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PubMed1987

Recent progress in the research of Alzheimer's disease.

The purpose of this review is to survey some of the recent advances made in the understanding of the basic mechanisms underlying cognitive functions and dysfunctions in Alzheimer's disease (AD). Cholinergic projections from the nucleus basalis of Meynert (nbM), which are involved in AD, have been related to certain memory functions. Information processing, attention or arousal may, however, be influenced by nbM neurons more than primary memory mechanisms. Perforant pathway and subiculum projections, which presumably use glutamate as a neurotransmitter, are involved in AD leading to the disconnection of the hippocampus from the neocortical areas. The hippocampus and entorhinal cortex seem to play an important role in learning and memory. The hippocampus can be regarded as a relay station for the processing of recent episodic memory, but information is bound to memory storage in the cortical association areas. An important finding has been the plasticity changes in the hippocampus seen after the destruction of entorhinal cortex. Antemortem markers of AD have been under extensive study. Alz-50 antigen may be one of the most promising findings in this area, but no definite biological marker of AD currently exists. A medication for treatment of AD is also under development.

Acetylcholine↗
PubMed1985

Characterization of the prodynorphin and proenkephalin neuropeptide systems in rat hippocampus.

Opioid peptides derived from prodynorphin were localized immunocytochemically to dentate granule cells and mossy fibers of the rat hippocampus with antisera against dynorphin A(1-17) and dynorphin B. Extracts of microdissected hippocampal regions were resolved by reverse phase and molecular exclusion chromatography to identify the molecular forms of the dynorphin A immunoreactivity and to quantify regional contents. Results demonstrated that the relative concentration of dynorphin A within each dissected region of hippocampus agreed well with the distribution of dynorphin A detected by immunocytochemical methods. Immunostaining of proenkephalin-derived opioid peptides, [Leu5]enkephalin and bovine adrenal medullary peptide-22P, was concentrated in cell bodies of the entorhinal cortex, nerve fibers in the perforant pathway, and terminals in the outer molecular layer of the dentate gyrus. Light immunostaining of granule cells and mossy fibers with these antisera was also found. The relative concentration of [Leu5]enkephalin immunoreactivity in each microdissected region of the hippocampus also agreed well with the distribution of [Leu5]enkephalin immunostaining. Chromatography of hippocampal regional extracts demonstrated that the immunoreactivity measured was due to the presence of authentic [Leu5]enkephalin. The probable neurotransmitter function of both [Leu5]enkephalin and dynorphin A was shown by their calcium-dependent release after in vitro depolarization of hippocampal tissue. The reported presence of beta-endorphin in hippocampus was not verified. Comparison of the hippocampal distribution and content of prodynorphin and proenkephalin-derived opioids suggests that separate populations of neurons containing these two peptide families form distinct neurotransmitter systems of roughly equal concentration.

Animals↗
PubMed1980

[Autoradiography of transneural substance transport in the entorhino-hippocampal system after [3H] proline injection into the entorhinal cortex in rat (author's transl)].

The entorhinal afferences to Fascia dentata and Stratum lacunoso-moleculare of CA1 could be visualised by means of anterograde axoplasmic transport 5 days after L-[5-3H]-proline injection into the entorhinal cortex. Furthermore, the macromolecule-bound tracer was found in the perikarya of granule cells and mossy fibres as well as in the cell bodies of the CA1 pyramids. These findings indicate that labelled material, released from the axonal terminals of the perforant pathway, is taken up by these neurons.

Afferent Pathways↗
PubMed1995

Morphological evidence for the sprouting of inhibitory commissural fibers in response to the lesion of the excitatory entorhinal input to the rat dentate gyrus.

