Biomedical subjects

H J Waldvogel

Publications and source records attributed to H J Waldvogel.

At least 19 recordsLinked to original sources

PubMed2006

Induced cerebral hypothermia reduces post-hypoxic loss of phenotypic striatal neurons in preterm fetal sheep.

Perinatal hypoxic-ischemic injury of the basal ganglia is a significant cause of disability in premature infants. Prolonged, moderate cerebral hypothermia has been shown to be neuroprotective after experimental hypoxia-ischemia; however, it has not been tested in the preterm brain. We therefore examined the effects of severe hypoxia and the potential neuroprotective effects of delayed hypothermia on phenotypic striatal neurons. Preterm (0.7 gestation) fetal sheep received complete umbilical cord occlusion for 25 min followed by cerebral hypothermia (fetal extradural temperature reduced from 39.4+/-0.3 degrees C to 29.5+/-2.6 degrees C) from 90 min to 70 h after the end of occlusion. Hypothermia was associated with a significant overall reduction in striatal neuronal loss compared with normothermia-occlusion fetuses (mean+/-SEM, 5.5+/-1.2% vs. 38.1+/-6.5%, P<0.01). Immunohistochemical studies showed that occlusion resulted in a significant loss of calbindin-28 kd, glutamic acid decarboxylase isoform 67 and neuronal nitric oxide synthase-immunopositive neurons (n=7, P<0.05), but not choline acetyltransferase-positive neurons, compared with sham controls (n=7). Hypothermia (n=7) significantly reduced the loss of calbindin-28 kd and neuronal nitric oxide synthase, but not glutamic acid decarboxylase-immunopositive neurons. In conclusion, delayed, prolonged moderate head cooling was associated with selective protection of particular phenotypic striatal projection neurons after severe hypoxia in the preterm fetus. These findings suggest that head cooling may help reduce basal ganglia injury in some premature babies.

Animals↗

PubMed2005

Activating transcription factor 2 expression in the adult human brain: association with both neurodegeneration and neurogenesis.

Activating transcription factor 2 (ATF2) is a member of the activator protein-1 family of transcription factors, which includes c-Jun and c-Fos. ATF2 is highly expressed in the mammalian brain although little is known about its function in nerve cells. Knockout mouse studies show that this transcription factor plays a role in neuronal migration during development but over-expression of ATF2 in neuronal-like cell culture promotes nerve cell death. Using immunohistochemical techniques we demonstrate ATF2 expression in the normal human brain is neuronal, is found throughout the cerebral cortex and is particularly high in the granule cells of the hippocampus, in the brain stem, in the pigmented cells of the substantia nigra and locus coeruleus, and in the granule and molecular cell layers of the cerebellum. In contrast to normal cases, ATF2 expression is down-regulated in the hippocampus, substantia nigra pars compacta and caudate nucleus of the neurological diseases Alzheimer's, Parkinson's and Huntington's, respectively. Paradoxically, an increase in ATF2 expression was found in the subependymal layer of Huntington's disease cases, compared with normal brains; a region reported to contain increased numbers of proliferating progenitor cells in Huntington's disease. We propose ATF2 plays a role in neuronal viability in the normal brain, which is compromised in susceptible regions of neurological diseases leading to its down-regulation. In contrast, the increased expression of ATF2 in the subependymal layer of Huntington's disease suggests a role for ATF2 in some aspect of neurogenesis in the diseased brain.

Activating Transcription Factor 2↗

PubMed2003

GABA(A) receptor subunit and gephyrin protein changes differ in the globus pallidus in Huntington's diseased brain.

Immunoreactivity of GABA(A) receptor subunits and the receptor anchoring protein gephyrin was investigated in the human globus pallidus using antibodies raised against the alpha(1) and gamma(2) subunits of the GABA(A) receptor complex and gephyrin. The results revealed increased GABA(A) receptor subunit immunoreactivity and unchanged levels of gephyrin immunoreactivity in Huntington's diseased (HD) globus pallidus (GP). The results demonstrate that gephyrin immunoreactivity did not change in unison with GABA(A) receptor changes in HD, suggesting that the receptor anchoring protein gephyrin is unaltered and maintains a stable lattice structure in the face of GABA(A) receptor changes in HD.

Carrier Proteins↗

PubMed2003

Distribution of gephyrin in the human brain: an immunohistochemical analysis.

