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PubMed1994

Synaptic and neuritic alterations during the progression of Alzheimer's disease.

Extensive synaptic and neuritic alterations in the neocortex and limbic system are characteristically found in Alzheimer's disease (AD). However, it is not known how early in the development of the disease these alterations occur. For the present study, we compared the synaptic and neuritic alterations among cases classified clinically and neuropathologically as early, mild and advanced AD. In early AD there was a 20% loss of synaptophysin-immunoreactive presynaptic terminals in the outer molecular layer of the hippocampal dentate gyrus (but not in the neocortex and entorhinal cortex), accompanied by increased amyloid precursor protein (APP) and Alz50 immunoreactivity in hippocampal and entorhinal cortex pyramidal neurons. These results suggest that abnormal neuronal expression of APP and cytoskeletal proteins in early stages might be involved in the mechanisms of synaptic pathology in AD.

Aged↗
PubMed1995

Cell-specific modulation of basal and seizure-induced neurotrophin expression by adrenalectomy.

Reports of glucocorticoid effects on neurotrophin expression suggest that adrenal hormones may contribute to the pattern of changes in the expression of these factors induced by neuronal activity and seizures. To examine this possibility, the present study evaluated the influence of adrenalectomy on basal expression and seizure-induced alterations in levels of nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 messenger RNAs in hippocampus, entorhinal cortex, and superficial neocortex. For determination of hormone effects on basal expression, adult male rats were adrenalectomized and killed 10-14 days later with paired adrenal-intact controls. For studies of adrenal steroid involvement in expression following seizure, adrenalectomized and adrenal-intact rats received a seizure-producing lesion of the dentate gyrus hilus. Changes in neurotrophin messenger RNA content were assessed by quantitative in situ hybridization. Adrenalectomy alone had no significant effect on brain-derived neurotrophic factor messenger RNA content but did result in cell-specific decreases in nerve growth factor and neurotrophin-3 messenger RNAs. Nerve growth factor messenger RNA levels were reduced in hippocampal stratum granulosum, entorhinal cortex, and neocortex but not in cells of the hippocampal molecular layers or hilus. With adrenalectomy, neurotrophin-3 messenger RNA was virtually eliminated from CA2 stratum pyramidale, partially reduced in stratum granulosum, but unaffected in neurons of the hippocampal molecular layers or entorhinal cortex. These effects were partially reversed by corticosterone (2 mg/l) supplement to the drinking saline. In experimental-seizure rats, adrenalectomy did not alter the direction or basic pattern of seizure-induced changes in neurotrophin expression but did change the time courses and magnitudes of these effects. In all areas measured, brain-derived neurotrophic factor messenger RNA content was more greatly and persistently elevated by seizure in adrenalectomized as compared with adrenal-intact rats. In contrast, with adrenalectomy seizures induced smaller increases in nerve growth factor messenger RNA content. Adrenalectomy augmented the decrease in neurotrophin-3 messenger RNA induced by seizure in hippocampus but not in entorhinal cortex. These results demonstrate that adrenal hormones play a major role in the regulation of basal nerve growth factor and neurotrophin-3 messenger RNA expression by specific populations of forebrain neurons. Moreover, the adrenal steroids have opposite effects on activity-dependent changes in brain-derived neurotrophic factor and nerve growth factor messenger RNA levels but are not required for the basic pattern of changes in neurotrophin messenger RNA expression elicited by recurrent seizures.

Adrenalectomy↗
PubMed1994

Axons regenerate with correct specificity in horizontal slice culture of the postnatal rat entorhino-hippocampal system.