Recently a commissural fiber projection that terminates in the outer molecular layer of the fascia dentata was described in normal rats (Deller et al., 1995). In the present article, Phaseolus vulgaris leucoagglutinin (PHAL) tracing was used to analyze the contribution of this previously unknown projection to the commissural sprouting response after entorhinal cortex lesion. Rats 4-8 weeks after unilateral entorhinal lesion received a single PHAL deposit into the hilus of the fascia dentata contralateral to the lesion side. Unlesioned control animals received a similar PHAL deposit. The degree of axonal arborization and the bouton density per axon length were determined for individual PHAL-labeled commissural axons to the outer molecular layer of the dentate gyrus. A significant increase in both parameters was observed in the lesioned group. The PHAL-labeled commissural fibers established symmetric synapses in the denervated outer molecular layer. Postembedding immunocytochemistry indicated that some of these sprouting commissural fibers are GABAergic. Our findings provide morphological evidence for lamina-specific sprouting of an inhibitory commissural projection that normally terminates in the outer molecular layer. This suggests that inhibitory fibers participate in the replacement of the excitatory perforant pathway after entorhinal lesion.

Afferent Pathways↗
PubMed1996

Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease.

The entorhinal cortex (EC) plays a crucial role as a gateway connecting the neocortex and the hippocampal formation. Layer II of the EC gives rise to the perforant pathway, the major source of the excitatory input to the hippocampus, and layer IV receives a major hippocampal efferent projection. The EC is affected severely in Alzheimer disease (AD), likely contributing to memory impairment. We applied stereological principles of neuron counting to determine whether neuronal loss occurs in the EC in the very early stages of AD. We studied 20 individuals who at death had a Clinical Dementia Rating (CDR) score of 0 (cognitively normal), 0.5 (very mild), 1 (mild), or 3 (severe cognitive impairment). Lamina-specific neuronal counts were carried out on sections representing the entire EC. In the cognitively normal (CDR = 0) individuals, there were approximately 650,000 neurons in layer II, 1 million neurons in layer IV, and 7 million neurons in the entire EC. The number of neurons remained constant between 60 and 90 years of age. The group with the mildest clinically detectable dementia (CDR = 0.5), all of whom had sufficient neurofibrillary tangles (NFTs) and senile plaques for the neuropathological diagnosis of AD, had 32% fewer EC neurons than controls. Decreases in individual lamina were even more dramatic, with the number of neurons in layer II decreasing by 60% and in layer IV by 40% compared with controls. In the severe dementia cases (CDR = 3), the number of neurons in layer II decreased by approximately 90%, and the number of neurons in layer IV decreased by approximately 70% compared with controls. Neuronal number in AD was inversely proportional to NFT formation and neuritic plaques, but was not related significantly to diffuse plaques or to total plaques. These results support the conclusion that a marked decrement of layer II neurons distinguishes even very mild AD from nondemented aging.

Aged↗
PubMed1997

[Neuropathological study on progression of the limbic degeneration in senile dementia of Alzheimer type].

Neuropathological study on the limbic lesion of 33 autopsy cases with senile dementia of Alzheimer type (SDAT) showed as follows. 1) The entorhinal cortex was more atrophied than the hippocampus. 2) Neuronal loss was found in the 2nd and 3rd layers of the entorhinal cortex, irrespective of the different numbers of senile plaques and neurofibrillary tangles (NFTs). 3) Fibrillary gliosis occurred in the stratum lacunosum of the hippocampus, irrespective of the different degrees of neuronal loss in the stratum pyramidale of the hippocampus. 4) The prosubiculum showed gliosis disproportional to neuronal loss. 5) The degree of fibrillary gliosis in the stratum lacunosum of the hippocampus and in the prosubiculum was proportional to that of the entorhinal cortical degeneration. 6) The shape of the hippocampus of the cases with SDAT was different from that in the cases with anoxic encephalopathy in which neuronal loss in the CA1 occurred primarily: 7) Distribution pattern of the lesion in the hippocampus of SDAT cases was almost the same as that found in the cases with infarct in the collateral sulcus involving the entorhinal cortex. It is assumed that the hippocampal atrophy is a primary degeneration attributable to appearance of senile plaques and NFTs. However, our present observations and previous report (Neurosci Lett 184: 141-144 1995) suggest that degeneration of the entorhinal cortex and its efferent fibres (perforant pathway) plays a considerable part of role in development of the hippocampal atrophy. The present study could contribute to understanding of progression of the limbic lesion in SDAT.

Aged↗
PubMed1997

[Mesial temporal sclerosis (I): histological data, physiopathological hypothesis and etiological factors].

