Acta Neurologica ScandinavicaVolume 38, Issue s1 p. 6-8 ENZYMOLOGY OF ENERGETICS AND IONIC MOVEMENT THE OPERATION OF THE KREBS CYCLE IN BRAIN MITOCHONDRIAL FRACTIONS R. Balazs, R. Balazs Medical Research Council, Neuropsychiatric Research Unit, Carshalton, Surrey, EnglandSearch for more papers by this authorD. Richter, D. Richter Medical Research Council, Neuropsychiatric Research Unit, Carshalton, Surrey, EnglandSearch for more papers by this author R. Balazs, R. Balazs Medical Research Council, Neuropsychiatric Research Unit, Carshalton, Surrey, EnglandSearch for more papers by this authorD. Richter, D. Richter Medical Research Council, Neuropsychiatric Research Unit, Carshalton, Surrey, EnglandSearch for more papers by this author First published: April 1962 https://doi.org/10.1111/j.1600-0404.1962.tb05247.xCitations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume38, Issues1April 1962Pages 6-8 RelatedInformation

The trisomy-16 (T-16) mouse is considered to be a promising model for human trisomy-21 (T-21) (Down's syndrome, DS). Therefore, the fatty acyl (PUFA) compositions of phosphoglycerides in embryonic brains (days E-17 and E-18) of T-16 mice have been compared with those of balanced heterozygotic embryos from the same litters, in order to determine whether similar abnormalities are present as have been found in foetal DS brain (Brooksbank et al., 1985, J. Neurochem. 44, 869-874). The analyses revealed that the ratio of (n-3) to (n-6) PUFA was significantly increased in ethanolamine (EPG) and in choline phosphoglycerides, as it is in EPG in the foetal T-21 brain. However, the abnormality was not so marked in the murine as in the human trisomy, and the (n-3)/(n-6) ratio in EPG was primarily elevated on account of decreased proportions of 20:4(n-6) and 22:4(n-6), there being no significant increase in (n-3) PUFA. The PUFA composition of the phosphoglycerides of the corresponding trisomic and balanced placentae was also determined, but no relevant differences could be discerned between the genetically different tissues. As 6-desaturase, the rate-limiting enzyme system in PUFA synthesis, reacts more readily with (n-3) than with (n-6) substrates, the shift in (n-3)/(n-6) ratio of PUFA might be related to an alteration in 6-desaturase activity in trisomy. Comparison of the specific activity of 6-desaturase in fresh brain homogenates of T-16 embryos with those from balanced litter-mates revealed, however, no differences.

We have observed recently that in vitro lipoperoxidation is enhanced in Down's syndrome brain homogenates of prenatal age. As this may relate to the composition of polyunsaturated acyl groups (PUFA) in phospholipids, we have examined the PUFA of ethanolamine and serine phosphoglycerides (EPG and SPG), which are particularly rich in PUFA, in the same series of cerebral cortex specimens of Down's syndrome and age-matched control fetuses. Although the total percentages of PUFA in the two phosphoglycerides were not altered, compared with controls the ratio of PUFA of the (n-3) series to those of the (n-6) series was very significantly elevated in Down's syndrome, from 0.32 to 0.55 in EPG and from 0.60 to 0.97 in SPG. In particular, docosahexaenoyl, 22:6(n-3), groups were uniformly increased in Down's syndrome compared with controls by 54% and 33% in EPG and SPG, respectively, while arachidonoyl, 20:4(n-6), groups were decreased by 16% and 30%, respectively. Similar changes occur during normal development, but the (n-3) to (n-6) ratio of PUFA in these phosphoglycerides of Down's syndrome at the fifth month of gestation resembled that of normal human cerebral grey matter at term. However, other developmental indices related to PUFA composition were not significantly affected. It seems therefore that in the developing Down's syndrome brain there may be a distortion of the normal transformations of essential fatty acids and of their incorporation into phosphoglycerides. The disproportion between docosahexaenoyl and arachidonoyl groups in membrane phosphoglycerides during prenatal development in Down's syndrome may also result in disturbances of the proper functioning, and the ontogenetic integration, of membrane enzymes and transport processes.