Gephyrin is an ubiquitously expressed protein that, in the central nervous system, generates a protein scaffold to anchor inhibitory neurotransmitter receptors in the postsynaptic membrane. It was first identified as a protein component of the glycine receptor complex. Recent studies have demonstrated that gephyrin is colocalized with several subtypes of GABA(A) receptors and is part of postsynaptic GABA(A) receptor clusters. Here, we describe a study of the regional and cellular distribution of gephyrin in the human brain, determined by immunohistochemical localisation at the light and confocal laser scanning microscopic levels. At the regional level, gephyrin immunoreactivity was observed in most of the major brain regions examined. The most intense staining was in the cerebral cortex, hippocampus and caudate-putamen, in various brainstem nuclei with more moderate levels in the thalamus and cerebellum. At the cellular level gephyrin immunoreactivity was present on the plasma membranes of the soma and dendrites of pyramidal neurons throughout the various cortical regions examined. In the hippocampus, intense staining was observed on the granule cells of the dentate gyrus, and neurons of the CA1 and CA3 regions showed intense punctate gephyrin staining on their apical dendrites and cell bodies. Gephyrin immunoreactivity was also observed on neurons in the thalamus, globus pallidus and substantia nigra. In the putamen intense labelling of the striosomes was observed; most of the medium-sized neurons in the caudate-putamen were weakly labelled and many large neurons of the striatum were conspicuously stained. Many of the brainstem nuclei, notably the dorsal motor nucleus of the vagus, hypoglossal nucleus, trigeminal nucleus and inferior olive were all labelled with gephyrin. The spinal cord also showed high levels of gephyrin immunoreactivity. Our results demonstrate that the anchoring protein gephyrin is ubiquitously present in the human brain. We therefore suggest that gephyrin may have a central organizer role in assembling and stabilizing inhibitory postsynaptic membranes in human brain and is similar in function to those observed in the rodent brain. These findings contribute towards elucidating the role of gephyrin in the human brain.

Aged↗

PubMed2003

Association of gephyrin and glycine receptors in the human brainstem and spinal cord: an immunohistochemical analysis.

Gephyrin is a postsynaptic clustering molecule that forms a protein scaffold to anchor inhibitory neurotransmitter receptors at the postsynaptic membrane of neurons. Gephyrin was first identified as a protein component of the glycine receptor complex and is also colocalized with several GABAA receptor subunits in rodent brain. We have studied the distribution of gephyrin and glycine receptor subunits in the human brainstem and spinal cord using immunohistochemistry at light and confocal laser scanning microscopy levels. This study demonstrates the novel localization of gephyrin with glycine receptors in the human brainstem and spinal cord. Colocalization of immunoreactivities for gephyrin and glycine receptor subunits was detected in the dorsal and ventral horns of the spinal cord, the hypoglossal nucleus and the medial vestibular nucleus of the medulla. The results clearly establish that gephyrin is ubiquitously distributed and is colocalized, with a large proportion of glycine receptor subunits in the human brainstem and spinal cord. We therefore suggest that gephyrin functions as a clustering molecule for major subtypes of glycine receptors in the human CNS.

Aged↗

PubMed2001

Comparative distribution of voltage-gated sodium channel proteins in human brain.

Antisera directed against unique peptide regions from each of the human brain voltage-gated sodium channel alpha subunits were generated. In immunoblots these were found to be highly specific for the corresponding recombinant polypeptides and to recognise the native holoprotein in human brain membrane preparations. These antisera were used to perform a comparative immunohistochemical distribution analysis of all four brain sodium channel subtypes in selected human CNS regions. Distinct but heterogeneous distribution patterns were observed for each of the alpha subunits. In general, these were complimentary to that previously shown for the corresponding human mRNAs. A high degree of conservation with respect to the distribution found in rat was also evident. The human alpha subunit proteins exhibited distinct subcellular localisation patterns. Types I, III and VI immunoreactivity was predominantly in neuronal cell bodies and proximal processes, whereas type II was concentrated along axons. This is similar to rat brain and suggests the different the sodium channel subtypes have distinct functions which are highly conserved between human and rodents. A notable difference was that the type III protein was detected in all human brain regions examined, unlike in rat brain where expression in adults is very restricted. Also in contrast to rat brain, the human type VI protein was not detected in axons of unmyelinated neurons. These differences may reflect true species variation and could have important implications for understanding the function of the sodium channel subtypes and their roles in human disease.