OBJECTIVE: To review the main anatomical, histological, physiopathological and aetiological data characteristic of the mesial temporal sclerosis syndrome (ETM). Development. The typical histological findings in ETM are: 1) A specific pattern of loss of neurone density which includes so-called endfolium sclerosis (considered to be a specific pathological entity always found in ETM), and which is usually accompanied by neurone loss in other hippocampal and extra-hippocampal regions. The CA2 region is never affected. 2) Phenomenon of 'mossy fibers sprouting' which are granulosa cells which form two types of synapses: with the the 'basket cells' which are inhibitory interneurones and with the dendrites of granulosa or pyramidal cells of the CA1, CA2 and CA3 Ammon horn cells which are excitatory cells. CONCLUSIONS: Probably these organic changes are both the cause and effect of repeated convulsions. Participation in this self-perpetuating circuit may be due to recognised risk factors of ETM (head injury, CNS infections, febrile convulsions in early stages of development) which cause, first of all, death of neurones of the dentate gyrus cells followed by reduced inhibitory activity of the 'basket' cells and therefore sustained hyper-excitability of the pyramidal cells (especially in the CA3 regions), which are responsible for complex partial seizures and massive liberation of glutamic acid. Glutamic acid can cause death of neurones of the granulosa cells of the dentate gyrus, thus closing the circuit. This hypothesis explains the progressive nature of the ETM syndrome. When there is pathology of the cortical structure there is another access via to this circuit--by means of cortical discharges of the so-called perforant pathway which stimulates activity of the pyramidal cells and sets off the chain of events described above. This hypothesis explains the so-called 'dual pathology'.

Brain Injuries↗
PubMed1997

Neuron loss, granule cell axon reorganization, and functional changes in the dentate gyrus of epileptic kainate-treated rats.

We sought to describe quantitatively the morphological and functional changes that occur in the dentate gyrus of kainate-treated rats, an experimental model of temporal lobe epilepsy. Adult rats were treated systemically with kainic acid, and, months later, after displaying spontaneous recurrent motor seizures, their dentate gyri were examined. Histological, immunocytochemical, and quantitative stereological techniques were used to estimate numbers of neurons per dentate gyrus of various classes and to estimate the extent of granule cell axon reorganization along the septotemporal axis of the hippocampus in control rats and epileptic kainate-treated rats. Compared with control rats, epileptic kainate-treated rats had fewer Nissl-stained hilar neurons and fewer somatostatin-immunoreactive neurons. There was a correlation between the extent of hilar neuron loss and the extent of somatostatin-immunoreactive neuron loss. However, functional inhibition in the dentate gyrus, assessed with paired-pulse responses to perforant-pathway stimulation, revealed enhanced, and not the expected reduced, inhibition in epileptic kainate-treated rats. Numbers of parvalbumin- and cholecystokinin-immunoreactive neurons were similar in control rats and in most kainate-treated rats. A minority (36%) of the epileptic kainate-treated rats had fewer parvalbumin- and cholecystokinin-immunoreactive neurons than control rats, and those few (8%) with extreme loss in these interneuron classes showed markedly hyperexcitable dentate gyrus field-potential responses to orthodromic stimulation. Compared with control rats, epileptic kainate-treated rats had larger proportions of their granule cell and molecular layers infiltrated with Timm stain. There was a correlation between the extent of abnormal Timm staining and the extent of hilar neuron loss. Granule cell axon reorganization and dentate gyrus neuron loss were more severe in temporal vs. septal hippocampus. These findings from the dentate gyrus of epileptic kainate-treated rats are strikingly similar to those reported for human temporal lobe epilepsy, and they suggest that neuron loss and axon reorganization in the temporal hippocampus may be important in epileptogenesis.

Action Potentials↗
PubMed1992

Modification of GABA-mediated inhibition by various injectable anesthetics.