We have used slice culture of the entorhino-hippocampal system to investigate (1) whether nerve fibres which are cut postnatally are able to regenerate and (2) whether the regenerating fibres are able to establish correct selective target specificity in the formation of their terminal fields. Slices of tissue were taken in the horizontal plane through the caudo-ventral pole of the cerebral hemisphere of 9- to 10-day-old rats. Such slices maintain the entorhinal cortex in continuity with the hippocampus and intervening retrohippocampal areas. However, because of the dorsal inclination of the entorhino-hippocampal projection fibres in situ, the segments of the entorhinal cortex and hippocampus contained within each individual horizontal slice were disconnected from each other. During subsequent culture, the formation of fibre connections between the entorhinal area and the hippocampal complex was studied by the extracellular and intracellular anterograde transport of biocytin or biotin dextran, the retrograde transport of biotin dextran or carbocyanine dyes, and by electrical stimulation and recording. For the first 24 h after taking the slice, there were no entorhinal projections beyond the deep white matter, and no fibres reached the hippocampus or dentate gyrus. After 3 days in culture a small number of growing fibres had perforated the subiculum and entered the target areas. Between 6 and 14 days these projections increased and matured. As in the normal adult brain, entorhinal layer II stellate cells projected correctly to the dentate gyrus and hippocampal field CA3, whereas layer III pyramidal cells projected to hippocampal field CA1 and the subiculum. The new fibres grew along both alvear and perforant pathways. Anterograde and retrograde labelling showed that the reciprocal projections from the pyramidal cells of the subiculum and CA1 to the entorhinal area had also been severed at the time of taking the slices, and had similarly regenerated. Our results demonstrate that by taking tissue slices in appropriate planes it is possible to study the regeneration of axons in the tissue environment through which they normally run. This approach avoids the use of coculture and the concomitant difficulties associated with the need for fibres to cross a coculture interface. In horizontal slices of postnatal tissue, severed fibre projections between the entorhinal cortex and the hippocampal complex can regenerate in both directions and re-establish their correct laminar, pathway and target specificity.

Animals↗
PubMed1999

Blockade of neuronal activity alters spine maturation of dentate granule cells but not their dendritic arborization.

Organotypic co-cultures of the entorhinal cortex and hippocampus were examined to determine the role of the entorhinal fibers in the dendritic development and formation of spines of dentate granule cells. Quantitative analysis of Golgi-impregnated granule cells in single hippocampal cultures and co-cultures with the entorhinal cortex revealed that the presence of entorhinal fibers promoted the elongation and differentiation of the target granule cell dendrites. This was accompanied by an increase in the total number of spines. The contribution of neuronal activity to this afferent-mediated dendritic development was tested by chronic application of the sodium channel blocker tetrodotoxin for 20 days in vitro. Tracing with biocytin showed that the formation of the entorhinohippocampal pathway was unaffected by the blockade of neuronal activity. The dendritic arbor of cultured granule cells and the number of dendritic spines did not differ between tetrodotoxin-treated slices and untreated controls. However, there was a significant increase in the relative number of filiform spines on granule cell dendrites in tetrodotoxin-treated co-cultures. Such filiform spines are a characteristic feature of immature neurons. These results suggest the cooperation of two mechanisms in the dendritic development of dentate granule cells: the specific afferent-mediated dendritic arborization and the activity-dependent maturation of spines.

Afferent Pathways↗
PubMed1992

Normal anatomy and neurophysiology of the hippocampal formation.

This article reviews the anatomy and neurophysiology of the normal hippocampal formation, with emphasis on the human hippocampus. The hippocampus receives inputs from numerous limbic, cortical, and subcortical areas, primarily via the entorhinal cortex and subiculum. The primary pathway of neural activity entering the hippocampus is from entorhinal cortex via the perforant path to the dentate granule cells, with collaterals to CA1 and CA3 pyramidal cells. Mossy fibers from granule cells excite CA3 pyramidal cells and hilar interneurons. CA3 pyramidal cells excite CA1 pyramidal cells, with local and commissural excitatory collaterals exciting other CA3 pyramidal cells and septum. CA1 pyramidal cells send efferent fibers to subiculum, entorhinal cortex, and several subcortical areas. The principal excitatory synapses are glutamatergic, with two important postsynaptic receptor types, alpha-amino-3-hydroxy-5-methyl-isoxazolepropionic acid and N-methyl-D-aspartate. The primary inhibitory transmitter is gamma-aminobutyric acid (GABA), with two postsynaptic receptor types, GABAA and GABAB. A number of modulatory transmitters and neuropeptides are also present. Inhibitory local synaptic networks in the hippocampus are described. Membrane ion channels in hippocampal neurons, particularly Ca2+ channels and K+ channels, are responsible for the regulation and patterning of neural activity. Long-term potentiation and axon sprouting are two experimental paradigms of neural plasticity presumably involved in hippocampal memory function.