Adult↗

PubMed2001

Insulin-like growth factor-1 reduces postischemic white matter injury in fetal sheep.

Insulin-like growth factor-1 (IGF-1) is known to be important for oligodendrocyte survival and myelination. In the current study, the authors examined the hypothesis that exogenous IGF-1 could reduce postischemic white matter injury. Bilateral brain injury was induced in near-term fetal sheep by 30 minutes of reversible carotid artery occlusion. Ninety minutes after ischemia, either vehicle (n = 8) or a single dose of 3 microg IGF-1 (n = 9) was infused intracerebroventricularly over 1 hour. White matter changes were assessed after 4 days recovery in the parasagittal intragyral white matter and underlying corona radiata. Proteolipid protein (PLP) mRNA staining was used to identify bioactive oligodendrocytes. Glial fibrillary acidic protein (GFAP) and isolectin B-4 immunoreactivity were used to label astrocytes and microglia, respectively. Myelin basic protein (MBP) density and the area of the intragyral white matter tracts were determined by image analysis. Insulin-like growth factor-1 treatment was associated with significantly reduced loss of oligodendrocytes in the intragyral white matter (P < 0.05), with improved MBP density (P < 0.05), reduced tissue swelling, and increased numbers of GFAP and isolectin B-4 positive cells compared with vehicle treatment. After ischemia there was a close association of PLP mRNA labeled cells with reactive astrocytes and macrophages/microglia. In conclusion, IGF-1 can prevent delayed, postischemic oligodendrocyte cell loss and associated demyelination.

Animals↗

PubMed2000

First localisation of somatostatin sst(4) receptor protein in selected human brain areas: an immunohistochemical study.

Somatostatin is known to have diverse neurophysiological effects in the mammalian CNS. To date, genes for five different receptors, termed sst(1-5), have been isolated. Recently several reports have been published on the localisation of the individual receptor protein in the rat CNS, but their localisation in the human CNS remains largely unknown. Until now little information about the function of the sst(4) receptor is available, and there is a lack of receptor specific agonists and antagonists. Here, we report for the first time the immunohistochemical localisation of the sst(4) receptor in selected human brain areas using an anti-peptide antibody raised against a carboxy-terminal portion of the receptor protein. Strong receptor immunoreactivity was found in several brain regions, including the hippocampal formation, the cerebellar cortex and the medulla. Further immunohistochemical labelling was observed in the cerebral cortex, the red nucleus and the globus pallidus. Somatodendritic as well as axonal staining was observed. Specific signals were entirely absent following antibody pre-adsorption with the synthetic peptide. The results are in good agreement with the previously published immunohistochemical localisation of the sst(4) receptor in the rat brain. This is the first immunohistochemical study of the localisation of the sst(4) receptor in the human brain, and implicates this receptor in the function of higher centres of the human nervous system.

Adult↗

PubMed2000

GABA(B) receptor heterodimer-component localisation in human brain.

In recombinant cell lines, functional GABA(B) receptors are only formed by the heterodimerisation between two related G-protein coupled receptor proteins GABA(B)R1 (GBR1) and GABA(B)R2 (GBR2), whilst the individual GBR1 or GBR2 do not produce fully functional receptors. To determine whether the heterodimerisation occurs in vivo, novel polyclonal antibodies targeting the C termini of GBR1 and GBR2, were raised in different species, characterised, and used to determine the relative localisation of the reported heterodimer components in human brain tissue, using immunohistochemistry. The use of different species for the raising of the antisera allowed double immunofluorescent labelling of the receptors as an indication of GBR1/GBR2 receptor co-localisation in human brain. The presence of both proteins is reported in cerebellum, hippocampus, cortex, thalamus and basal ganglia. Regions of the brainstem including pons and medulla, also express GBR1 and GBR2 protein. The double immunofluorescence demonstrated that GBR1 and GBR2 are co-localised in the human cerebellar cortex. Together these results suggest the widespread distribution of GABA(B) receptors in human brain, and that GABA(B) receptors GBR1 and GBR2 can exist in the same cell, and therefore may function as a heterodimer in the human brain.

Aged↗

PubMed2000

N-terminal tripeptide of IGF-1 (GPE) prevents the loss of TH positive neurons after 6-OHDA induced nigral lesion in rats.

