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PubMed2002

Regional quantitative analysis of NFT in brains of non-demented elderly persons: comparisons with findings in brains of late-onset Alzheimer's disease and limbic NFT dementia.

Brains of non-demented elderly people were divided into two groups according to the presence or absence of senile plaques (SP(+) and SP(-)). The regional number of NFT in each group were then quantitatively investigated and compared with that in the late-onset Alzheimer's disease (AD) group and the limbic NFT dementia (LNTD) group. NFT were divided into type 1, type 2 and type 3 according to the developmental stage. In addition, polymorphism of the apolipoprotein E (Apo E) gene was analyzed in all groups. The most frequent regions of NFT common to all groups were the transentorhinal cortex, the entorhinal cortex, the subiculum and cornu ammonis (CA)1 of the hippocampus. In the SP(+) group the proportion of type 3 was high in the transentorhinal cortex and entorhinal cortex, while type 1 or 2 were high in the subiculum and CA1, suggesting that NFT formation progresses from the parahippocampal cortex to the hippocampus. In the SP(-) group the proportion of type 3 was higher in the subiculum and CA1 than in the transentorhinal cortex and entorhinal cortex, suggesting that NFT formation is accelerated in the hippocampus. The late-onset AD group and LNTD group showed the patterns of NFT formation similar to those of the SP(+) group and SP(-) group, respectively. The frequency of the epsilon4 allele of the Apo E gene was significantly higher in the late-onset AD group and SP(+) group than in the LNTD group and SP(-) group, respectively. From these findings it is suggested that persons in the SP(+) group are likely to remain non-demented elderly persons or become a developmental matrix of late-onset AD with a risk factor of the epsilon4 allele, while those in the SP(-) group are likely to remain non-demented elderly persons or pass into LNTD without a risk factor of the epsilon4 allele.

Age of Onset↗
PubMed1994

Regional brain activity of free radical defense enzymes in autopsy samples from patients with Alzheimer's disease and from nondemented controls.

Several lines of evidence support the hypothesis that oxygen free radicals are involved in the destruction of neurons in various degenerative disorders of the central nervous system. The activities of superoxide dismutase, catalase and glutathione peroxidase, three enzymes that contribute to the cellular defenses against free radical damage, were measured in different areas of autopsy brains from patients with Alzheimer's disease and from age matched controls. All brains were removed within 24 hours of the time of death and were cut in half sagitally. One half was stored frozen at -86 degrees C and the other half was examined histologically to confirm the presence or absence of Alzheimer's disease. Samples were taken from the frozen half for the enzyme assays. In control brains, the activity of superoxide dismutase is significantly higher in the cerebellum, frontal cortex and hippocampus than it is in the temporal cortex, parietal cortex and entorhinal cortex. The activity of catalase is significantly higher in cerebellum and frontal cortex than in hippocampus, parietal cortex and entorhinal cortex. Glutathione peroxidase activity is uniform across all brain areas studied. In Alzheimer's brains, superoxide dismutase activity is not statistically different among the various brain regions studied, but it is significantly lower than control in the cerebellum (-27%), frontal cortex (-27%) and hippocampus (-35%). Catalase is significantly higher in Alzheimer's cerebellum, frontal cortex and temporal cortex than in Alzheimer's hippocampus, parietal cortex and entorhinal cortex. However, there are no significant differences in catalase activity between Alzheimer's and control samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Alzheimer Disease↗
PubMed2001

Neuronal expression of mint1 and mint2, novel multimodular proteins, in adult murine brain.