Animals↗
PubMed1999

Neurofibrillary tangles in nondemented elderly subjects and mild Alzheimer disease.

BACKGROUND: The relationship between neuropathological lesions and mild, "preclinical," cognitive impairments of Alzheimer disease is poorly understood. Identification of the lesions that are most closely associated with the earliest symptoms of Alzheimer disease is crucial to the understanding of the disease process and the development of treatment strategies to affect its progression. DESIGN AND MAIN OUTCOME MEASURES: We examined the extent of neurofibrillary tangles (NFTs) in 4 neocortical regions, the hippocampus, the entorhinal cortex, and the amygdala in 65 elderly subjects with no dementia, questionable dementia, mild dementia, or moderate dementia as assessed using the Clinical Dementia Rating Scale (CDR). SETTING AND PATIENTS: Postmortem study of nursing home residents. RESULTS: Neurofibrillary tangles were present in the entorhinal cortex and the hippocampus of all subjects, including those without cognitive deficits. Neocortical NFTs were mostly absent in the nondemented (CDR score, 0.0) subjects. The density of NFTs in the questionably demented (CDR score, 0.5) subjects was not significantly increased (P>.20) relative to the nondemented group in any of the brain regions studied. Significant increases (P<.04) in NFT density become apparent first in the amygdala and the temporal cortex in subjects rated to be mildly impaired (CDR score, 1.0). By the time that cognitive impairments were judged to be moderately severe (CDR score, 2.0), all regions of the brain examined, except for the occipital cortex, were significantly (P<.05) involved. CONCLUSIONS: Some NFTs are present in the entorhinal cortex and hippocampus of most elderly individuals irrespective of their cognitive status, but the density of NFTs increases as a function of dementia severity.

Aged↗
PubMed1988

Comparison of the efferents of the amygdala and the hippocampal formation in the rhesus monkey: II. Reciprocal and non-reciprocal connections.

The pattern of direct connections between the amygdala and the hippocampal formation in the rhesus monkey (Macaca mulatta) was delineated by using both anterograde and retrograde tract-tracing techniques. From the amygdala the accessory basal, medial basal, and the cortical nuclei and the cortical amygdaloid transition area send projections to the hippocampal formation. The efferents from the magnocellular part of the accessory basal nucleus and the cortical nuclei terminate in the molecular layer of subfields CA3, CA2, and CA1', and to a lesser extent in the molecular layer and the superficial part of the pyramidal cell layers of the prosubiculum. In contrast, the projections from the medial basal nucleus and the cortical amygdaloid transition area terminate in the molecular layer and the superficial part of the pyramidal cell layers of the prosubiculum only. From the hippocampal formation, subfield CA1' and the prosubiculum send efferents that terminate in the medial basal nucleus, the cortical transition area, and the ventral part of the cortical nuclei. In addition, the CA1' subfield projects to the ventral, parvicellular part of the accessory basal nucleus. The present data emphasize an important role for the prosubiculum and the CA1' subfield in medial temporal lobe area connections. Both regions, in addition to supporting direct connections between the amygdala and the hippocampal formation, also have extensive connections with the entorhinal cortex. As for the amygdala, the accessory basal nucleus sends efferents to both the hippocampal formation and the entorhinal cortex. The data demonstrate an anatomical means by which the amygdala, hippocampal formation, and the entorhinal cortex may interact. It is proposed that these connections may be important in the limbic memory system.

Amino Acids↗
PubMed2002

Entorhinal axons exhibit sprouting in CA1 subfield of the adult hippocampus in a rat model of temporal lobe epilepsy.

