Cerebrospinal fluid levels of orexin-A are not a clinically useful biomarker for Huntington disease.
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Animals↗
Biomedical subjects
B Landwehrmeyer
Publications and source records attributed to B Landwehrmeyer.
Myoclonus-dystonia: detection of novel, recurrent, and de novo SGCE mutations.
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Adolescent↗
CAG expansion affects the expression of mutant Huntingtin in the Huntington's disease brain.
A trinucleotide repeat (CAG) expansion in the huntingtin gene causes Huntington's disease (HD). In brain tissue from HD heterozygotes with adult onset and more clinically severe juvenile onset, where the largest expansions occur, a mutant protein of equivalent intensity to wild-type huntingtin was detected in cortical synaptosomes, indicating that a mutant species is synthesized and transported with the normal protein to nerve endings. The increased size of mutant huntingtin relative to the wild type was highly correlated with CAG repeat expansion, thereby linking an altered electrophoretic mobility of the mutant protein to its abnormal function. Mutant huntingtin appeared in gray and white matter with no difference in expression in affected regions. The mutant protein was broader than the wild type and in 6 of 11 juvenile cases resolved as a complex of bands, consistent with evidence at the DNA level for somatic mosaicism. Thus, HD pathogenesis results from a gain of function by an aberrant protein that is widely expressed in brain and is harmful only to some neurons.
Adult↗
Alterations of neurotransmitter receptors and neurotransmitter transporters in progressive supranuclear palsy.
Neurotransmitter receptors and neurotransmitter transporters were studied postmortem in the brains of 9 PSP patients by receptor autoradiography. Densities of dopamine uptake sites and neurotensin receptors were significantly reduced in striatum and substantia nigra consistent with a localization of these binding sites on degenerating dopaminergic nigrostriatal projection neurons. The densities of dopamine D1 receptors were unchanged. Dopamine D2 receptors were unaltered when labeled by [125I]-Iodosulpride or [3H]-CV 205 502, but appeared to be significantly reduced when labeled by [3H]-spiperone. Levels of D2 mRNA were comparable to control levels, suggesting that only subtypes of Dopamine D2-like receptors may be affected in PSP. Serotonin (5-HT) uptake sites and 5-HT receptors were not altered. The density of muscarinic receptors was reduced in striatum, possibly related to a degeneration of cholinergic striatal interneurons, but increased in internal globus pallidus. GABAA/BZ receptor binding sites were significantly reduced in both segments of globus pallidus, probably as a consequence of severe degeneration of intrinsic pallidal neurons in PSP. Binding of substance P in striatum tended to be decreased but failed to reach statistical significance. Compared to Parkinson's disease, the densities of more neurotransmitter receptors were altered in PSP. With the exception of increased muscarinic receptor binding sites in medial globus pallidus, the alterations seen in PSP seem to reflect cell loss rather than functional changes.
Aged↗
Studies on the striatal dopamine uptake system of weaver mutant mice and effects of ventral mesencephalic grafts.
The dopamine (DA) uptake system was investigated in the mesostriatal system of normal and weaver mutant mice, which lose mesencephalic DA neurons, as well as in weaver mutants with ventral mesencephalic grafts to the striatum. Assays of [3H]DA uptake in striatal synaptosomal fractions in vitro and autoradiography of [3H]mazindol binding in brain sections were carried out in wild-type mice (+/+) and in the two hemispheres of homozygous weaver mutants (wv/wv) that had received unilateral grafts of mesencephalic cell suspensions to the right side. Net [3H]DA uptake, expressed as pmol/mg-protein/2-min, was on the average 50.6 in the striatum of wild-type mice, 7.9 in the non-grafted, and 10.1 in the transplanted striatum of weaver mutants. [3H]DA uptake in wild-type mice differed significantly from both the grafted and non-grafted weaver striata (P < 0.001). Paired comparisons for [3H]DA uptake between right and left sides of recipient weaver mice showed a significant side effect (P < 0.02), the right side being 28-38% higher than the left side [mean of all individual (R-L)/L values]. The results of amphetamine-induced turning behavior tests were compared with the biochemical findings. Mice with grafts to the right side rotated an average of 22 turns to the left and 7 turns to the right during the five one-minute sessions; the mean value L/(L + R) was 64%. A plot of (L-R) rotations against (R-L) [3H]DA uptake gave a correlation coefficient of 0.552 (P < 0.05), indicating that animals with a strong rotational bias to the left tended to have higher [3H]DA on the right. Similarly, the animals that were used for [3H]mazindol binding autoradiographic studies displayed on the average 72% rotations to the left side. In the [3H]mazindol binding data, non-grafted weaver mutants showed the severest depletion relative to wild-type in the dorsomedial and dorsolateral caudate-putamen (86% and 87%, respectively). Mice with unilateral grafts to the right side showed an increase in [3H]mazindol binding signal in the transplanted side of 40-64% (depending on dorsoventral topography) over the contralateral, non-grafted side. These findings attest to the functional effects of the grafts at the anatomical, biochemical, and behavioral levels. The parallel measurements of motor performance and DA uptake in the same animals offers an index of behavioral recovery as a function of transmitter-related activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Alterations in dopamine and serotonin uptake systems in the striatum of the weaver mutant mouse.