Mints are multimodular adapter proteins in functioning membrane transport and organization. Mint1 and mint2 are neuron-specific. We localized these isoforms in mouse brain. By in situ hybridization, mRNA encoding mint1 or mint2 was expressed in neurons throughout the brain. Mint1 mRNA expression was greatest in the limbic system including cingulate cortex, hippocampus, anterior thalamic nuclei, medial habenular nucleus, and mammillary body. Mint2 mRNA was rich in cerebral cortex, entorhinal cortex, and hippocampus, but less prominent in other limbic structures. Mint1 mRNA and mint2 mRNA were distributed among hippocampal pyramidal neurons, while mint2 mRNA was especially abundant in CA3. Mint1, but not Mint2 mRNA was abundant in the substantia nigra pars compacta. Immunohistochemistry visualized mint proteins in axon terminals and neuronal somata, generally following mRNA distribution. In the hippocampus, mint1 was rich in the entorhinal projections and mossy fibers of the dentate gyrus, while mint2 was rich in commisural fibers from the contralateral hippocampus and in CA1. Mint1 intensely stained catecholamine-containing neurons such as the substantia nigra pars compacta, ventral tegmental area, and locus ceruleus. Mint2 protein was ubiquitous in these regions. Mint1 and mint2 distribution also differed elsewhere in the brainstem and in the cerebellum. Central nervous system neurons, then, predominantly express either mint1 or mint2. Mints may be involved in synaptic vesicle transport toward the active zone, also participating in transport of certain membrane proteins toward the postsynaptic density. Mint1 and mint2 may divide roles either regionally or depending on neuronal functional characteristics.

Adaptor Proteins, Signal Transducing↗
PubMed1989

Lateralization of brain morphologic and cholinergic abnormalities in Alzheimer's disease.

The extent of left-right asymmetry in the densities of senile plaques and neurofibrillary tangles and the levels of the cholinergic enzymes choline acetyltransferase and acetylcholinesterase were quantified in the middle frontal and superior temporal cerebral cortex, entorhinal cortex, and prosubiculum of the hippocampus from 21 patients who died with Alzheimer's disease. Morphologic lesions were more asymmetrically distributed than deficits in the cholinergic enzymes. Neither cerebral hemisphere showed consistently higher densities of senile plaques and neurofibrillary tangles, or lower levels of choline acetyltransferase and acetylcholinesterase. Deficits in the cholinergic enzymes tended to colateralize, while asymmetries of senile plaques and neurofibrillary tangles did not. Finally, left-right asymmetry in the density of senile plaques diminished with increasing neuropathologic severity, while similar evidence for diminishing left-right asymmetry of neurofibrillary tangle density or cholinergic enzyme activity with increasing severity was not found.

Acetylcholinesterase↗
PubMed2006

Relation of quantitative indexes of concurrent alpha-synuclein abnormalities to clinical outcome in autopsy-proven Alzheimer disease.

BACKGROUND: Lewy bodies (LBs) and Lewy neurites are frequent concomitant neuropathologic observations in clinical and neuropathologically defined Alzheimer disease (AD), but their relation to clinical features in AD is uncertain. Most studies used semiquantitative measures to determine the presence or absence of LB abnormalities. OBJECTIVE: To determine the clinical consequences of LB abnormalities in the setting of AD. DESIGN: Prospective study. SETTING: Three outpatient research and treatment centers. PARTICIPANTS: Fourteen autopsy cases with a pathologic diagnosis of AD abnormalities and concomitant LBs followed semiannually for up to 8 years (mean age at intake, 72 years; mean age at death, 77 years; mean education, 15 years; 12 women). MAIN OUTCOME MEASURES: The modified Mini-Mental State Examination was used to assess cognitive function. The Unified Parkinson Disease Rating Scale was used to rate extrapyramidal motor signs. Hallucinations were evaluated using the Columbia University Scale for Psychopathology in Alzheimer's Disease. Time from the first evaluation in which diagnostic criteria for probable AD were met to death was used to determine illness duration. Quantitative measures of LB abnormalities were obtained for the frontal cortex, entorhinal cortex, substantia nigra, and hippocampus. RESULTS: Independent-samples t tests were used to assess whether the degree of LB abnormality varied as a function of the presence or absence of hallucinations and extrapyramidal signs. Pearson r correlations were run to examine whether there was a relation among LB abnormalities, cognitive function, and illness duration. There was no relation between quantitative neuropathologic indexes of LB abnormalities and clinical outcome. CONCLUSION: The variability of clinical features in AD was not related to the presence or degree of LB abnormalities.

Aged↗
PubMed1996

Neuronal expression of hippocampal cholinergic neurostimulating peptide (HCNP)-precursor mRNA in rat brain.