Intracerebroventricular kainic acid administration in rat, a model of temporal lobe epilepsy, results in CA3 pyramidal neuron degeneration leading to deafferentation of CA1 pyramidal neurons. Denervation in CA1 shows a near-complete recovery of synaptic density over 2-3 months, but the source of axons participating in the reinnervation is not clear. This study investigated the contribution of the entorhinal cortex in this reinnervation by comparing the distribution of the entorhinal axons in the CA1 subfield between the intact hippocampus and the CA3-lesioned hippocampus at 3 months after administration of kainic acid. Entorhinal axons were visualized by anterograde tracing using injections of the biotinylated dextran amine into the entorhinal cortex. In the CA1 subfield of the intact hippocampus, entorhinal axons were conspicuous in the alveus and the stratum lacunosum moleculare. The distribution in the strata oriens, pyramidale, and radiatum was sparse and was characterized by isolated entorhinal fibers of the alvear pathway crossing these strata to the stratum lacunosum moleculare. However, after kainic acid-induced CA3 lesion, the density of entorhinal axons increased significantly in the CA1 stratum radiatum (375% of the intact hippocampus), as a large number of axons emanating from the entorhinal fiber plexus in the stratum lacunosum moleculare invaded the stratum radiatum. The stratum radiatum also exhibited wavy entorhinal axons filled with boutons and oriented parallel to the stratum pyramidale, suggesting collateral sprouting from entorhinal axons traversing the stratum radiatum. Thus, a significant aberrant sprouting of entorhinal axons occurs into the CA1 stratum radiatum after CA3 lesion. The sprouted fibers appear to come from both entorhinal fiber plexus in the stratum lacunosum moleculare (translaminar sprouting) and entorhinal axons traversing the stratum radiatum (intralaminar sprouting). However, the major contribution appears to be from the entorhinal plexus in the stratum lacunosum moleculare. This aberrant sprouting may lead to altered afferent excitatory connectivity in the CA1 subfield and contribute to the persistent CA1 hyperexcitability that occurs after the CA3 lesion.

Animals↗
PubMed2004

Comparison of the effects of entorhinal and retrosplenial cortical lesions on habituation, reaction to spatial and non-spatial changes during object exploration in the rat.

This study was aimed at comparing the effects of damage to the entorhinal cortex and retrosplenial cortex on exploration and reaction-to-change in rats. Following habituation to a configuration of objects, a familiar object was displaced therefore producing a spatial change. A non-spatial change was made by substituting a familiar object by a novel object. Both entorhinal cortex lesions and retrosplenial cortex lesions elicited a deficit in the rat's reaction to a spatial change. In addition, rats with entorhinal lesions showed hypoactive object exploration and exhibited a mild deficit in reaction to a non-spatial change. This may reflect the importance of temporal cortical input in object recognition. Overall, these results suggest that the entorhinal cortex and the retrosplenial cortex contribute to the processing of the geometric properties of the environment and have thus close functional links.

Animals↗
PubMed2005

Random or selective neuroanatomical connectivity. Study of the distribution of fibers over two populations of identified interneurons in cerebral cortex.

We present a neuroanatomical tracing method in a stereological approach to study the proportional distribution of fibers of a particular projection over two chemically different populations of neurons. The fiber projection from the presubiculum to the medial division of the entorhinal cortex of the rat serves as a model projection. Potential target interneurons express calcium binding proteins, either parvalbumin or calretinin. The three markers were simultaneously stained in one and the same histological section. The procedure is according to a three-phase procedure, i.e., in vivo tracer injection phase, histology phase, laserscanning phase. Steps involved are: (1) Surgical application to the presubiculum (injection) of the neuroanatomical tracer, biotinylated dextran amine (BDA), with the purpose of labeling fibers innervating the entorhinal cortex. After surgery, transport of the tracer takes place during the one-week survival period; (2) Fluorescence detection of the labeled fibers through staining with fluorochromated avidin (avidin-Alexa Fluor 488 [green fluorescence]); (3) Simultaneous Immunofluorescence detection of two interneuron markers (using the appropriate primary antibodies and secondary antibodies conjugated to the fluorochromes Alexa Fluor 594 [red fluorescence] and Alexa Fluor 633 [infrared fluorescence]); (4) Acquisition of low-magnification images in a confocal laserscanning microscope and the preparation on a computer of a montage image covering the entire entorhinal cortex; (5) Overlaying this montage with a sampling grid; (6) Acquisition at high magnification of Z-series of confocal images in a statistical valid way based on this grid. Each marker was visualized in its own laser excitation/emission channel: 488, 568 and 647 nm; (7) Image processing and 3D reconstruction followed by evaluation of the results. The present approach can be used to examine whether or not a particular class of chemically identified neurons receives preferential innervation by a particular fiber projection.

