubMed2006

Hughlings Jackson and the role of the entorhinal cortex in temporal lobe epilepsy: from patient A to Doctor Z.

Hughlings Jackson's insightful bedside observations of patients with epilepsy paved the way for the first effective surgical epilepsy treatments. Jackson's most famous case, that of Doctor Z, concerned a medical doctor with partial complex seizures who was reported to have a discrete and circumscribed medial temporal lobe (mTL) lesion on autopsy. Although integral to Jackson's argument for mTL resection, the case remains controversial due to inadequate pathological descriptions of Doctor Z's lesion. This motivated us to describe the case of a patient, whom we call Patient A, who suffered from a form of epilepsy similar to that of Doctor Z, accompanied by a discrete and circumscribed mTL lesion in the exact same location. The lesion, a cavernous hemangioma, spared the hippocampus and was restricted to the lateral aspect of the entorhinal cortex. This finding validates Jackson's original description and suggests that the entorhinal cortex can play a role in seizure genesis.

Aged↗