The expression of hippocampal cholinergic neurostimulating peptide (HCNP)-precursor mRNA in rat brain was examined by Northern blot and in situ hybridization analyses. Northern blot analysis using rat HCNP-precursor cDNA revealed a 1.1-kilobase (kb) transcript. A message of identical size was also detected with the antisense precursor riboprobe. In situ hybridization disclosed that HCNP-precursor mRNA was expressed in many areas of the brain, including the basal forebrain cholinergic system, the olfactory system, and the cerebellum. Very high levels were seen in the pyramidal cells of the CA3 region and in the hilus of the dentate gyrus of the hippocampal formation. High levels were also found in the septal area, piriform cortex, entorhinal cortex, thalamic nuclei, subthalamic nuclei, medial habenular nuclei, substantia nigra, Purkinje cells of the cerebellum, and choroid plexus. By contrast, glial cells were not labeled by the antisense HCNP-precursor riboprobe. The expression of HCNP-precursor mRNA by a variety of neurons suggests that HCNP and its precursor protein play significant roles in the stimulation of cholinergic activity, as well as in other not yet defined functions.

Animals↗
PubMed1999

Intrinsic theta-frequency membrane potential oscillations in layer III/V perirhinal cortex neurons of the rat.

The firing of a proportion of neurons in the in vivo perirhinal cortex, a brain region involved in object recognition memory, has recently been shown to be synchronized with hippocampal theta activity. The purpose of the present study was to determine whether neurons located in perirhinal cortex have intrinsic properties that might encourage their participation in theta activity. To these ends, current clamp recordings were made from 98 neurons located in layer III/V of the in vitro rat perirhinal cortex. The intrinsic properties of these neurons were investigated, and a subset of 61 neurons were tested for the presence of membrane potential oscillations at threshold levels of depolarization. Thirty-nine percent of these neurons displayed a theta-frequency membrane potential oscillation (MPO; mean frequency = 8.6 Hz). When depolarized past spike threshold, these neurons tended to fire in clusters, with a within-cluster interspike interval close to the peak to peak interval of the MPOs. Neurons that did not generate MPOs generated nonaccomodating action potential trains with a frequency that spanned the theta range. Biocytin staining indicated that MPOs could be generated in cells with both pyramidal and nonpyramidal morphology. These findings demonstrate that a large proportion of perirhinal neurons exhibit intrinsic properties that could assist in the entrainment and synchronization of theta-frequency oscillations. These properties may enhance the communication of information between the perirhinal cortex, entorhinal cortex, and hippocampus.

Animals↗
PubMed2002

Immunohistochemical localization of candidates for vesicular glutamate transporters in the rat brain.

Vesicular glutamate transporter 1 (VGluT1) is one of the best markers for glutamatergic neurons, because it accumulates transmitter glutamate into synaptic vesicles. Differentiation-associated Na(+)-dependent inorganic phosphate cotransporter (DNPI) shows 82% amino acid identity to VGluT1, and is another candidate for vesicular glutamate transporters. Here, we report the immunocytochemical localization of DNPI and compare it with that of VGluT1 in the adult rat brain. Both DNPI and VGluT1 immunoreactivities were found mostly in neuropil, presumably in axon terminals, throughout the brain. In the telencephalic regions, intense DNPI immunoreactivity was observed in the glomeruli of the olfactory bulb, layer IV of the neocortex, granular layer of the dentate gyrus, presubiculum, and postsubiculum. In contrast, VGluT1 immunoreactivity was intense in the olfactory tubercle, layers I-III of the neocortex, piriform cortex, entorhinal cortex, hippocampus, dentate gyrus, and subiculum. In the thalamic nuclei, DNPI-immunoreactive terminal-like profiles were much larger than VGluT1-immunoreactive ones, suggesting that DNPI immunoreactivity was subcortical in origin. DNPI immunoreactivity was much more intense than VGluT1 immunoreactivity in many brainstem and spinal cord regions, except the pontine nuclei, interpeduncular nucleus, cochlear nuclei, and external cuneate nucleus. In the molecular layer of the cerebellar cortex, climbing-like fibers showed intense DNPI immunoreactivity, whereas neuropil contained dense VGluT1-immnoreactive deposits. Both DNPI and VGluT1 immunoreactivities were observed as mossy fiber terminal-like profiles in the cerebellar granular layer. DNPI and VGluT1 immunoreactivities appeared associated with synaptic vesicles in the axon terminals forming asymmetric synapses in several regions examined electron microscopically. The present results indicate that DNPI and VGluT1 are used by different neural components in most, if not all, brain regions, suggesting the complementary functions of DNPI and VGluT1.

Animals↗
PubMed2004

Synaptic structural abnormalities in the Ts65Dn mouse model of Down Syndrome.