In the striatum of the homozygous weaver mutant mouse (wv/wv), dopamine content, uptake and tyrosine hydroxylase activity are decreased compared to wild-type (+/+) mice. In mice heterozygous for the weaver gene (wv/+), these dopaminergic parameters exhibit only minor reductions compared to +/+ mice. The wv/wv striatum has recently been shown to have an increase in serotonin content. In the present study, the serotonin uptake system of the weaver striatum was investigated. Synaptosomal uptake of [3H] serotonin was determined in the dorsal portion of wv/wv and +/+ striatum, and serotonin uptake sites were examined by the binding of [3H] citalopram in the striatum of wv/wv, wv/+ and +/+ mice. The dopamine uptake system was also investigated in all three genotypes via the binding of [3H] mazindol. Synaptosomal uptake of [3H] serotonin was increased by 79% in the dorsal portion of the wv/wv striatum compared to that seen in the +/+ striatum. The binding of [3H] citalopram was increased by 62% in the dorsolateral and by 111% in the dorsomedial portions of the wv/wv striatum compared to +/+. [3H] Citalopram binding in the wv/+ striatum was also higher than +/+, but this increase did not reach statistical significance. Within the wv/wv striatum, [3H] mazindol binding was almost completely absent (88-89% reduction) in the dorsal portion and severely reduced in the other striatal areas. These data support the notion that the dorsal portion of the wv/wv striatum, which has the severest reduction in dopamine uptake, is hyperinnervated by serotonin fibers.
Animals↗
A comparative autoradiographic study of 5-HT1D binding sites in human and guinea-pig brain using different radioligands.
Quantitative receptor autoradiography was used to examine the 5-hydroxytryptamine (5-HT, serotonin) binding sites labelled with serotonin-5-O-carboxymethyl-glycyl-[125I]tyrosinamide ([125I]GTI) in human and guinea-pig brain. Competition experiments using 5-carboxamidotryptamine (5-CT), 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP 93129) and sumatriptan revealed monophasic displacement curves in various brain regions, suggesting that a homogeneous population of 5-HT1D binding sites was labelled. Displacement of [3H]5-HT (in the presence of 100 nM 8-hydroxy-2(N-dipropylamino)tetralin (8-OH-DPAT) and 100 nM mesulergine) with unlabelled GTI resulted in monophasic competition curves in substantia nigra, globus pallidus and central gray. In contrast, biphasic displacement was observed in hippocampus, nucleus accumbens, claustrum, caudate-putamen and frontal cortex. The distribution of [125I]GTI sites was compared to that of [3H]5-HT binding sites (under so-called '5-HT1D conditions', i.e. in the presence of 100 nM 8-OH-DPAT and 100 nM mesulergine, in order to block 5-HT1A and 5-HT1C sites, respectively) in human and guinea-pig brain. Qualitative analysis revealed differences in the distributions of [125I]GTI and [3H]5-HT binding sites. Regions such as CA3 and CA4 of the hippocampus, claustrum and putamen showed [3H]5-HT binding (under '5-HT1D conditions') but no [125I]GTI binding sites, indicating that [3H]5-HT labels besides a GTI sensitive (5-HT1D) receptor population, a non-5-HT1A/1B/1C/1D [3H]5-HT binding site in human and guinea-pig brain. The distribution of these non-5-HT1A/1B/1C/1D [3H]5-HT binding sites was studied with [3H]5-HT under conditions where 5-HT1A, 5-HT1C and 5-HT1D [3H]5-HT binding sites were saturated by the presence of 100 nM 8-OH-DPAT, 100 nM mesulergine and 1 microM GTI. Significant densities of these non-5-HT1A/1B/1C/1D sites were observed in cortical areas, hippocampal structures, nucleus accumbens, amygdala, caudate-putamen and claustrum. It is concluded that [125I]GTI does not label the 5-HT1E binding site, since all competition curves obtained with this radioligand were monophasic. By contrast, [3H]5-HT labels non-5-HT1A/1B/1C/1D [3H]5-HT binding sites, but it remains to be established whether these sites represent a single receptor population.