Increasing doses of the injectable anesthetics etomidate, Saffan, thiopental, ketamine, and xylazine and the vehicles saline and propylene glycol were administered to urethane-anesthetized rats. Their effects in vivo on perforant pathway-evoked field excitatory post-synaptic potentials and population spikes in the hippocampal dentate gyrus were determined. The primary purpose was to ascertain whether these compounds affect hippocampal excitability in a manner consistent with their proposed mechanisms of action. Compared with their respective vehicles, thiopental, etomidate, and xylazine reduced the amplitude of population spikes to single perforant pathway stimulation by 20-30% at the highest doses tested. Xylazine also increased the latency to onset of the population spike. No other effects were observed. Using paired pulse paradigms, it was determined that etomidate produced a dramatic, prolonged reduction in granule cell excitability at interpulse intervals of 10-100 ms. The magnitude of the effect was dose related and was reversible with the discontinuance of administration of the drug. Similar changes occurred with Saffan (althesin) and thiopental. Ketamine produced a small but significant depression in granule cell excitability during intervals of 10-200 ms. Xylazine had no effect. These data corroborate the importance of a prolongation of gamma-aminobutyric acid A-mediated inhibition to the mechanism of actions of etomidate, thiopental, and Saffan at relevant exposure concentrations in vivo.

Anesthetics↗
PubMed1999

A-Current down-modulated by sigma receptor in frog pituitary melanotrope cells through a G protein-dependent pathway.

Gramicidin perforated patch-clamp recordings were used to study the effects of two sigma 1 receptor ligands, (+)-N-cyclopropylmethyl-N-methyl-1, 4-diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride (JO 1784) and (+)-pentazocine, on the transient outward potassium current (IA) in cultured frog melanotrope cells. (+)-Pentazocine reversibly decreased the current amplitude in a dose-dependent manner. The effects of (+)-pentazocine were mimicked by JO 1784 and were markedly reduced by the sigma 1 receptor antagonist, N, N-dipropyl-2-[4-methoxy-3-2(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE 100). Inactivation rate of IA was best fitted with a double exponential function, yielding time constants of 23.7 and 112.5 ms. (+)-Pentazocine (20 microM) accelerated the current decay, decreasing the time constants to 10.7 and 59 ms, respectively. Current-voltage experiments revealed that (+)-pentazocine (20 microM) did neither modify the open-state I/V curves nor the voltage dependence of IA. However, (+)-pentazocine (20 microM) shifted the steady-state inactivation curve toward more negative potentials and increased the time constant of the time-dependent removal of inactivation. In whole-cell experiments, internal dialysis of guanosine-5'-O-(3-thiophosphate) (100 microM) irreversibly prolonged the response to (+)-pentazocine. In addition, cholera toxin pretreatment (1 microgram. ml-1; 12 h) suppressed the inhibition of IA by (+)-pentazocine (20 microM). It is concluded that in frog melanotrope cells, a cholera toxin-sensitive, G protein-dependent inhibition of IA through a sigma 1 receptor activation, at least partially, underlies the excitatory effect of sigma ligands.

Animals↗
PubMed2004

Computational constraints between retrieving the past and predicting the future, and the CA3-CA1 differentiation.

The differentiation between the CA3 and CA1 fields of the mammalian hippocampus is one of the salient traits that set it apart from the organization of the homologue medial wall in reptiles and birds. CA3 is widely thought to function as an autoassociator, but what do we need CA1 for? Based on evidence for a specific role of CA1 in temporal processing, I have explored the hypothesis that the differentiation between CA3 and CA1 may help solve a computational conflict. The conflict is between pattern completion, or integrating current sensory information on the basis of memory, and prediction, or moving from one pattern to the next in a stored sequence. CA3 would take care of the former, while CA1 would concentrate on the latter. I have found the hypothesis to be only weakly supported by neural network simulations. The conflict indeed exists, but two mechanisms that would relate more directly to a functional CA3-CA1 differentiation were found unable to produce genuine prediction. Instead, a simple mechanism based on firing frequency adaptation in pyramidal cells was found to be sufficient for prediction, with the degree of adaptation as the crucial parameter balancing retrieval with prediction. The differentiation between the architectures of CA3 and CA1 has a minor but significant, and positive, effect on this balance. In particular, for a fixed anticipatory interval in the model, it increases significantly the information content of hippocampal outputs. There may therefore be just a simple quantitative advantage in differentiating the connectivity of the two fields. Moreover, different degrees of adaptation in CA3 and CA1 cells were not found to lead to better performance, further undermining the notion of a functional dissociation.