The effect of the N-terminal tripeptide of insulin-like growth factor (IGF)-1, glycine-proline-glutamate (GPE), as a neuroprotective agent for nigro-striatal dopaminergic neurons was examined in the present study using a rat model of Parkinson's disease. A unilateral nigro-striatal lesion was induced in rats by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle (MFB). GPE (3 microgram) or its vehicle was administered intracerebroventricularly (i.c.v.) 2 h after the 6-OHDA lesion. Tyrosine-hydroxylase (TH) immunohistochemistry in the substantia nigra compacta (SNc) and the striatum were examined 2 weeks after the lesion. Following 6-OHDA injection, the number of TH immunopositive neurons in the ipsilateral SNc was reduced. The density of TH immunostaining was also reduced in the ipsilateral SNc and the striatum. Treatment with a single dose of GPE (n=9) significantly prevented the loss of TH immunopositive neurons (p<0. 001) and restored the TH immunoreactivity in both the SNc and the striatum compared with the vehicle control group (n=9, p<0.001). The results suggest that GPE showed promise as a potential treatment for Parkinson's disease.

Animals↗

PubMed2000

Selective neuroprotective effects with insulin-like growth factor-1 in phenotypic striatal neurons following ischemic brain injury in fetal sheep.

Severe perinatal asphyxia can lead to injury and dysfunction of the basal ganglia. Post insult administration of insulin-like growth factor-1 is neuroprotective, particularly in the striatum. Insulin-like growth factor-1 is also known to be a neuromodulator of several types of striatal neurons. The striatum comprises various phenotypic neurons with a complex neurochemical anatomy and physiology. In the present study, we examined the specificity of neuronal rescue with insulin-like growth factor-1 on different striatal neurons. Bilateral brain injury was induced in near term fetal sheep by 30 min of reversible carotid artery occlusion. A single dose of 3 microg of insulin-like growth factor-1 was infused over 1 h into the lateral ventricle 90 min following ischemia. The histological and immunohistochemical outcome were examined after 4 days recovery using paraffin tissue preparations. Insulin-like growth factor-1 treatment (n = 11) significantly reduced the percentage of neuronal loss in the striatum compared with the vehicle treated group (n = 10, 28.3+/-5.1% vs 55.5+/-17.3%, P < 0.005). Immunohistochemical studies showed that ischemia resulted in a significant loss of calbindin-28kd, choline acetyltransferase, parvalbumin, glutamate acid decarboxylase, neuronal nitric oxide synthase and neuropeptide Y immunopositive neurons, compared with sham controls. Insulin-like growth factor-1 markedly prevented the loss of calbindin-28kd (n = 7, P < 0.05), choline acetyltransferase (n = 7, P < 0.05), neuropeptide Y (n = 7, P < 0.05), neuronal nitric oxide synthase (n = 8, P < 0.05) and glutamate acid decarboxylase (n = 9, P < 0.05) immunopositive neurons, but failed to protect parvalbumin (n = 6) immunopositive neurons. The present study indicates that the therapeutic effect of insulin-like growth factor-1 in the basal ganglia is selectively associated with cholinergic and some phenotypic GABAergic neurons. These data suggest a potential role for insulin-like growth factor-1 in preventing cerebral palsy due to perinatal asphyxia.

Animals↗

PubMed2000

The distribution of calbindin, calretinin and parvalbumin immunoreactivity in the human thalamus.

UNLABELLED: Calcium-binding proteins show a heterogeneous distribution in the mammalian central nervous system and are useful markers for identifying neuronal populations. The distribution of the three major calcium-binding proteins - calbindin-D28k (calbindin), calretinin and parvalbumin - has been investigated in eight neurologically normal human thalami using standard immunohistochemical techniques. Most thalamic nuclei show immunoreactive cell bodies for at least two of the three calcium-binding proteins; the only nucleus showing immunoreactivity for one calcium-binding protein is the centre médian nucleus (CM) which is parvalbumin-positive. Overall, the calcium-binding proteins show a complementary staining pattern in the human thalamus. In general terms, the highest density of parvalbumin staining is in the component nuclei of the ventral nuclear group (i.e. in the ventral anterior, ventral lateral and ventral posterior nuclear complexes) and in the medial and lateral geniculate nuclear groups. Moderate densities of parvalbumin staining are also present in regions of the mediodorsal nucleus (MD). By contrast, calbindin and calretinin immunoreactivity both show a similar distribution of dense staining in the thalamus which appears to complement the pattern of intense parvalbumin staining. That is, calbindin and calretinin staining is most dense in the rostral intralaminar nuclear group and in the patchy regions of the MD which show very low levels of parvalbumin staining. However, calbindin and calretinin also show low levels of staining in the ventral nuclear complex and in the medial and lateral geniculate bodies which overlaps with the intense parvalbumin staining in these regions. These results show that the calcium-binding proteins are heterogeneously distributed in a complementary fashion within the nuclei of the human thalamus. They provide further support for the concept recently proposed by Jones (Jones, E.G., 1998. VIEWPOINT: the core and matrix of thalamic organization. Neuroscience 85, 331-345) that the primate thalamus comprises of a matrix of calbindin immunoreactive cells and a superimposed core of parvalbumin immunoreactive cells which may have differential patterns of cortical projections.