The Ts65Dn mouse is a genetic model for Down syndrome. Although this mouse shows abnormalities in cognitive function that implicate hippocampus as well as marked deficits in hippocampal long-term potentiation, the structure of the hippocampus has been little studied. We characterized synaptic structure in Ts65Dn and control (2N) mice, studying the hippocampus (fascia dentata, CA1) as well as the motor and somatosensory cortex, entorhinal cortex, and medial septum. Confocal microscopy was used to examine immunostained presynaptic boutons and to detail the structure of dendrites after Lucifer yellow microinjection. Both presynaptic and postsynaptic elements were significantly enlarged in Ts65Dn in all regions examined. The changes were detected at the youngest age examined (postnatal day 21) and in adults. In studies detailing the changes in fascia dentata and motor cortex, the enlargement of spines affected the entire population, resulting in the presence of spines whose volume was greatly increased. Electron microscopy confirmed that boutons and spines were enlarged and demonstrated abnormalities in the internal membranes of both. In addition, spine density was decreased on the dendrites of dentate granule cells, and there was reorganization of inhibitory inputs, with a relative decrease in inputs to dendrite shafts and an increase in inputs to the necks of spines. Taken together, the findings document widespread abnormalities of synaptic structure that recapitulate important features seen in Down syndrome. They establish the Ts65Dn mouse as a model for abnormal synapse structure and function in Down syndrome and point to the importance of studies to elucidate the mechanisms responsible for synapse enlargement.

Animals↗
PubMed2006

Reduced density of functional 5-HT1A receptors in the brain, medulla and spinal cord of monoamine oxidase-A knockout mouse neonates.

Abnormally high brain 5-HT levels in monoamine oxidase-A knockout (MAO-A KO) mouse neonates raise the question of whether the distribution and density of the 5-HT1A receptors (5-HT1AR) expressed in the brain by postnatal day P7 are affected and, if so, whether the 5-HT1A autoreceptors in the dorsal raphe are modified in the same way as the postsynaptic 5-HT1AR present in raphe target structures. [3H]8-OH-DPAT binding and quantitative autoradiography were performed to answer these questions. Binding specificity was first confirmed in adult wild-type mice and rat brain sections. 5-HT1AR binding was then analyzed in four MAO-A mutant vs. five wild-type neonatal brains, from olfactory bulb to cervical cord. Among 12 structures expressing postsynaptic 5-HT1AR in wild-type neonates, the highest densities involved the retrosplenial cortex, entorhinal cortex, and septum (52-46 fmol/mg tissue); low densities occurred in the hippocampus and spinal cord (24 fmol/mg tissue); in addition, the raphe autoreceptor density was only 20 fmol/mg tissue. In mutants, the distribution of postsynaptic 5-HT1AR was unchanged, but an overall decrease in density occurred (-32% to -63%); the raphe autoreceptors decreased in mutants by at least -79%. Data are discussed with reference to the ectopic 5-HT uptake and accumulation reported to occur during the first 10 postnatal days in wild-type and MAO-A KO mice. As previously suggested to explain the raphe autoreceptor loss in 2-month-old MAO-A KO mice, the overall 5-HT1AR down-regulation in mutant pups probably results from extracellular 5-HT excess in both raphe and target structures. The greater the 5-HT excess, the more the functional receptor density decreases.

Animals↗
PubMed1991

Dual serotoninergic projections to forebrain in the rat: morphologically distinct 5-HT axon terminals exhibit differential vulnerability to neurotoxic amphetamine derivatives.

