Biomedical subjects

A Najlerahim

Publications and source records attributed to A Najlerahim.

At least 19 recordsLinked to original sources

PubMed1994

Distribution of mRNA for the GABA transporter GAT-1 in the rat brain: evidence that GABA uptake is not limited to presynaptic neurons.

Cells containing mRNA for the gamma-aminobutyric acid (GABA) transporter GAT-1 were identified in rat brain by in situ hybridisation. They were found in most of the known locations of GABAergic neurons, as defined by the distribution of mRNA for glutamic acid decarboxylase, the synthetic enzyme for GABA. Within the cerebellum there was substantial labelling of basket and stellate cells in the molecular layer, and of Golgi cells but no others in the granule cell layer. Many Purkinje cells were unlabelled while others, particularly in the hemispheres, were moderately labelled. Many of the Purkinje cells negative for GAT-1 mRNA had adjacent intensely labelled small cells whose size and position corresponded to Bergmann glia. Numerical comparison of cells labelling for GAT-1 mRNA and the mRNAs for the two known isoforms of glutamic acid decarboxylase were made on serial sections of cerebral cortex. Cells positive for GAT-1 mRNA were more numerous, indicating that expression of the transporter is not just limited to GABAergic cells and we suggest that it may also be expressed postsynaptically by some non-GABAergic neurons.

Animals↗

PubMed1993

Abundant Gs alpha mRNA in basket cells of the dentate gyrus in adult rat hippocampus.

In situ hybridization histochemistry (ISHH) has been used to study the differential distribution and relative abundance of mRNAs encoding a stimulatory alpha subunit of the G-protein (Gs alpha) and glutamic acid decarboxylase (GAD) in the dorsal hippocampus in adult rat brain. The present quantitative study shows that GABAergic neurons containing high levels of GAD mRNA, express considerably more Gs alpha message than excitatory principal neurons, the granule cells of the dentate gyrus and the pyramidal cells of CA1 subfield. A subpopulation of basket cells of the dentate gyrus exhibited a uniquely high level of Gs alpha mRNA, in addition to GAD. These findings may indicate a specific functional role for Gs alpha in these GABAergic neurons in the hippocampus.

Animals↗

PubMed1993

Heat shock protein (hsx70) mRNA expression in human brain: effects of neurodegenerative disease and agonal state.

Heat shock proteins (hsps) are involved in the response by cells to stress including hyperthermia, hypoxia and injury. Previous work has demonstrated expression of messenger RNA (mRNA) encoding 70 kDa hsps (hsp70) in animal brain in response to stimuli such as these. We have used in situ hybridization histochemistry to assess the distribution and quantity of a specific hsp70 (called hsx70) mRNA in frontal cortex and cerebellum from normal and demented patients whose pre-mortem course had been documented. In cortex, hsx70 mRNA was concentrated over pia mater and glia but was also present over neurons; in cerebellum, hsx70 mRNA was prominent over granule cells but absent from Purkinje cells. Detection of hsx70 mRNA did not correlate with pre-mortem factors such as pyrexia or coma. Increased hsx70 mRNA was found in frontal cortex white matter in Alzheimer's disease and in a mixed group of other neurodegenerative disorders. No changes occurred in cerebellum. The data provide further evidence for altered hsp gene expression in dementia, and support the existence of a stress response occurring in brains affected by such diseases.

Aged↗

PubMed1993

Pre- and postmortem influences on brain RNA.

Many potentially valuable techniques for the understanding of human neurobiological and neuropathological processes require the use of RNA obtained from postmortem tissue. As with earlier neurochemical studies, there are two particular problems posed by such tissue in comparison with tissue from experimental animals. These are the postmortem interval and the condition of the patient prior to death, referred to as the agonal state. We review the nature and extent of the effects of postmortem interval and agonal state on RNA in brain tissue, with particular reference to the study of neuropsychiatric disorders. Perhaps surprisingly, postmortem interval has at most a modest effect on RNA. Abundant intact and biologically active RNA is present in tissue frozen 36 h or more after death. Postmortem interval does not account for the marked variability observed among human brains in all RNA parameters. Despite the overall stability of RNA after death, some evidence suggests that individual RNAs may undergo postmortem decay. Less attention has been paid to the effects of agonal state. The existing data indicate that events in the premortem period such as hypoxia and coma can affect the amount of some messenger RNAs. The nature of agonal state influences depends on the messenger RNA in question, though the basis for this selective vulnerability is unknown. No agonal state effect on overall RNA level or activity has been found. The data show that postmortem brain tissue can be used for RNA research. However, considerable attention must be paid to controlling for the influences of pre- and postmortem factors, especially when quantitative analyses are performed.