Action Potentials↗
PubMed2000

Effects of MK-801 on clozapine-induced potentiation of excitatory synaptic responses in the perforant path-dentate gyrus pathway in chronically prepared rabbits.

We previously found that the atypical antipsychotic drug, clozapine, when intraperitoneally (i.p.) injected, long-lastingly potentiated excitatory synaptic responses elicited in the dentate gyrus by single electrical stimulations to the perforant path in chronically prepared rabbits, and called this phenomenon 'clozapine-induced potentiation'. In the present study, we likewise examined whether clozapine-induced potentiation is caused by NMDA receptor-mediated neurotransmission in the perforant path-dentate gyrus pathway of chronically prepared rabbits. The non-competitive NMDA receptor antagonist - 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imino hydrogen maleate (MK-801; 1.0 mg/kg, i.p.) - completely prevented the potentiation of synaptic responses induced by subsequent administration of 20 mg/kg clozapine, whereas the 0.5 mg/kg dose had virtually no effect on the potentiation. These results suggest that the effect of clozapine requires NMDA receptor activation.

Analysis of Variance↗
PubMed1980

Autoradiography of the olfactory-hippocampal pathway in the cat with special reference to the perforant path.

The anatomical pathway from the prepyriform cortex to the hippocampus in the cat was traced autoradiographically by means of anterograde transport of [3H] leucine. A direct projection from the prepyriform cortex to the lateral entorhinal area was confirmed in the cat: the termination of these fibers was largely confined to the outer part of the molecular layer. From the lateral entorhinal area, the perforant path fibres terminate on the most distal parts of the dendrites of the hippocampal granule and pyramidal cells. However, differences between cat and rat were found with respect to the terminations in the CA1 area.

Animals↗
PubMed2003

Increased dendritic excitability in hippocampal ca1 in vivo in the kainic acid model of temporal lobe epilepsy: a study using current source density analysis.

We used kainic acid in rats as an animal model of temporal lobe epilepsy, and studied the synaptic transmission in hippocampal subfield CA1 of urethane-anesthetized rats in vivo. Dendritic currents were revealed by field potential mapping, using a single micropipette or a 16-channel silicon probe, followed by current source density analysis. We found that the population excitatory postsynaptic potentials in the basal dendrites and distal apical dendrites of CA1 were increased in kainate-treated as compared with control rats following paired-pulse, but not single-pulse, stimulation of CA3b or medial perforant path. In contrast, the trisynaptic midapical dendritic response in CA1 following medial perforant path stimulation was decreased in kainate-treated as compared with control rats. Increased coupling between excitatory postsynaptic potential and the population spike in CA1 was found after kainate seizures. Short-latency, presumably monosynaptic CA1 population spikes following medial perforant path stimulation was found in kainate-treated but not control rats. An enhancement of dendritic excitability was evidenced by population spikes that invaded into or originated from the distal apical dendrites of CA1 in kainate-treated but not control rats. Reverberation of hippocampo-entorhinal activity was evidenced by recurrent excitation of CA1 following CA3b stimulation in kainate-treated but not control rats. Blockade of inhibition by intraventricularly administered bicuculline induced excitatory potentials in CA1 that were stronger and more prolonged in kainate-treated than control rats. The bicuculline-induced excitation was mainly blocked by non-N-methyl-D-aspartate receptor antagonists. We conclude that kainate seizures induced disinhibition in CA1 that unveiled excitation at the basal and distal apical dendrites, resulting in enhancement of the direct entorhinal cortex to CA1 input and reverberations via the hippocampo-entorhinal loop. These changes in the output of the hippocampus from CA1 are likely detrimental to the behavioral functions of the hippocampus and they may contribute to increased seizure susceptibility after kainate seizures.

Action Potentials↗
PubMed2002

Early integrative processes physiologically observed in dentate gyrus during an olfactory associative training in rat.