The cerebral cortex of the rat and other mammals is innervated by two morphologically distinct classes of serotoninergic (5-HT) axon terminals: fine axons with minute varicosities and beaded axons characterized by large, spherical varicosities. Fine and beaded 5-HT axons exhibit different regional and laminar distributions in forebrain and arise from separate brainstem nuclei, the dorsal and median raphe nuclei, respectively. The present neuroanatomic study, based on immunocytochemical methods to visualize 5-HT axons, demonstrates that the two axon types differ markedly in their vulnerability to the neurotoxic amphetamine derivatives, methylenedioxyamphetamine (MDA), and p-chloroamphetamine (PCA). While both drugs cause extensive degeneration of fine 5-HT axons throughout forebrain, beaded 5-HT axons are consistently spared. Fine 5-HT axons, which richly innervate most regions of dorsal forebrain in control rats, are rarely seen 2 weeks after treatment with MDA or PCA; this loss of fine axons reflects a marked denervation that persists for months after drug administration. The serotoninergic axon terminals remaining after MDA or PCA administration are almost entirely of the beaded type and appear to be unaffected by both drugs. Over a wide range of doses (2.5-40 mg/kg PCA) and survival times (2 weeks to 2 months), these spared 5-HT axons with large, spherical varicosities cannot be distinguished from the normal, beaded 5-HT axons in control rats by morphologic criteria. Moreover, beaded 5-HT axons exhibit a highly characteristic regional distribution which is the same in control as in MDA- and PCA-treated rats: these axons innervate specific zones or layers within parietal and occipital cortex, hippocampus, cingulate cortex, entorhinal cortex, and the olfactory bulb, among other forebrain areas, and they form a dense plexus lining the ventricular system. Taken together, the results of this study demonstrate that fine 5-HT axons are highly vulnerable to the neurotoxic effects of the amphetamine derivatives MDA and PCA, while beaded 5-HT axons are markedly resistant. These findings are consistent with the hypothesis that there are two anatomically and functionally distinct sets of serotoninergic neurons projecting to forebrain. While both of these neuronal systems utilize 5-HT as a neurotransmitter, they differ in several features: 1) origin from separate nuclei in the brainstem (the dorsal and median raphe), 2) two types of morphologically distinct axon terminals, 3) markedly different distribution and innervation patterns in forebrain, and 4) dissimilar pharmacological properties. The results further suggest that psychotropic amphetamine derivatives have a selective action upon fine serotoninergic axons that arise from the dorsal raphe nucleus.

3,4-Methylenedioxyamphetamine↗
PubMed1993

Connections of somatosensory cortex in megachiropteran bats: the evolution of cortical fields in mammals.

The cortical connections of the primary somatosensory area (SI or 3b), a caudal somatosensory field (area 1/2), the second somatosensory area (SII), the parietal ventral area (PV), the ventral somatosensory area (VS), and the lateral parietal area (LP) were investigated in grey headed flying foxes by injecting anatomical tracers into electrophysiologically identified locations in these fields. The receptive fields for clusters of neurons were mapped with sufficient density for injection sites to be related to the boundaries of fields, and to representations of specific body parts within the fields. In all cases, cortex was flattened and sectioned parallel to the cortical surface. Sections were stained for myelin and architectonic features of cortex were related to physiological mapping and connection patterns. We found patterns of topographic and nontopographic connections between 3b and adjacent anterior parietal fields 3a and 1/2, and fields caudolateral to 3b (SII and PV). Area 1/2 had both topographic and nontopographic connections with 3b, PP, and SII. Connections of SII and PV with areas 3b, 3a, and 1/2 were roughly topographic, although there was clear evidence for nontopographic connections between these fields. SII was most densely connected with area 1/2, while PV was most densely connected with 3b. SII had additional connections with fields in lateral parietal cortex and with subdivisions of motor cortex. Other connections of PV were with subdivisions of motor cortex and pyriform cortex. Laminar differences in connection patterns of SII and PV with surrounding cortex were also observed. Injections in the ventral somatosensory area revealed connections with SII, PV, area 1/2, auditory cortex, entorhinal cortex, and pyriform cortex. Finally, the lateral parietal field had very dense connections with posterior parietal cortex, caudal temporal cortex, and with subdivisions of motor cortex. Our results indicate that the 3b region is not homogeneous, but is composed of myelin dense and light regions, associated with 3b proper and invaginations of area 1/2, respectively. Connections of myelin dense 3b were different from invaginating portions of myelin light area 1/2. Our findings that 3b is densely interconnected with PV and moderately to lightly interconnected with SII supports the notion that SII and PV have been confused across mammals and across studies. Our connectional evidence provides further support for our hypothesis that area 1/2 is partially incorporated in 3b and has led to theories of the evolution of cortical fields in mammals.

Animals↗
PubMed1994

The organization of the embryonic and early postnatal murine hippocampus. II. Development of entorhinal, commissural, and septal connections studied with the lipophilic tracer DiI.