Animals↗
PubMed1996

Regional variability and postsynaptic targets of chandelier cells in the hippocampal formation of the rat.

Chandelier cells are specialized cortical GABAergic neurons that establish synaptic contacts exclusively with the axon initial segments of principal neurons. They are found in all regions of the hippocampal formation. Here we describe their morphological features in the hilus and in regions CA1 and CA3 by using Golgi/electron microscopy. Attempts were also made to identify the target neurons of chandelier cells in the hilus and entorhinal cortex. Golgi-impregnated chandelier cells display a complex axonal arbor in CA1, with many collaterals forming strings of boutons. The axon plexuses of such cells are less developed in CA3, whereas those in the hilus cover the entire region, although single collaterals are rather simple, with only a few boutons. The dendrites of chandelier cells in CA1 and CA3 have an orientation similar to that of pyramidal cell dendrites and are thus likely to be activated by the same afferent fiber systems. The hilar chandelier cells do not give rise to dendrites invading the molecular layer. Thus, these cells may not receive a dense input from the entorhinal cortex but may be driven by the abundant mossy fiber collaterals in the hilar region. In the CA1 and CA3 regions, the axons of chandelier cells contact the axon initial segments of pyramidal cells. In the hilar region, gold-toned boutons were found to impinge on the initial segments of neurons displaying characteristics of mossy cells. This notion was substantiated by electron microscopic analysis of mossy cells identified by intracellular injection of Lucifer yellow. Those cells regularly showed numerous symmetric synapses on their axon initial segments. Entorhinohippocampal projection cells, identified by injection of horseradish peroxidase into the hippocampus, were found to be preferential targets of chandelier cells in the entorhinal cortex. Our data point to regional variations in chandelier cell morphology and connectivity and indicate that chandelier cells are a principal component of inhibitory mechanisms in all stations of the main excitatory pathway of the hippocampal formation.

Animals↗
PubMedDate not supplied

Volumes of the entorhinal and perirhinal cortices in Alzheimer's disease.

We measured the volumes of the entorhinal, perirhinal, and temporopolar cortices on magnetic resonance images by using a recently designed histology-based protocol in 30 patients with early Alzheimer's disease (AD) and 32 healthy control subjects. Compared to the controls, all of these cortical regions were significantly atrophied in AD patients (p < 0.0001). However, the entorhinal cortex was the most severely involved brain region studied, with 40% volume loss, and this region provided the highest discriminative accuracy (92%) in separating patients with AD from healthy control subjects. Importantly, the entorhinal volume loss was evident already in mild AD. In addition, the volume of the entorhinal cortex was not dependent on age, but it did correlate significantly with the severity of the disease. Because it assesses the major site of initial neuropathological changes in AD, magnetic resonance imaging volumetric measurement of the entorhinal cortex can offer a tool for distinguishing AD patients even in the very early stages of the disease from healthy aged subjects.

Aged↗
PubMed1976

Potentiation of excitatory synaptic transmission in the normal and in the reinnervated dentate gyrus of the rat.

Following destruction of the ipsilateral temporo-ammonic tract, which originates in the entorhinal cortex, and terminates on the granule cells of the dentate gyrus, fibers from the surviving contralateral entorhinal area proliferate forming extensive new connections with the denervated dentate granule cells. Utlizing extracellular recording techniques, we have compared the characteristics of synaptic transmission in the lesion induced afferents with the characteristics of the normal ipsilateral afferents by analyzing the responses of dentate granule cells to paired pulse activation of temporo-dentate circuitry. In the dentate gyrus of the normal rat, and extracellularly recorded EPSP evoked by stimulation of the ipsilateral entorhinal cortex is enhanced by as much as 100% by a "conditioning" pulse to the same afferent system. This is called paired pulse potentiation. In the reinnervated dentate gyrus, the extracellular EPSP evoked by a test stimulus delivered to the contralateral entorhinal cortex is also potentiated by a conditioning pulse. Thepaired pulse potentiation in the reinnervated dentate gyrus has a time course which is comparable to that of the normal ipsilateral afferent system, but the magnitude of the potentiation is somewhat less, averaging approximately 140% of control...