The distribution of neuropeptide Y in the developing rat brain was studied with immuno-cytochemistry, using the peroxidase-antiperoxidase method. Immunoreactive perikarya were first seen on embryonic day 13 and staining of fibres appeared from embryonic day 15 onwards: perikaryal staining was generally more intense prenatally than after birth. Areas rich in neuropeptide Y immunostaining included the monoaminergic regions of the brain stem from embryonic day 13 (especially the lateral reticular nucleus and the medullary reticular formation), the dorsal mesencephalon (with spots of immunoreactivity in the outer subventricular zone at embryonic days 13 or 14 and many cells and fibres in the inferior colliculus from embryonic days 16–20) and the olfactory tubercle/ventral striatum from embryonic day 15 until birth. The period of development of cortical neurones extended from embryonic day 19 until postnatal day 21. A hitherto unreported feature unique to neuropeptide Y was the presence in certain parts of the cerebral cortex of transient cells at the base of the cortical plate bearing radial processes which transverse its width. They were present from embryonic day 17 until postnatal day 4 and were maximally developed at embryonic days 20 or 21, contributing at this age a substantial fibre projection through the immature corpus callosum.

International Journal of Developmental NeuroscienceVolume 3, Issue 4 p. 418-418 Abstract Development of the brain in down's syndrome (DS) R. Balazs, R. BalazsSearch for more papers by this authorB.W.L. Brooksbank, B.W.L. BrooksbankSearch for more papers by this authorM. Martinez, M. MartinezSearch for more papers by this author R. Balazs, R. BalazsSearch for more papers by this authorB.W.L. Brooksbank, B.W.L. BrooksbankSearch for more papers by this authorM. Martinez, M. MartinezSearch for more papers by this author First published: 1985 https://doi.org/10.1016/0736-5748(85)90086-3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume3, Issue41985Pages 418-418 RelatedInformation

Journal of Intellectual Disability ResearchVolume 29, Issue 1 p. 1-14 NEUROCHEMICAL APPROACHES TO THE PATHOGENESIS OF DOWN'S SYNDROME Robert Balazs, Robert Balazs MRC Developmental Neurobiology Unit, Institute of Neurology, 33 John's Mews, London WC1N2NSSearch for more papers by this authorBenjamin W. L. Brooksbank, Benjamin W. L. Brooksbank MRC Developmental Neurobiology Unit, Institute of Neurology, 33 John's Mews, London WC1N2NSSearch for more papers by this author Robert Balazs, Robert Balazs MRC Developmental Neurobiology Unit, Institute of Neurology, 33 John's Mews, London WC1N2NSSearch for more papers by this authorBenjamin W. L. Brooksbank, Benjamin W. L. Brooksbank MRC Developmental Neurobiology Unit, Institute of Neurology, 33 John's Mews, London WC1N2NSSearch for more papers by this author First published: March 1985 https://doi.org/10.1111/j.1365-2788.1985.tb00302.xCitations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume29, Issue1March 1985Pages 1-14 RelatedInformation

Abstract: The expression of the neurone‐specific D2 protein changes both quantitatively and qualitatively during development in vivo and in cultures of cerebellar nerve cells. The total D2 content per unit protein shows a twofold increase in vivo from birth to postnatal day 6, after which it declines progressively to about 50% of the maximal value. This increase can be accounted for by an immature form of the protein anodic D2 being preferentially expressed at the early stages of cerebellar development. After postnatal day 9 this form gradually switches to a mature form cathodic D2. This switch can be mimicked by neuraminidase treatment, suggesting a developmental loss of sialic acid from the D2 protein. In freshly isolated cells the total D2 content per unit protein is only 30% of that in the corresponding intact tissue from 8‐day‐old cerebella, but it increases rapidly during the first 8 days of culture to levels similar to those of the equivalent age in vivo. The switch from anodic D2 to cathodic D2 also occurs at a faster rate in culture, probably reflecting the culture conditions that favour differentiation. The changes in the expression of D2 during development of cerebellar nerve cells in culture suggest that anodic D2 is preferentially expressed on nerve cells that are proliferating, migrating, or in the initial stages of differentiation, whereas cathodic D2 is associated with differentiated neurones. The transition between the two forms appears to occur during the formation of interneuronal contacts.