Adult↗

PubMed1999

Regional and cellular localisation of GABA(A) receptor subunits in the human basal ganglia: An autoradiographic and immunohistochemical study.

The regional and cellular localisation of gamma-aminobutyric acid(A) (GABA(A)) receptors was investigated in the human basal ganglia using receptor autoradiography and immunohistochemical staining for five GABA(A) receptor subunits (alpha(1), alpha(2), alpha(3), beta(2, 3), and gamma(2)) and other neurochemical markers. The results demonstrated that GABA(A) receptors in the striatum showed considerable subunit heterogeneity in their regional distribution and cellular localisation. High densities of GABA(A) receptors in the striosome compartment contained the alpha(2), alpha(3), beta(2, 3), and gamma(2) subunits, and lower densities of receptors in the matrix compartment contained the alpha(1), alpha(2), alpha(3), beta(2,3), and gamma(2) subunits. Also, six different types of neurons were identified in the striatum on the basis of GABA(A) receptor subunit configuration, cellular and dendritic morphology, and chemical neuroanatomy. Three types of alpha(1) subunit immunoreactive neurons were identified: type 1, the most numerous (60%), were medium-sized aspiny neurons that were immunoreactive for parvalbumin and alpha(1), beta(2,3), and gamma(2) subunits; type 2 (38%) were medium-sized to large aspiny neurons immunoreactive for calretinin and alpha(1), alpha(3), beta(2,3), and gamma(2) subunits; and type 3 (2%) were large sparsely spiny neurons immunoreactive for alpha(1), alpha(3), beta(2,3), and gamma(2) subunits. Type 4 neurons were calbindin-positive and immunoreactive for alpha(2), alpha(3), beta(2,3), and gamma(2) subunits. The remaining neurons were immunoreactive for choline acetyltransferase (ChAT) and alpha(3) subunit (type 5) or were neuropeptide Y-positive with no GABA(A) receptor subunit immunoreactivity (type 6). The globus pallidus contained three types of neurons: types 1 and 2 were large neurons and were immunoreactive for alpha(1), alpha(3), beta(2,3), and gamma(2) subunits and for parvalbumin alone (type 1) or for both parvalbumin and calretinin (type 2); type 3 neurons were medium-sized and immunoreactive for calretinin and alpha(1), beta(2, 3), and gamma(2) subunits. These results show that the subunit composition of GABA(A) receptors displays considerable regional and cellular variation in the human striatum but are more homogeneous in the globus pallidus.

Acetylcholinesterase↗

PubMed1999

Localization of calcium-binding proteins and GABA transporter (GAT-1) messenger RNA in the human subthalamic nucleus.