Afferent Pathways↗
PubMed1999

Stereotactic amygdalohippocampotomy for the treatment of medial temporal lobe epilepsy.

PURPOSE: This study was carried out to assess the safety and efficacy of stereotactic ablation of the amygdala and hippocampus for the treatment of medial temporal lobe epilepsy. METHODS: Twenty-two stereotactic amygdalohippocampotomies were performed in 19 patients with unilateral temporal lobe seizures by using magnetic resonance imaging (MRI) localization for target planning and radiofrequency techniques for lesion production. Seizure frequency was assessed at 3-monthly follow-up visits. Two lesion groups were defined. In group I, four to 11 (mean, 6.4) discrete lesions were made, encompassing the amygdala and anterior 13-21 mm (mean, 16.8 mm) of the hippocampus. In group II, a large number of confluent lesions were made (mean, 26.0; range, 12-54) encompassing the amygdala and anterior 15-34 mm (mean, 21.5 mm) of the hippocampus. MRI scanning was carried out 24 h and 6-9 months after surgery. RESULTS: In five group I patients, one (20%) experienced a favorable seizure outcome. Of 15 group II patients, one of whom had previously undergone limited lesioning and was also analyzed as part of group I, nine (60%) experienced a favorable seizure outcome, with two seizure free. MRI scans at 6- to 9-months' follow-up disclosed discrete areas of atrophy in the amygdala and hippocampus, interspersed with preserved brain in the group I patients. More uniform and complete destruction of amygdala and hippocampus was evident in group II patients. All lesions were confined to the amygdala and hippocampus, sparing the parahippocampal gyrus (PHG). CONCLUSIONS: The extensive amygdalohippocampal ablation in group II patients improved seizure outcome compared with more limited ablation in group I, but these results were not so good as those from temporal lobectomy in a similar patient group. When considered together with the results of selective amygdalohippocampectomy, and temporal resections that spare hippocampus or amygdala (all producing similar outcomes, and all involving resection of the entorhinal cortex), this study suggests a pivotal role of the entorhinal cortex in temporal epileptogenesis.

Adolescent↗
PubMed2003

Inhibitory function of zinc against excitation of hippocampal glutamatergic neurons.

The function of zinc released from the neuron terminals is poorly understood. Here, the action of zinc in excitatory neurotransmission in rat hippocampal CA1 was studied by using in vivo microdialysis. Glutamate concentration in the perfusate was significantly decreased by perfusion with 10-300 microM ZnCl2, suggesting that presynaptic release of glutamate is inhibited by zinc in the CA1. While gamma-amino butyric acid (GABA) concentration in the perfusate was increased by perfusion with zinc. Furthermore, to study the action of zinc in postsynaptic response, the response of the CA1 pyramidal cells in the presence of 50 microM zinc was examined in the entorhinal cortex, which is connected with CA1 pyramidal cells. Perfusion of the hippocampal CA1 with zinc decreased glutamate concentration not only in the CA1, but also in the entorhinal cortex. The increase in glutamate concentration in the entorhinal cortex during perfusion of the CA1 with 50 microM glutamate was inhibited by the addition of zinc in the CA1. Zinc seems to be an inhibitory neuromodulator of glutamate release.

Animals↗
PubMed2000

CA3-released entorhinal seizures disclose dentate gyrus epileptogenicity and unmask a temporoammonic pathway.

We have investigated the propagation of epileptiform discharges induced by 4-aminopyridine (4-AP, 50 microM) in adult mouse hippocampus-entorhinal cortex slices, before and after Schaffer collateral cut. 4-AP application induced 1) ictal epileptiform activity that disappeared over time and 2) interictal epileptiform discharges, which continued throughout the experiment. Using simultaneous field potential and [K(+)](o) recordings, we found that entorhinal and dentate ictal epileptiform discharges were accompanied by comparable elevations in [K(+)](o) (up to 12 mM from a baseline value of 3.2 mM), whereas smaller rises in [K(+)](o) (up to 6 mM) were associated with ictal activity in CA3. Cutting the Schaffer collaterals disclosed the occurrence of ictal discharges that were associated with larger rises in [K(+)](o) as compared with the intact slice. Further lesion of the perforant path blocked ictal activity and the associated [K(+)](o) increases in the dentate gyrus, indicating synaptic propagation to this area. Time delay measurements demonstrated that ictal epileptiform activity in the intact hippocampal-entorhinal cortex slice propagated via the trisynaptic path. However, after Schaffer collateral cut, ictal discharges continued to occur in CA1 and subiculum and spread to these areas directly from the entorhinal cortex. Thus our data indicate that the increased epileptogenicity of the dentate gyrus (a prominent feature of temporal lobe epilepsy as well), may depend on perforant path propagation of entorhinal ictal discharges, irrespective of mossy fiber reorganization. Moreover, hippocampal neuronal damage that is acutely mimicked in our model by Schaffer collateral cut, may contribute to "short-circuit" propagation of activity by pathways that are masked when the hippocampus is intact.