The rate of protein synthesis was estimated in structurally preserved perikaryal preparations from 8-day-old rat cerebellum under conditions which overcome the problems of intracellular compartmentation. The rates were lower than the in vivo estimates at comparable ages, but they were of similar magnitude, and very much higher than previous estimates on isolated cells. Protein synthesis rate depended on the cell type. When expressed per cell the rank order in the preparations enriched in the indicated classes of cells was: Purkinje cells > astrocytes > granule cells in the S, G2 and M phase of the cell cycle > granule cells in G1 and G0. However, after normalizing the results for size differences between cell types, by expressing the rates in terms of unit protein or as a percentage replacement of the protein bound amino acid, astrocytes and replicating granule cells displayed greater rates than the Purkinje cells. The resolution of labelled proteins using SDS-PAGE indicated marked differences in the rate of synthesis of particular proteins. The results were consistent with the view that certain polypeptides are uniquely expressed in particular cell classes.

Certain aspects of the metabolism of oxygen derivatives were investigated in the cerebral cortex from Down's syndrome (trisomy 21) fetuses. In comparison with controls of similar gestational age, the specific activity of the cytosolic Cu/Zn-dependent superoxide dismutase (SOD-I) was significantly elevated by 60 ± 5%. This is consistent with a gene dosage effect, as the gene coding for SOD-I is on chromosome 21. In order to determine whether the increase in SOD-I activity is associated with an adaptive rise in glutathione peroxidase (GSHPx), as has been observed in other tissues, the activity of this enzyme was also estimated but was found not to be altered in the Down's syndrome brain.

The development of the gamma-aminobutyrate (GABA)-ergic system in the human cerebral cortex and cerebellum was studied in post mortem specimens, by estimating the activity of glutamate decarboxylase (GAD) and the binding capacity for muscimol as markers of GABA-ergic nerve terminals and GABA receptors respectively. The age periods studied were as follows (number of specimens in parentheses): fetal period, 17--24 and 28 weeks, gestational age (GA) (15); perinatal period, 26--42 weeks GA (9); postnatal period, 43--56 and 74 weeks GA (11); adult life, 26, 47, 57--73 years (9). Total protein and DNA were estimated in all specimens. Differences between the cerebral cortex and the cerebellum in the ontogenesis of the GABA-ergic system were revealed. In the cerebral cortex, GAD-specific activity increased progressively during development, but at term had only reached approximately 20% of the adult value, and the trend in the postnatal specimens indicated that the adult level is not reached until some time after 60 weeks GA. The concentration of muscimol binding sites, on the other hand, rose more rapidly than GAD activity with age in the cerebral cortex, attaining adult values by 60 weeks GA and being already at term approximately 45% of the mean adult figure. In the cerebellum, the relative development of pre- and postsynaptic markers was the reverse of that in the cerebral cortex: GAD specific activity had reached the adult value by 60 weeks GA and approximately 40% of this adult level was attained at term, while the muscimol binding site concentration was only about 10% of the adult value at term and was still increasing at 60 weeks GA. The affinity of the receptor for [3H]-muscimol did not change during development, and was the same in cerebral cortex and cerebellum.

Conference Abstract| April 01 1981 CELLULAR DISTRIBUTION OF CERTAIN ENZYMES ASSOCIATED WITH TRANSMITTER AMINO ACIDS A. J. PATEL; A. J. PATEL 1MRC Developmental Neurobiology Unit, Institute of Neurology, 33 John's Mews, London WC1N 2NS, U.K. Search for other works by this author on: This Site PubMed Google Scholar A. HUNT; A. HUNT 1MRC Developmental Neurobiology Unit, Institute of Neurology, 33 John's Mews, London WC1N 2NS, U.K. Search for other works by this author on: This Site PubMed Google Scholar R. D. GORDON; R. D. GORDON 1MRC Developmental Neurobiology Unit, Institute of Neurology, 33 John's Mews, London WC1N 2NS, U.K. Search for other works by this author on: This Site PubMed Google Scholar R. BALÁZS R. BALÁZS 1MRC Developmental Neurobiology Unit, Institute of Neurology, 33 John's Mews, London WC1N 2NS, U.K. Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1981) 9 (2): 196P. https://doi.org/10.1042/bst009196pd Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation A. J. PATEL, A. HUNT, R. D. GORDON, R. BALÁZS; CELLULAR DISTRIBUTION OF CERTAIN ENZYMES ASSOCIATED WITH TRANSMITTER AMINO ACIDS. Biochem Soc Trans 1 April 1981; 9 (2): 196P. doi: https://doi.org/10.1042/bst009196pd Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 1981 Biochemical Society1981 Article PDF first page preview Close Modal You do not currently have access to this content.

