Biomedical subjects
P J Harrison
Publications and source records attributed to P J Harrison.
Crossed actions on group II-activated interneurones in the midlumbar segments of the cat spinal cord.
1. Evidence has been sought for crossed actions on midlumbar propriospinal neurones activated by ipsilateral group II muscle afferents, with particular emphasis on those neurones with projections to the ipsilateral hindlimb motor nuclei. 2. A large majority of group II-activated midlumbar neurones were influenced by stimulation of contralateral group II afferents. The most frequent and most powerful actions were from those nerves which most effectively influenced ipsilateral midlumbar neurones. Crossed actions from group I afferents were rare. 3. In the great majority of neurones the pattern of actions was similar from both limbs, the neurones being bilaterally excited, bilaterally inhibited or had both EPSPs and IPSPs from both sides. 4. The latencies of crossed actions suggest that the earliest crossed EPSPs from group II afferents were evoked disynaptically (i.e. via a single commissural neurone) and that the crossed IPSPs were evoked trisynaptically. 5. The pattern of crossed actions suggests a strong bilateral interaction between midlumbar neurones. The possible role of these neurones in postural control and the production of co-ordinated movements of the hindlimbs is discussed.
Nicotine intake and Alzheimer's disease.
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Alzheimer's disease and the beta amyloid gene.
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Decreased hippocampal expression of a glutamate receptor gene in schizophrenia.
A striking and specific loss of the messenger RNA that encodes a non-N-methyl D-aspartate (non-NMDA) glutamate receptor was found in hippocampal tissue obtained at necropsy from 6 patients with schizophrenia, when compared to specimens from 8 controls without neurological or psychiatric signs or symptoms. These findings support suggestions of aberrant glutamatergic function in schizophrenia. Evidence that gene expression may be abnormal in schizophrenia, with decreased production of an excitatory neurotransmitter receptor, may have therapeutic as well as pathogenetic implications.
Alzheimer's disease: specific increases in a G protein subunit (Gs alpha) mRNA in hippocampal and cortical neurons.
The GTP binding protein, Gs, activates adenyl cyclase in direct response to stimulation of several neurotransmitter receptors. In situ hybridization histochemistry (ISHH) with a 35S-labelled oligonucleotide has been used to detect the mRNA encoding the alpha subunit of Gs (Gs alpha) in human hippocampus, temporal and visual cortices and cerebellum, and its level has been compared between Alzheimer's disease (AD) and control brains. A marked regional increase was found in the hippocampus of AD cases. Analysis of levels of Gs alpha mRNA in individual constituent pyramidal cells confirmed this increase (3 to 4-fold in densitometric units) in hippocampal fields CA1, CA3 and CA4, as well as in temporal cortex. Levels of Gs alpha mRNA were also determined relative to total poly(A)+ mRNA in the same cell populations in each case. Gene-specific elevation of Gs alpha mRNA was thereby confirmed in hippocampal fields, and also in temporal cortex. No changes were seen in visual cortex. The increase in Gs alpha mRNA may represent a response by AD neurons in affected areas to receptor alterations, or to an abnormality in receptor-G protein coupling. Alternatively, altered G protein gene expression might be a pathogenic event underlying changes in linked receptor populations.
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.
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.
Immunoblotting for the detection of TSH receptor autoantibodies.
Immunoblotting was optimized to detect autoantibodies to TSH receptors from human and porcine thyroid tissue and to determine their epitope specificity. Autoantibodies to putative TSH receptor proteins in thyroid particulate membranes were detected in approximately 35% of sera from patients with Graves' disease. However, despite modifications to increase immunoblotting sensitivity and specificity, only a minority (less than 15%) of Graves' disease sera contained autoantibodies that identified epitopes within TSH affinity-purified human or porcine receptor proteins. In these sera there was no correlation between the TSH receptor antibody titre, determined by radioreceptor assay, and receptor epitope reactivity. The sensitivity of immunoblotting was limited by reduced transfer of purified receptor from the gel. However, in addition, the inability to immunoblot the purified receptor with a majority of Graves' sera, under conditions designed to enhance receptor renaturation, appears to reflect a strict conformational requirement for immunoreactivity. Immunoblotting of purified receptors therefore has a limited application in detecting, and defining the epitope reactivity of, TSH receptor autoantibodies.
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.
Expression of amyloid beta-protein precursor mRNAs in familial Alzheimer's disease.
The amyloid beta-protein precursor (APP) gene and its products are implicated in the pathogenesis of Alzheimer's disease. The differential expression of APP transcripts may contribute to this process. In the present study, the distribution of mRNAs encoding APP variants has been determined in the brain of three cases of familial Alzheimer's disease (FAD) using in-situ hybridization histochemistry. One FAD case was associated with a mutation in the APP gene. No differences in distribution or quantity of APP transcripts were observed between FAD cases and controls. Overexpression of APP mRNAs is therefore an unlikely explanation for the deposition of the beta-amyloid (beta/A4) peptide in FAD brains.
Are mental states a useful concept? Neurophilosophical influences on phenomenology and psychopathology.
Recent trends in neurophilosophy question the validity of conceptions as to the nature of mental states and of "folk psychology" (FP) in general. One school of thought, the "eliminative materialistics," see FP as a misdirected and scientifically redundant approach to the mind which should be discarded; the "functionalists," in contrast, consider FP categories, such as belief, to be essential. Between these extremes other neurophilosophical positions affect the way we view mental life. This paper extends the debate to include a consideration of abnormal mental states. It is argued that approaches to phenomenology and psychopathology cannot be immune from any conceptual reconfiguration of normal mental life which might occur. The manner and extent to which psychiatric theory and practice may be affected as a result of these developments is discussed.
The effects of compression upon conduction in myelinated axons of the isolated frog sciatic nerve.
1. Action potential conduction along frog sciatic nerve fibres has been monitored during compression of a mid-portion of the nerve. 2. The effects of compressing a 24 mm length of nerve with a pressure of 250 mmHg applied pneumatically were investigated by recording unitary action potentials. A plot of time before conduction failure (survival time) against initial conduction velocity revealed that the faster myelinated axons tend to fail before the slower myelinated axons. A large degree of scatter was evident in the pooled data as well as in the data from individual experiments. 3. When the compression was made more severe by increasing the applied pressure to 750 mmHg, the order of block was reversed, i.e. the slower myelinated axons tended to block first. Similar scatter in the order of conduction block was observed. 4. The average survival time of units following application of compression was considerably different between these two series of experiments. When 750 mmHg pressure was applied, units survived for, on average, 10.9 min (n = 246). When 250 mmHg pressure was applied units survived for, on average, 50.4 min (n = 148). 5. The results are discussed in relation to the underlying causes of conduction failure as a result of compression and in relation to results from previous investigations.
"Life, Jim, but not as we know it"? Transmissible dementias and the prion protein.
The spongiform encephalopathies are unusual in several respects. Firstly, they are transmissible, and in some cases inheritable. Secondly, variants of these disorders occur in many species and can be transmitted by consumption of infected material; this has led to concern as to the potential risk from eating contaminated animal products. Thirdly, increasing evidence suggests that a 'prion' protein is central to their aetiology and pathogenesis, and that no nucleic acid is involved in the infective process. The role of the prion gene and its protein is outlined and proposed as the basis for an improved classification of the transmissible dementias.
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.
In situ hybridization histochemistry and the study of gene expression in the human brain.
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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.