4-Aminopyridine↗
PubMed1995

Increased levels of statin, a marker of cell cycle arrest, in response to hippocampal neuronal injury.

Injured neurons in the CNS are known to synthesize high levels of proliferation related oncogene products and heat shock proteins without dividing. Statin is a cell cycle regulated nuclear phosphoprotein, selectively associated with the non-proliferative state in a wide variety of cell types. In the present study, neuronal statin was examined following lethal or sublethal neuronal injuries in the hippocampus of Alzheimer's disease patients, in rats receiving kainate lesions to the dorsal hippocampus and in entorhinal cortex lesioned rats. Immunolabelling of nuclear statin showed that statin immunoreactivity increased preferentially in CA1 pyramidal neurons of the hippocampus in Alzheimer's disease. In kainate lesioned rats, statin immunoreactivity was markedly induced in the CA3 hippocampal region in association with neuronal loss. Entorhinal cortex lesioned rats showed a transient induction of statin between 2 and 6 days post lesion in CA1 neurons. However, cell counts in entorhinal cortex lesioned rats remained unaltered in the CA1 and granule cell layers during the entire 30 day time course, indicating that increased statin levels are not secondary to neuronal degeneration and are not necessarily accompanied by irreversible neuronal death. It is concluded that, in addition to proliferation related gene products, neuronal injury induces an increase in levels of statin, a nuclear marker of cell cycle arrest. Furthermore, statin may be a potentially useful marker of injurious neuronal stress, even under conditions that do not necessarily lead to irreversible cell death.

Alzheimer Disease↗
PubMed1997

Noradrenaline modulates glutamate-mediated neurotransmission in the rat basolateral amygdala in vitro.

The entorhinal cortex and the amygdala are interconnected structures of the limbic system in which paroxysmal activity occurs during temporal lobe epilepsy. Conflicting evidence shows that noradrenaline (i) inhibits the spreading to other parts of the limbic system of paroxysmal activity generated in the amygdala or the entorhinal cortex, but also (ii) increases glutamatergic transmission in the basolateral amygdala. Given our previous work on the inhibitory effect of noradrenaline on entorhinal cortex neurons, we developed an in vitro slice preparation to study the synaptic transmission in the basolateral amygdala and its modulation by noradrenaline. Noradrenaline reduced the fast excitatory postsynaptic potential (EPSP) by approximately 40% at 100 microM and the slow EPSP by approximately 50% at 50 microM. A similar effect was obtained with the alpha2-agonist UK 14304 at 100 and 50 microM respectively. In contrast, the beta-agonist isoproterenol increased the fast EPSP by approximately 40% at 100 microM and the slow EPSP by approximately 20% at 50 microM. Accordingly, the effect of noradrenaline on the EPSPs was blocked by the alpha2-antagonist yohimbine (10 microM) but not by the alpha1-antagonist prazosine (10 microM) and the beta-antagonist propranolol (10 microM). Noradrenaline (50-100 microM) was ineffective on most (14/16) of the isolated inhibitory postsynaptic potentials (IPSPs). These experiments provide evidence that noradrenaline inhibits the excitatory synaptic response of basolateral amygdala neurons. A pharmacological analysis revealed that the noradrenergic modulation of the excitatory transmission in the basolateral amygdala can be dissected into a predominant alpha2-adrenoreceptor-mediated inhibition and a beta-adrenoreceptor-mediated excitation.

Amygdala↗