Aged↗
Differential visualization of dopamine D2 and D3 receptor sites in rat brain. A comparative study using in situ hybridization histochemistry and ligand binding autoradiography.
At least five members of the dopamine receptor family have been characterized at the gene level. D2, D3 and D4 dopamine receptors are related pharmacologically. In order to visualize the differential expression of D1, D2 and D3 receptors in rat brain we have combined in situ hybridization histochemistry with receptor autoradiography. Regions enriched with D3 messenger RNA (mRNA) included the islands of Calleja (ioC) and nucleus accumbens. Very low or undetectable levels were present in the caudate-putamen. In contrast, no D2 transcripts were observed in the islands of Calleja, but there were high levels in the nucleus accumbens, caudate-putamen (CP) and pyramidal layer of the olfactory tubercle. A comparison of the binding pattern of six dopamine receptor radioligands hitherto regarded as D2 receptor-selective showed that the islands of Calleja were intensely labelled by [125I]iodosulpride, [3H]CV 205 502 and [3H]SDZ 205 501, while the binding of [3H]spiperone, [3H]raclopride and [3H]YM 09151-2 was much lower or undetectable. Pharmacological analysis of the binding of D2/D3 ligands to the islands of Calleja and caudate-putamen suggests that binding sites in these two regions are of different pharmacology, consistent with the presence of D3 sites in the islands of Calleja and the predominance of D2 sites in the caudate. These results demonstrate the expression of D3 binding sites in the rat brain and provide a procedure to differentiate D2 and D3 receptor populations in binding studies.
Animals↗
Dopamine D3 receptor mRNA and binding sites in human brain.
Dopamine D3 receptors (Sokoloff et al., 1990) have been shown to be related to dopamine D2 receptors and have been suggested to play a role in mediating the antipsychotic effects of neuroleptics. So far studies on the expression of D3 mRNA and of binding sites with pharmacological characteristics of D3 receptors have been restricted to rat brain. Using in situ hybridization histochemistry, we demonstrate that D3 mRNAs are enriched in human n, accumbens and in the islands of Calleja. In addition, D3 mRNA was detected at very low levels in anterior caudate and putamen with a rostro-caudally decreasing gradient and in hypothalamic mammillary nuclei. In receptor autoradiographic binding studies, the islands of Calleja were found to be labeled by [125I]iodosulpride and [3H]CV 205 502 but not by [3H]raclopride and [3H]YM 09151-2. Pharmacological analysis of binding of the D2/D3 ligand [3H]CV 205 502 in n. accumbens and caudate-putamen is consistent with the presence of D3 receptor sites in ventral striatum. Overall distribution and pharmacology of D3 sites in human and rat brain appear to be similar. Presence and distribution of D3 receptors in human brain are compatible with the notion that D3 receptors might be involved in mediating the clinical effects of antipsychotics.
Aminoquinolines↗
Expression of acetylcholinesterase messenger RNA in human brain: an in situ hybridization study.
The distribution of messenger RNA coding for acetylcholinesterase was studied in human post mortem brain and rhesus monkey by in situ hybridization histochemistry and compared to the distribution of acetylcholinesterase activity. Acetylcholinesterase messenger RNA had--similar to acetylcholinesterase enzymatic activity--a widespread distribution in human bain. Acetylcholinesterase messenger RNA positive cells corresponded to perikarya rich in acetylcholinesterase activity in most but not all regions. Examples for mismatches included the inferior olive and human cerebellar cortex. The presence of hybridization signals in cerebral cortex and an enrichment in layer III and V of most isocortical areas confirmed that perikaryal acetylcholinesterase in cerebral cortex is of postsynaptic origin and not derived from cholinergic projections. In striatum the expression of high levels of acetylcholinesterase messenger RNA was restricted to a small population of large striatal neurons. In addition, low levels of expression were found in most medium sized striatal neurons. Cholinergic neurons tended to express high levels of acetylcholinesterase messenger RNA whereas in cholinoceptive neurons the levels were moderate to low. However, some noncholinergic neurons like dopaminergic cells in substantia nigra, noradrenergic cells in locus coeruleus, serotoninergic cells in raphé dorsalis, GABAergic cells in thalamic reticular nucleus, granular cells in cerebellar cortex and pontine relay neurons expressed levels comparable to cholinergic neurons in basal forebrain. It is suggested that neurons expressing high levels of acetylcholinesterase messenger RNA may synthesize acetylcholinesterase for axonal transport whereas neurons with an expression of acetylcholinesterase confined to somatodendritic regions tend to contain lower levels of acetylcholinesterase messenger RNA.