Animals↗

PubMed1992

Increased expression of GAD mRNA during the chronic epileptic syndrome due to intrahippocampal tetanus toxin.

A few mouse minimum lethal doses (MLD) of tetanus toxin injected into rat hippocampus triggers prolonged changes in neuronal function. Spontaneously recurring epileptic discharges arise in both the injected and the contralateral, uninjected hippocampus. The seizures remit after about 6 weeks, to be succeeded by a permanent depression of hippocampal neuronal responses. There is no evidence of any loss of pyramidal cells at this low dose of toxin. Here we studied presumptive inhibitory, GABAergic neurons, using in situ hybridization (ISH) with a probe directed against the mRNA encoding glutamic acid decarboxylase (GAD), at each of 1, 2, 4 and 8 weeks after injection of tetanus toxin. Epileptic activity was recorded from hippocampal slices prepared from both injected and contralateral hippocampi of rats at each time point, unexpectedly persisting until 8 weeks. There were no significant differences in the numbers of neurons containing GAD mRNA between toxin- and vehicle-injected and control rats in any hippocampal subfield, at any survival time, except for an apparently transient loss of hilar signal in vehicle-injected rats at 1 and 2 weeks which we attribute to a significant, transient loss of neuronal GAD mRNA to below the threshold for detection by ISH using this probe. In contrast there was a marked increase in GAD mRNA in the toxin-injected group, which reached a peak at 4 weeks, and returned to control levels by 8 weeks. The changes were bilateral and were most marked in the hilus of the dentate area, but were also significant in CA3 and CA1. Upregulation of GAD mRNA was preceded by an increase in the levels of the mRNA for the alpha subunit of the GTP binding protein, Gs (Gs alpha), at 2 weeks which affected the GABAergic neurons selectively, and not the pyramidal or granule cells. These marked changes in GAD mRNA may contribute to putative adaptive responses within GABAergic neurons, which would help contain epileptic activity in these chronic foci. The changes in GAD expression may be due to mechanisms acting through an increase in mRNA encoding Gs alpha.

Animals↗

PubMed1992

Changes in glutamic acid decarboxylase mRNA in the pallidum of the rat following unilateral damage of the striatum and overlying cortex.

The messenger RNA encoding glutamic acid decarboxylase (GAD) has been examined in the pallidum of the rat using in situ hybridization histochemistry following damage of the striatum and overlying frontal neocortex of one side. Following a postoperative survival time of 5 weeks, ipsilateral shrunken pallidal neurons showed significant decrease in GAD mRNA. The mRNA for GAD is significantly increased in neurons of the contralateral pallidum. These neurons are also significantly enlarged. These findings may be related to pathological changes in pallidal neurons in Huntington's disease.

Animals↗

PubMed1991

Transient increase in glutamic acid decarboxylase mRNA in the cerebral cortex following focal cortical lesion in the rat.

In situ hybridization histochemistry (ISHH) was used to study the expression of glutamic acid decarboxylase (GAD) mRNA changes in the rat cerebral cortex following unilateral frontal and somatosensory cortical lesion by devascularisation. 4 days after the lesion, a significant transient increase in GAD mRNA level in the ipsilateral cortex was observed when compared with contralateral, ipsi-sham operated and ipsi-normal control cortices. The change occurred throughout the ipsilateral neocortex, with no significant difference between the magnitude of increase in frontal, parieto-occipital, parieto-temporal, cingulate or retrosplenial areas; no obvious change was seen in pyriform, entorhinal or hippocampal cortices. This unexpected GAD mRNA increase in neocortex may be part of a long term adaptive functional alteration and changes in the gene expression of the cerebral cortex following focal cortical injury.

Animals↗

PubMed1991

Increased muscarinic receptor messenger RNA in Alzheimer's disease temporal cortex demonstrated by in situ hybridization histochemistry.

A 35S-labelled synthetic oligonucleotide directed against part of the mRNA coding for the M1 subtype muscarinic receptor was used for in situ hybridization histochemistry in sections of human temporal cortex. M1 receptor mRNA was found in cell populations throughout the grey matter, especially in pyramidal cells. Quantitative densitometric analysis of autoradiograms was used to compare levels of this mRNA between Alzheimer's disease and controls. A significant (2.7-fold) increase in hybridization signal was found in Alzheimer's disease cases, both in absolute terms and relative to total polyadenylated mRNA as determined by hybridization with an oligodeoxythymidine probe. Elevated levels of muscarinic receptor mRNA may reflect up-regulation of transcription of this gene in response to the cholinergic deficits occurring in the disease.

Alzheimer Disease↗

PubMed1991

Terminal coma affects messenger RNA detection in post mortem human temporal cortex.