: The distribution of GABA receptors in the cerebellum is not homogeneous. In comparison with detergent‐treated membranes from the whole tissue the number of [3H]muscimol binding sites per mg protein (Bmax) is about doubled in preparations enriched in large fragments of the cerebellar glomeruli, and it is about one‐third in the dissected deep nuclei. On the other hand, the apparent affinity (Kd) is similar in the different preparations. Comparison of the results with earlier studies suggests a heterogeneity in cerebellar GABA receptors and/or their control.

A study was made of the effects of age, neonatal hypothyroidism and hyperthyroidism on the development in rat brain of muscarinic cholinergic and GABA receptors. The former receptors were estimated by the binding of [3H]quinuclidinylbenzilate and the latter by binding of [3H]muscimol to crude membrane preparations from the forebrain and the cerebellum. In the normal forebrain, the density of muscarinic cholinergic receptors (in terms of unit membrane proteins) doubled during the period 6-35 days after birth. Thyroid state had relatively little effect on this development. In contrast, in the normal cerebellum the peak of the density of the receptors was attained in the early neonatal period followed by a progressive decline reaching about half of the maximum at day 35. Furthermore, in the cerebellum this development was significantly influenced by thyroid disorders: the rate of decrease in receptor density was accelerated by hyperthyroidism and retarded in thyroid deficiency. In comparison with euthyroid rats, the density of muscarinic receptors in the cerebellum was 30% lower in the hyperthyroidism (at day 21) and 40% higher in thyroid deficiency (at day 35). The increase in the density of GABA receptors with age was very small in the normal forebrain relative to the marked rise in the cerebellum. In the forebrain, thyroid state had no significant effect on this development. In contrast, in the cerebellum the ontogenesis of GABA receptors was advanced by thyroid hormone treatment and retarded in thyroid deficiency. However, by day 35 receptor density was normal in both conditions. Thyroid state had no significant influence on the affinity of either [3H]muscimol or the [3H]quinuclidinylbenzilate binding. The results suggest that thyroid hormone disorders during early life may lead to distortions rather than synchronized shifts in the relative development of several central transmitter systems.

Rats aged 11 days were injected with reserpine (2.5 mg/kg body wt.) and the rate of [3H]thymidine incorporation into brain DNA was followed over a period of 36h. In the forebrain this was significantly depressed by 2h, and it reached a nadir of about 30% of the control level at 4h, at which it remained for another 26h. A partial recovery occurred by 36h. The effect was less pronounced in the cerebellum. On the basis of this information brains of rats were examined histologically and by autoradiography between 7 and 36 h after reserpine to obtain estimates of cell cycle parameters and of rates of cell proliferation and cell loss. In the forebrain lateral ventricular subependymal layer the labelling index was markedly reduced in comparison withe controls. Cell cycle time was prolonged by 50% and turnover time increased by 60%. In the cerebellar external granular layer, the mitotic index was reduced and increased numbers of degenerate postmitotic nuclei were found, notably in the latter part of the experimental period. These effects are potentially of functional and clinical significance.

Drugs which alter the balance of neurotransmitter activity may, while failing to cause gross structural malformations of the brain, produce long-lasting functional disturbances if given when the brain is developing. Subtle anatomical changes may underlie such disturbances; reserpine has been shown to interfere with cell proliferation in the brain of suckling rats, and long-term alterations in behaviour reported after treatment with reserpine may be related to this effect of the drug. Neurotransmitters, apart from their conventional role, may also function as neurohumours and be involved in the regulation of cell proliferation in the nervous system. Thus drugs influencing central neurotransmitter activity, such as phenothiazines and adrenergic agonists and antagonists, which in clinical practice are often given to pregnant mothers, may affect the developing brain through mechanisms similar to those reported for reserpine. More experimental information is needed about the influence of such drugs on cell proliferation in the brain, and about their "behavioural teratogenicity".