Acetylcholinesterase↗
Serotoninergic terminal transporters are differentially affected in Parkinson's disease and progressive supranuclear palsy: an autoradiographic study with [3H]citalopram.
Receptor autoradiography with [3H]citalopram as ligand was used to study the distribution of serotonin uptake binding sites in post mortem brain tissues from patients with Parkinson's disease, progressive supranuclear palsy and from age-matched controls. Significant decreases in [3H]citalopram binding sites were found in the cerebral cortex of patients with Parkinson's disease and progressive supranuclear palsy. Densities of [3H]citalopram binding sites were significantly reduced in all components of the basal ganglia of Parkinson's disease but only in the head of caudate nucleus of progressive supranuclear palsy patients. The density of [3H]citalopram binding sites in the raphe nuclei of Parkinson's disease was comparable to control values. Our results suggest that serotoninergic terminals are differentially affected in Parkinson's disease and in progressive supranuclear palsy.
Aged↗
Evidence for the presence of 5-HT1B receptor messenger RNA in neurons of the rat trigeminal ganglia.
In situ hybridization histochemistry and receptor autoradiography were used to determine the presence of 5-HT1B receptor messenger RNA (mRNA) and 5-HT1B receptor proteins, respectively, in rat trigeminal ganglia. Receptor autoradiography on rat trigeminal ganglia, using appropriate 5-HT1B radioligands, did not demonstrate any specific labelling. In contrast, in situ hybridization showed that many ganglion cells contain 5-HT1B receptor mRNA, suggesting the presence of presynaptic 5-HT1B receptors on trigeminovascular neurons.
Animals↗
Homogeneous 5-HT1D recognition sites in the human substantia nigra identified with a new iodinated radioligand.
The novel iodinated radioligand, serotonin-5-O-carboxymethyl-glycyl[125I] tyrosinamide, was used for binding studies with membranes of human substantia nigra. Evidence is provided for the existence in this tissue of a homogeneous population of recognition sites with the pharmacological profile of the 5-HT1D site.
Dipeptides↗
Changes of slow cortical negative DC-potentials during the acquisition of a complex finger motor task.
To study whether electrophysiological correlates of increasing motor skill can be demonstrated in man, we recorded cortical negative DC-potentials during the acquisition of a complex finger movement in 21 subjects. The movement consisted in moving a matchstick to and fro between the index finger (II) and the little finger (V). Cortical negative DC-potentials were recorded at Fz, Cz, C1, C2 and Pz. As a control a simple finger movement was performed during the same session by 7 of the Ss. Both tasks were repeated 60-80 times and averages of the first and the last 15 artifact-free single runs were compared. Whereas only a slight, inconstant decrease in surface electronegativity during the simple motor task was observed, a significant reduction in potential size occurred during the complex task at Cz (maximum), C1, C2 and Pz but not at Fz. In addition, a significant difference in the decrease of surface electronegativity between various electrode positions was observed. We suggest that these changes in potential size during the process of motor learning may reflect an altered cortical organisation of movement control during the acquisition of a complex motor task.
Adult↗
Patterns of task-related slow brain potentials in dyslexia.
Six dyslexic youths who met the Hughes and Denckla criteria of "dyslexia pure" and 10 normal control subjects were investigated with DC recordings of task-related cortical negativity using 10 leads over the right and left hemispheres. Potentials were recorded during the following tasks: reading, orthographic error detection, letter series, word assembly, word fluency, finding of antonyms, and viewing of Necker cubes. Both groups exhibited greater right hemisphere negativity during the Necker cube task. Whereas controls revealed greater left hemisphere negativity during linguistic tasks, the reverse was found with dyslexics. The right shift was pronounced with the reading, orthographic error detection, and antonym conditions. Differences between the two groups were also found for the pattern of cortical distribution. We conclude that dyslexia is associated with changes in the lateral distribution of cortical activity during certain types of language processing.
Adolescent↗
Premotor programming and cortical processing in the cerebral cortex. Electrophysiological correlates of hemispheric dominance.