In situ hybridization histochemistry has been used to study the amount of M1 muscarinic receptor mRNA in temporal cortex from subjects with Alzheimer's disease and other neurodegenerative disorders, where the duration of terminal coma was known. Total polyadenylated mRNA and glutamate decarboxylase activity were also measured. Both muscarinic receptor mRNA and enzyme activity showed a significant decline with increasing duration of terminal coma, but were not related to diagnosis. Polyadenylated mRNA signal did not show an association with coma. These data indicate the need to consider the nature of the terminal illness in post mortem studies of mRNA as well as for neurochemical research.

Alzheimer Disease↗

PubMed1991

Regional and neuronal reductions of polyadenylated messenger RNA in Alzheimer's disease.

Messenger RNA (mRNA) is the key intermediate in the gene expression pathway. The amount of mRNA in Alzheimer's disease (AD) brains has been determined using in situ hybridization histochemistry (ISHH) to detect the poly(A) tails of polyadenylated mRNA (poly(A) + mRNA). On a regional basis, AD cases had significantly less poly(A) + mRNA than controls in hippocampus (field CA3) and cerebellum (granule cell layer). Analysis of constituent pyramidal neurons showed mean reductions per cell within AD hippocampus (field CA3) and temporal cortex, but not in visual cortex. Similar changes were seen in a small group of non-AD dementias. The finding of reduced poly(A) + mRNA content is another indication of the altered brain gene expression occurring in AD. It is proposed that measurement of poly(A) + mRNA may be valuable in identifying functionally impaired neuronal populations. The methodology also provides a means by which changes in the quantitative distribution of individual mRNAs can be determined relative to that of poly(A) + mRNA as a whole.

Adult↗

PubMed1990

Distribution of messenger RNAs encoding the enzymes glutaminase, aspartate aminotransferase and glutamic acid decarboxylase in rat brain.

In situ hybridization histochemistry (ISHH) using synthetic oligonucleotide probes has been used to identify cells containing the mRNAs coding for glutaminase (GluT), aspartate aminotransferase (AspT) and glutamic acid decarboxylase (GAD). The distribution of GAD mRNA confirms previous descriptions and matches the distribution of GAD detected using specific antibodies. AspT mRNA is widely distributed in the brain, but is present at high levels in GABAergic neuronal populations, some that may be glutamatergic, and in a subset of neurons which do not contain significant levels of either GAD or GluT mRNA. Particularly prominent are the neurons of the magnocellular division of the red nucleus, the large cells in the deep cerebellar nuclei and the vestibular nuclei and neurons of the lateral superior olivary nucleus. GluT mRNA does not appear to be present at high levels in all GAD-containing neurons, but is seen prominently in many neuronal populations that may use glutamate as a neurotransmitter, such as neocortical and hippocampal pyramidal cells, the granule cells of the cerebellum and neurons of the dentate gyrus of the hippocampus. The heaviest labelling of GluT mRNA is seen in the lateral reticular nucleus of the medulla. ISHH using probes directed against the mRNAs encoding these enzymes may be an important technique for identifying glutamate and aspartate using neuronal populations and for examining their regulation in a variety of experimental and pathological circumstances.

Animals↗

PubMed1990

Distribution of a kainate/AMPA receptor mRNA in normal and Alzheimer brain.

In-situ hybridization (ISH) has been used to determine the distribution of the mRNA encoding a non-NMDA glutamatergic receptor subtype in rat and human brain. In the rat, signal is concentrated over neurons in hippocampus and cerebellum, with moderate labelling of neocortex and diencephalon. In human brain, a similar hippocampal and cerebellar distribution is seen, although with lower overall levels. Quantitative comparison between normal and Alzheimer's disease (AD) brain reveals a modest increase of this mRNA in AD subiculum and CA4 hippocampal field with no change in cerebellum. The significance of the increase is discussed in relation to other data suggesting glutamatergic involvement in AD.

Alzheimer Disease↗

PubMed1990

Increased tau messenger RNA in Alzheimer's disease hippocampus.

The microtubule-associated protein tau is present in the pathologic hallmarks of Alzheimer's disease and its production and deposition have been implicated in the pathogenesis of the disease. We detected tau mRNA using in situ hybridization histochemistry in the hippocampus, visual cortex, and cerebellum, and compared its level in Alzheimer's disease with controls. The amount of tau mRNA also was determined as a ratio of total polyadenylated mRNA in each area. A significant and gene-specific increase in tau mRNA hybridization was found in hippocampal fields CA4 and CA3, with a similar trend in the dentate gyrus. In contrast, no change was found in the visual cortex or cerebellum in Alzheimer's disease. Increased hippocampal expression of tau mRNA also was present in cases of non-Alzheimer's dementia. Enhanced tau mRNA may be a marker of attempted plasticity involving the cytoskeleton in neuronal populations affected by various neurodegenerative disorders.