We have analyzed the early development of the main hippocampal afferents in the mouse. Following injections of the lipophilic tracer 1-1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) in the entorhinal cortex, entorhinal axons were observed for the first time in the hippocampus at E15, in the white matter. At E17, entorhinal fibers arborized within the stratum lacunosum-moleculare. At subsequent stages entorhinal axons formed dense networks that were restricted to their appropriate termination zone in the lacunosum-moleculare. The first axons invading the fascia dentata were noticed at E19, their density increasing at later stages. These axons were mainly present in the outer molecular layer. This onset of entorhinohippocampal projections was corroborated by retrograde labeling data after injections in the hippocampus. Commissural fibers first entered the contralateral hippocampus at E18, their number increasing at the following stages. Commissural axons arborized within the stratum oriens and radiatum in the hippocampus proper. In the fascia dentata, the earliest commissural fibers were seen at P2, terminating in the inner zone of the molecular layer and in the hilus. We conclude that developing entorhinal and commissural axons show a high degree of laminar specificity from the earliest stages of formation, which is compatible with the notion that distinct subsets of early maturing neurons populating the hippocampal plexiform layers may attract particular fiber systems. Hippocamposeptal fibers develop at E15, before the first septal fibers can be detected in the hippocampus. These early hippocamposeptal fibers originated from nonpyramidal neurons and terminated in the medial septal area, which is the main source of septal afferents to the hippocampus. In contrast, septohippocampal fibers were not seen in the hippocampus until E17. At perinatal stages, the hippocamposeptal connection reshapes, sending axons to the dorsolateral septal area as the innervation of the medial septum becomes less conspicuous. This sequence suggests that hippocampal neurons pioneer the formation of septohippocampal connections.

Animals↗
PubMedDate not supplied

Soman-induced morphological changes: an overview in the non-human primate.

A review of the literature was conducted to provide an overview of organophosphorus (OP)-induced morphological changes in the non-human primate. Most studies have evaluated effects of the OP nerve agent soman (pinacolyl methylphosphonofluoridate), an irreversible inhibitor of acetylcholinesterase. Soman-induced acute and chronic morphological changes have been examined. The effects of nerve agent therapy (i.e. pyridostigmine, praloxidime chloride and atropine), with and without an anticonvulsant (i.e. diazepam, midazolam), on soman-induced lesions have also been studied. Acute changes in the central nervous system of rhesus and cynomolgus monkeys exposed to soman alone or soman and therapy, without an anticonvulsant, were characterized by neuronal degeneration and necrosis and neuropil edema. The lesions were usually present in the frontal cortex, entorhinal cortex, amygdaloid complex, caudate nucleus, thalamus and hippocampus. Morphologically, these lesions resemble lesions produced by hypoxic-ischemic injury or by seizures and are similar to soman-induced changes in other laboratory animals. Nerve agent therapy supplemented with an anticonvulsant reduced or prevented soman-induced acute neural lesions. Acute changes in non-neural tissues were limited to the heart (e.g. hemorrhage, myofiber necrosis, myocarditis) and skeletal muscle (e.g. myofiber necrosis). Heart lesions in the non-human primate are similar to OP-induced heart lesions in man. The pathogenesis of the acute lesions in both the central nervous system and heart is discussed. Consistent soman-induced chronic morphological changes have not been produced in the rhesus monkey or baboon.

Animals↗
PubMed1995

Activation of astrocytes during epileptogenesis in the absence of neuronal degeneration.

The issue of whether neuronal degeneration is a primary factor in activation of astrocytes during epileptogenesis was addressed using the kindling model of epilepsy. No degenerative changes specific to the kindling process were observed in brain sections from kindled animals, sampled from the olfactory bulbs through to cerebellum and processed with the degeneration-sensitive cupric silver stain. Also, examination of lectin-stained sections did not reveal any reactive microglia. At the same time, reactive astrocytes, as judged by an increase in glial fibrillary acidic protein immunoreactivity and a de novo vimentin immunoreactivity, were prominent in amygdala, piriform cortex, entorhinal cortex and hippocampus. These results suggest that loss of neurones is not a prerequisite for establishment of epilepsy-prone state, that seizures of short duration do not necessarily result in neuronal death, and that in kindling, astrocytes are activated by factors that are not related to neuronal degeneration, but which are likely associated with abnormal neuronal activity.

Animals↗
PubMed1995

Inhibitory avoidance training induces rapid and selective changes in 3[H]AMPA receptor binding in the rat hippocampal formation.