The distribution of messenger RNA encoding the human GAT-1 (a high-affinity GABA transporter) was investigated in the subthalamic nucleus of 10 neurologically normal human post mortem cases. Further, the distribution of messenger RNA and protein encoding the three neuronally expressed calcium-binding proteins (calbindin D28k, parvalbumin and calretinin) was similarly investigated using in situ hybridization and immunohistochemical techniques. Cellular sites of calbindin D28k, parvalbumin, calretinin and GAT-1 messenger RNA expression were localized using human-specific oligonucleotide probes radiolabelled with [35S]dATP. Sites of protein localization were visualized using specific anti-calbindin D28k, anti-parvalbumin and anti-calretinin antisera. Examination of emulsion-coated tissue sections processed for in situ hybridization revealed an intense signal for GAT-1 messenger RNA within the human subthalamic nucleus, indeed the majority of Methylene Blue-counterstained cells were enriched in this transcript. Further, a marked heterogeneity was noted with regard to the expression of the messenger RNA's encoding the three calcium-binding proteins; this elliptical nucleus was highly enriched in parvalbumin messenger RNA-positive neurons and calretinin mRNA-positive cells but not calbindin messenger RNA-positive cells. Indeed, only an occasional calbindin messenger RNA-positive cell was detected within the mediolateral extent of the nucleus. In marked contrast, numerous parvalbumin messenger RNA-positive cells and calretinin messenger RNA-positive cells were detected and they were topographically distributed; parvalbumin messenger RNA-positive cells were highly enriched in the dorsal subthalamic nucleus extending mediolaterally; calretinin messenger RNA-positive cells were more enriched ventrally although some degree of overlap was apparent. Computer-assisted analysis of the average cross-sectional somatic area of parvalbumin, calretinin and GAT-1 messenger RNA-positive neurons revealed them all to be in the range of 300 microm2. The unique patterns of calcium-binding protein gene expression were similarly reflected at the protein level; an abundance of parvalbumin- and calretinin-immunopositive neurons were observed whereas only occasional intensely-labelled calbindin-immunopositive fibres were seen, no calbindin-immunopositive cells were detected. Single and double labelling studies show that parvalbumin-immunopositive neurons were mainly localized in the dorsal region of the nucleus, and calretinin-immunopositive neurons were mainly localized in the ventral region although there was overlap with double-labelled neurons located in the middle and dorsal regions. The significance of these findings, in particular the expression of GAT-1, a high-affinity GABA uptake protein, for basal ganglia signalling is discussed.

Basal Ganglia↗

PubMed1999

The effects of the N-terminal tripeptide of insulin-like growth factor-1, glycine-proline-glutamate in different regions following hypoxic-ischemic brain injury in adult rats.

Insulin-like growth factor-1 has pleiotropic effects in the central nervous system and can act both as a survival and a differentiation factor. Insulin-like growth factor-1 can be proteolytically cleaved into des-N-(1-3)-insulin-like growth factor-1 and a N-terminal tripeptide fragment, glycine-proline-glutamate. Both insulin-like growth factor-1 and des-N-(1-3)-insulin-like growth factor-1 can improve neuronal survival after hypoxic-ischemic brain injury in vivo. The present study investigates the effects of glycine-proline-glutamate on different brain regions and neuronal populations after hypoxic-ischemic injury. Unilateral hypoxic-ischemic injury was induced in adult rats. Glycine-proline-glutamate (3 microg) was administered centrally 2 h after the injury and the extent of brain damage determined five days later. In a separate trial immunohistochemical techniques were used to determine the effects of glycine-proline-glutamate on specific populations of neurons in the striatum after the injury. Compared to the vehicle treatment, glycine-proline-glutamate (n=19) treatment reduced the extent of cortical damage and neuronal loss in the CA1-2 subregions of the hippocampus (P<0.05). In the striatum, there was a trend towards a reduction in neuronal loss after glycine-proline-glutamate treatment (P=0.053) compared to the vehicle (n=21)-treated animals. In a separate study, glycine-proline-glutamate (n=8) treatment prevented the loss of choline acetyltransferase (P<0.05), glutamate acid decarboxylase (P<0.05) and somatostatin (P<0.05) containing neurons in the ipsilateral striatum following hypoxic-ischemic brain injury and also increased the numbers of neuronal nitric oxide synthase (P<0.05) containing neurons in the contralateral side. These studies suggest that in addition to neuroprotective effects, glycine-proline-glutamate can influence neuronal activity after hypoxic-ischemic injury.

Animals↗

PubMed1999

Calcium-binding protein immunoreactivity delineates the intralaminar nuclei of the thalamus in the human brain.

Immunohistochemical studies have shown that the three calcium-binding proteins (calbindin-D28k, calretinin and parvalbumin) are heterogeneously distributed in the mammalian brain and are useful for delineating nuclear boundaries. We have investigated the distribution of the three calcium-binding proteins in the human thalamus in order to assist in the delineation of the equivocal nuclear boundaries of the intralaminar nuclei of the thalamus. The results show that each of the "functional" nuclear complexes in the human thalamus demonstrates a characteristic pattern of calcium-binding protein immunoreactivity. In particular, the intralaminar nuclei are characterized by a unique combination of calcium-binding protein staining which clearly delineates the component nuclei in this complex from the other nuclei of the human thalamus. The anterior group of intralaminar nuclei (central lateral nucleus, paracentral nucleus and central medial nucleus) showed intense staining for both calbindin-D28k and calretinin. By contrast, the posterior group of intralaminar nuclei (centre median nucleus and parafascicular nucleus) showed a complementary pattern of staining; the centre median nucleus showed immunoreactivity only for one calcium-binding protein, parvalbumin, while the parafascicular nucleus showed immunoreactivity for both calbindin-D28k and calretinin. No other nucleus in the human thalamus showed these particular combinations of calcium-binding protein staining. Since the intralaminar nuclei also have unique topographically organized connectional affiliations with both the cerebral cortex and the basal ganglia, these results suggest that the calcium-binding proteins may play an important role in the influence of the intralaminar nuclei on interactions between the cerebral cortex and the basal ganglia.