Aged↗

PubMed1989

Messenger RNA encoding the D2 dopaminergic receptor detected by in situ hybridization histochemistry in rat brain.

A 30 base synthetic oligonucleotide probe was used to detect the mRNA encoding the rat D2 dopaminergic receptor. On Northern analysis, the probe identified a single species of mRNA of approximately 2.9 kb, present at highest levels in the striatum but also found in the brainstem, neocortex and diencephalon. On sections, neurons containing high levels of the mRNA were detected in the striatum, the substantia nigra pars compacta and the ventral tegmental area. Lower levels of signal were seen over neurons in the hypothalamus, the frontal neocortex, and the globus pallidus.

Animals↗

PubMed1989

Brain amino acid concentrations and Ca2+-dependent release in intractable depression assessed antemortem.

The concentrations of 3 putative neurotransmitters (glutamate, aspartate and gamma-aminobutyrate), 4 related amino acids and 5 non-transmitter-related amino acids have been measured in neurosurgical samples (frontal cortex) from patients with intractable depression and controls. In addition, the glutamate receptor agonist 2-amino-4-sulpho-butanoic acid (homocysteic acid) has been identified in human brain and measured in these samples. There were no changes in the concentrations of amino acids in depressed patients compared to control with the exception of aspartic and homocysteic acids which were elevated in a sub-group of patients with depression compared to control. The Ca2+-dependent release (K+-stimulated) of putative neurotransmitters has been demonstrated for the first time from brain tissue of depressed patients. Glutamate release was unaltered from the control value. Aspartate values showed unexplained variability but it's release and that of gamma-aminobutyrate were elevated in some depressed subjects. These results do not support the hypothesis of reduced amino acid function in depressive illness.

Aged↗

PubMed1989

Circumscribed changes of the cerebral cortex in neuropsychiatric disorders of later life.

The extent and distribution of biochemical abnormalities thought to reflect disorders of subpopulations of neurons have been determined in the cerebral cortex from brains of patients with Alzheimer-type dementia and depressive illness who died of natural causes. In dementia, loss of gray matter from areas of the parietal and temporal lobes is most obvious. In depression, these areas are not affected, but the pars opercularis and temporal pole are smaller than in controls. Results expressed per unit mass of total protein indicate selective reductions in both disorders of serotonin 2 recognition sites in all areas examined and of somatostatin content in only the temporal pole of the six areas examined. In dementia alone a selective loss was found of somatostatin content of the superior parietal lobule and of serotonin 1A sites and choline acetyltransferase activity in all areas examined. Results for depression expressed per entire area indicate additionally reduced somatostatin content and serotonin 1A sites in the pars opercularis and serotonin 1A sites in the temporal pole. These multiple analyses performed on each sample provide further support for a prominent disorder of pyramidal neurons in dementia as well as more evidence for alterations in cortical neurons in depression, either as a result of the disease itself or its treatment.

Aged↗

PubMed1988

Biochemical measurements in Alzheimer's disease reveal a necessity for improved neuroimaging techniques to study metabolism.

A series of Alzheimer's disease and control brains were dissected to determine the extent of atrophy (based on total protein content) and loss of choline acetyltransferase activity in the cerebral cortex from the entire surface of the diseased brains. The distribution of intensity of pathology so determined is strikingly similar to the degree of hypometabolism as shown by positron emission tomography. It is argued that the hypometabolism can be explained (at least in part) by focal areas of atrophy.

Aged↗

PubMed1988

Regional weight loss of the cerebral cortex and some subcortical nuclei in senile dementia of the Alzheimer type.

All the cerebral cortex and some subcortical nuclei from six examples of senile dementia of the Alzheimer type (SDAT) and six age- and sex-matched controls have been dissected and weighed. The weight of the parietal and temporal cortex are significantly reduced. The parietal lobe shows the largest weight loss and this is most obvious in the precuneus and the superior lobule. The posterior cingulate, the middle and superior temporal, the supramarginal and the superior frontal gyri also show significant weight reduction. Weight loss of the amygdala is more than that of the hippocampus, the caudate nucleus and the putamen, but the weights of all are reduced significantly. These results are rather unexpected but are consistent with other data (e.g. the clinical parietal lobe syndrome and focus of glucose hypometabolism in Alzheimer's disease). They indicate that prominent changes occur in SDAT in the association areas of the parietal lobe as well as in the amygdala.

Aged↗