Modifications of synaptic efficacy in the dentate gyrus were investigated during an olfactory associative task. A group of rats was trained to discriminate between a patterned electrical stimulation of the lateral olfactory tract, used as an artificial cue, associated with a water reward, and a natural odor associated with a flash of light. Monosynaptic field potential responses evoked by single electrical stimuli to the lateral perforant path were recorded in the granular layer of the ipsilateral dentate gyrus prior to and just after each training session. An early increase in this response was observed just after the first learning session but disappeared 24 hours later. Inversely, a synaptic depression developed across sessions, becoming significant at the onset of a last (fifth) session. When a group of naive animals was pseudo-conditioned, no increase was observed and the synaptic depression was noted since the onset of the second session. In a group of rats similarly trained for only one session, and in which EPSPs were recorded throughout the 24 hours that followed, it was demonstrated that the increase lasted at least two hours, while the significant synaptic depression started after the fourth hour. These results are consistent with the early involvement of the dentate gyrus in learning the association between the cues and their respective rewards. These early integrative processes physiologically observed in dentate gyrus suggest early hippocampal processing before dentate gyrus reactivation via entorhinal cortex which will allow long-term memory storage in cortical areas once the meaning of the olfactory cues is learned.

Animals↗
PubMedDate not supplied

Effects of risperidone, an atypical antipsychotic drug, on excitatory synaptic responses in the perforant path-dentate gyrus pathway in chronically prepared rabbits.

The effects of an atypical antipsychotic drug, risperidone, were examined on excitatory synaptic responses in the dentate gyrus by single electrical stimulations to the perforant path and the induction of long-term potentiation (LTP) in this pathway in chronically prepared rabbits. Any of 0.5, 1.0 and 2.0 mg/kg doses of risperidone intraperitoneally injected had virtually no effect on the excitatory synaptic responses. However, these three doses of risperidone dose-dependently suppressed the LTP induction.

Animals↗
PubMed2002

Effects of zotepine on excitatory synaptic responses in the perforant path-dentate gyrus pathway in chronically prepared rabbits.

The effects of an atypical antipsychotic drug, zotepine, were examined on excitatory synaptic responses elicited in the dentate gyrus by single electrical stimulation of the perforant path and the induction of long-term potentiation in this pathway in chronically prepared rabbits. Doses of 1.0, 2.0 and 5.0 mg/kg of zotepine intraperitoneally injected had virtually no effect on the excitatory synaptic responses. However, these doses of zotepine dose dependently suppressed the induction of long-term potentiation. According to our previous studies, these results indicate that the effects of zotepine are different from those of the other atypical antipsychotic drugs, clozapine, but are rather similar to those of a typical antipsychotic drug, haloperidol and the 5-HT-dopamine receptor antagonist, risperidone. Furthermore, the zotepine-induced blockade of long-term potentiation induction may be associated with drug-induced cognitive dysfunction such as memory disturbance.

Animals↗
PubMed2003

Differences in lesion-induced hippocampal plasticity between mice and rats.

We studied the differences between mice and rats in lesion-induced sprouting in the hippocampus. The entorhinal cortex was unilaterally lesioned with ibotenic acid in adult, female mice and rats. Four weeks later the subsequent axonal sprouting in the dentate gyrus was analysed, by measuring the density of the synaptophysin immunohistochemical and acetylcholinesterase histochemical staining in the termination area of the entorhinal cortex axons. The data demonstrate that both mice and rats display a significantly increased density of staining for synaptophysin and acetylcholinesterase in the molecular layer of the dentate gyrus, indicative of axonal sprouting. Both species also show an upregulation in the density of staining for acetylcholinesterase in the molecular layer of the dentate gyrus. Further, rats, but not mice, show a significant upregulation of synaptophysin staining in stratum lacunosum moleculare of CA1 following the lesions. However, whereas rats show significant shrinkage of the molecular layer of the dentate gyrus, mice do not show any shrinkage of that layer following entorhinal cortex lesions. Taken together, these data indicate that whereas the process of reinnervation in the hippocampus is similar between the mouse and the rat, the hippocampal response to denervation shows clear differences between these two species.

Acetylcholinesterase↗