Adult↗

PubMed1999

Chemical and anatomical changes in the striatum and substantia nigra following quinolinic acid lesions in the striatum of the rat: a detailed time course of the cellular and GABA(A) receptor changes.

The pattern and time-course of cellular, neurochemical and receptor changes in the striatum and substantia nigra were investigated following unilateral quinolinic acid lesions of the striatum in rats. The results showed that in the central region of the striatal lesion there was a major loss of Nissl staining of the small to medium sized cells within 2 h and a substantial loss of neuronal staining within 24 h after lesioning. Immunohistochemical studies showed a total loss of calbindin immunoreactivity, a known marker of GABAergic striatal projection neurons, throughout the full extent of the quinolinic acid lesion within 24 h. Similarly, within 24 h, there was a total loss of somatostatin/neuropeptide Y cells in the centre of the lesion but in the periphery of the lesion these cells remained unaltered at all survival times. Striatal GABA(A) receptors remained unchanged in the lesion for 7 days, and then declined in density over the remainder of the time course. Glial fibrillary acidic protein immunoreactive astrocytes were present in the periphery of the lesion at 7 days, occupied the full extent of the lesion by 4 weeks, and remained elevated for up to 2 months. In the substantia nigra, following placement of a striatal quinolinic acid lesion, there was: a loss of substance P immunoreactivity within 24 h; a marked astrocytosis evident from 1-4 weeks postlesion; and, a major increase in GABA(A) receptors in the substantia nigra which occurred within 2 h postlesion and was sustained for the remainder of the time course (15 months). This study shows that following quinolinic acid lesions of the striatum there is a major loss of calbindin and somatostatin/neuropeptide Y immunoreactive cells in the striatum within 24 h, and a marked increase in GABA(A) receptors in the substantia nigra within 2 h. These findings are similar to the changes in the basal ganglia in Huntington's disease and provide further evidence supporting the use of the quinolinic acid lesioned rat as an animal model of Huntington's disease.

Animals↗

PubMed1998

GABA(A) receptors in the primate basal ganglia: an autoradiographic and a light and electron microscopic immunohistochemical study of the alpha1 and beta2,3 subunits in the baboon brain.

The distribution of gamma-aminobutyric acid(A) (GABA(A)) receptors was investigated in the basal ganglia in the baboon brain by using receptor autoradiography and the immunohistochemical localisation of the alpha1 and beta2,3 subunits of the GABA(A) receptor by light and electron microscopy. In the caudate-putamen, the alpha1 subunit was distributed in high densities in the matrix compartment, and the beta2,3 subunits were more homogeneously distributed; the globus pallidus showed lower levels of the alpha1 and beta2,3 subunits. Four types of alpha1 subunit immunoreactive neurons were identified in the baboon striatum: the most numerous (75%) were type 1 medium-sized aspiny neurons; type 2 (2%) were large aspiny neurons with an indented nuclear membrane located in the ventral striatum; type 3 neurons were the least numerous (1%) and were comprised of large neurons in the ventromedial regions of the striatum; and type 4 (22%) neurons were medium to large aspiny neurons located in striosomes. At the ultrastructural level, alpha1 and beta2,3 subunit immunoreactivity was localised in the neuropil of the striatum in both symmetrical and asymmetrical synaptic contacts. In the globus pallidus, alpha1 and beta2,3 subunits were localised on large neurons and were found in three types of synaptic terminals: type 1 terminals were small and established symmetrical synapses; type 2 terminals were large; and type 3 terminals formed small synaptic terminals with subjunctional dense bodies. These results show that the subunit composition of GABA(A) receptors varies between the striosome and the matrix compartments in the striatum and that there is receptor subunit homogeneity in the globus pallidus.

Animals↗