Slow brain potentials were averaged from 12-15 EEG records (t = DC or 5 s) before and during voluntary hand movements and writing, spatial vision, language, and calculation tasks without vocalization and with visual fixation. EOG and writing pressure or EMG were recorded simultaneously. Skilled actions caused largest negative potentials in the contralateral sensorimotor hand area. Left-sided lateralization or bilaterally equal surface-negative potential shifts appeared during language and calculation tasks in 90% of the right-handers and in 75% of the left-handers. Right-sided lateralizations occurred during the viewing of perspective Necker figures or random-dot stereograms in the large majority of all subjects.
Adolescent↗
Localization of 5-HT1B, 5-HT1D alpha, 5-HT1E and 5-HT1F receptor messenger RNA in rodent and primate brain.
In situ hybridization histochemistry (ISHH) was used to study the distribution of various 5-HT1 receptor messenger RNAs (mRNA) in the mammalian nervous system. Since the cDNAs encoding the different 5-HT1 receptors, have not been cloned in one single species, brains of the species appropriate for the 5-HT1 receptor messenger RNA (mRNA) have been used. Thus, 5-HT1B and 5-HT1D alpha mRNA were determined in rat and mouse brain, while 5-HT1E and 5-HT1F mRNA were studied in human (and monkey) and guinea-pig brain, respectively. 5-HT1B and 5-HT1D alpha hybridization signals were predominantly present in caudate-putamen and cortical areas; in addition, 5-HT1B mRNA was also detected in hippocampus, cerebellum and cerebral arteries. In general, the distribution of 5-HT1B mRNA was characterized by high densities, whereas 5-HT1D alpha mRNA was expressed at very low levels. Comparison of the localization of the mRNAs to the regional distributions of the 5-HT1B and 5-HT1D binding sites in rat brain (described in a previous study), revealed that both receptor subtypes could be putative presynaptic heteroreceptors, modulating the release of various neurotransmitters in the central nervous system. The mRNA encoding the recently cloned 5-HT1E receptor, which has low affinity for the 5-HT1 receptor ligand 5-carboxamidotryptamine (5-CT), was localized in human brain. It was found to be present in cortical areas, caudate, putamen and amygdala, areas known to contain 5-CT insensitive 5-HT1 binding sites. The regional distribution of the 5-HT1F mRNA was determined in guinea-pig brain: high densities were observed in various cortical areas, the hippocampal formation and claustrum, which are regions known to contain 5-CT insensitive 5-HT1 or non 5-HT1A/1B/IC/ID [3H]5-HT binding sites. Altogether, this ISHH study describes the distribution of mRNAs of recently cloned 5-HT1 receptors in rodent and primate brain and compares these results to the distribution of the heterogeneous population of 5-HT1 binding sites.
Animals↗
Ventral mesencephalic grafts in the neostriatum of the weaver mutant mouse: structural molecule and receptor studies.
Mesencephalic cell suspensions were prepared from E12 wild-type (+/+) mouse embryos and stereotaxically implanted into the dorsal neostriatum of weaver mutant mice (wv/wv), which have a genetic mesostriatal dopamine (DA) deficiency. Survival of DA neurons in the grafts was documented by tyrosine hydroxylase (TH) immunocytochemistry. Axon growth was monitored by immunocytochemistry using a battery of antibody markers, and the cellular localization of structural protein and receptor RNA transcripts was studied by in situ hybridization histochemistry using [32P]oligonucleotide probes. The cell suspension grafts exhibited strong immunoreactivity for neural cell adhesion molecule (N-CAM), growth-associated phosphoprotein GAP-43, microtubule-associated protein 2 (MAP2), beta-amyloid protein precursor (beta APP), and phosphorylated neurofilament epitopes (clone SMI-31); intermediate-to-high levels of immunoreactivity were seen for synaptophysin. High levels of hybridization were found in the grafts for the RNA transcripts of GAP-43, MAP2, and isoforms beta APP695, beta APP714 and beta APP751 of the beta APP. No hybridization signal was detected in the grafts for DA D2 or neurotensin receptor mRNAs, both of which are normally expressed by nigral DA neurons. DA receptor autoradiography using the D2/D3 agonist [3H]CV 205-502 as a ligand showed no binding in the transplants, indicating an apparent abnormality of grafted cells; neurotensin binding sites, labeled with [125I]neurotensin, were visualized in the suspensions, indicating the possibility that receptors could be present but that RNA message levels might be too low to allow detection. These findings offer a molecular correlate of axonal, dendritic and structural protein expression by transplanted mesencephalic neurons; further, they suggest that specific functional properties of grafted nigral cells are maintained after transplantation, while other aspects of their cellular biology may be compromised.
Animals↗