The AMPA receptor has been shown to participate in the synaptic mechanisms involved in certain forms of learning and memory. We have previously demonstrated that the posttraining infusion of 6-cyano-7-nitroquinoxaline-2,3-dione, an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor blocker, into the dorsal hippocampus of rats, causes retrograde amnesia of an inhibitory avoidance training. Here, we report on the effect of this learning task on 3[H]AMPA binding to frozen rat brain sections. By using a quantitative autoradiographic analysis, we were able to demonstrate that the binding of 3[H]-AMPA was increased by 40-80% in the CA1, CA2, CA3, and dentate gyrus subregions of the hippocampal formation of rats trained in a step-down inhibitory avoidance paradigm, compared to naive, shocked, and free exploration controls. This effect was evident between 30 and 180 min after training, and it was mainly due to an increase in the density, but not in the affinity of binding sites. No alterations in 3[H]AMPA binding were observed either in those animals that received only the footshock (shocked group) or in animals that were submitted to 1 min of free exploration of the training box (free exploration group). In the rest of the brain regions, including the frontal cortex, entorhinal cortex, striatum, amygdala, cerebellum, and thalamus, the 3[H]AMPA binding remained unchanged. In addition, the binding of 3[H]muscimol and 3[H]-flunitrazepam to the GABAA/benzodiazepine receptor complex was unaltered in all the experimental groups. In conclusion, rats submitted to a one-trial inhibitory avoidance training showed a rapid, selective, and specific increase in 3[H]AMPA binding in the hippocampal formation. The present findings support the hypothesis that hippocampal AMPA receptors are involved in the neural mechanisms underlying certain forms of learning and memory.

Animals↗
PubMed1987

Tyrosine hydroxylase-immunoreactive intrinsic neurons in the rat cerebral cortex.

Using specific antisera against the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH), in combination with the peroxidase-antiperoxidase method and/or the avidin-biotin complex method, we have found a new group of TH immunoreactive (TH-I) neurons in the rat cerebral cortex. Numerous TH-I cells were observed all over the isocortex, that is, frontal, temporal, parietal and occipital regions, and in some parts of the allocortex such as the anterior cingulate cortex, the retrosplenial cortex and anterior part of the insular cortex. In contrast, they were rare in the perirhinal cortex, posterior part of the insular cortex, piriform cortex, entorhinal cortex and hippocampal formation. TH-I cells were situated throughout all cortical layers, but were most concentrated in layer II/III. Although TH-I cells were heterogeneous in shape, the majority were bipolar. All TH-I cells so far examined appeared to be of the nonpyramidal type. The majority of these intrinsic TH-I neurons also contained the GABA-like immunoreactivity and thus could be regarded as a subpopulation of cortical GABAergic neurons.

Animals↗
PubMed1990

Regional variations in protein phosphorylating activity in rat brain studied in micro-slices labeled with [32P]phosphate.

Regional variations in protein phosphorylating activity in the rat brain were studied. Micro-slices (1 mm diameter) were prepared from 19 brain areas, phosphoproteins labeled by incubation with [32P]phosphate, and the tissue analyzed by nonequilibrium two-dimensional electrophoresis and autoradiography. Attention was focused on three phosphorylating systems that showed consistent variation in activity. (1) A system that phosphorylates a substrate of 47 kDa (ppH-47) whose activity was highest in the hippocampus. The next highest activity of this system was observed in the globus pallidus, followed by the periventricular gray matter of the aqueduct, lateral septum, cerebellar cortex, entorhinal cortex, hypothalamus, mammillary nuclei, amygdala, and substantia nigra. Activity was low or undetectable in the cerebral cortex, neostriatum, and the colliculi. (2) A system that phosphorylates a substrate of 50 kDa (ppC-50) whose activity was highest in the caudate nucleus. The activity of this system was roughly inversely correlated with that of the ppH-47 system. (3) The protein kinase C system that phosphorylates an 82- to 87-kDa substrate known as MARCKS. The highest activity of this system was observed in the cerebellar cortex, followed by the hypothalamus, mammillary nuclei, periventricular gray matter of the aqueduct, and the superior colliculus. Activity of this system was relatively low in several regions of the cerebral cortex, the neostriatum, and the inferior colliculus.

Animals↗