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PubMed1998

Transient expression of calretinin in the trout habenulo-interpeduncular system during development.

Calcium-binding proteins control calcium homeostasis during neural development. The expression of one of these proteins, calretinin (CR), was monitored by immunohistochemistry in the developing habenulo-interpeduncular system of the rainbow trout, a conserved region of the brain along vertebrate phylogeny that undergoes a neurochemical reorganization in late development. No CR-immunoreactivity was observed in the habenulo-interpeduncular system during the embryonic development. CR-immunolabeling appeared in newly hatched fry and during the fry development the number of CR-immunostained elements increased progressively. During the juvenile stages (from 30 days post-hatching onwards) a gradual decrease in the number of CR-immunostained cells occurred, until its complete disappearance in adults. These variations in CR expression may represent the variable calcium-buffering needs during different developmental stages.

Age Factors↗
PubMed1999

Unipolar brush cells in the cochlear nuclei of a primate (Callithrix jacchus).

Unipolar brush cells (UBCs) have been recognized in the cerebella of many species including primates. They have also been identified in the cochlear nuclei (CN) of many mammals, however, not in any primate. Our immunohistochemical study in the marmoset demonstrates the presence of abundant calretinin immunoreactive (CR-ir) UBCs in the cerebellum, as in other mammals. In the marmoset CN, in contrast, CR-ir UBCs could hardly be identified. The reverse pattern was evident in sections immunostained for a metabotropic glutamate receptor (mGluR2/3-IR): beautifully stained UBCs were present in the CN, but the stained cerebellar structures were difficult to identify as UBCs. The present findings indicate that UBCs are present in the CN of primates, as in other mammals, but that cerebellar and CN UBCs might differ in their molecular equipment in primates.

Animals↗
PubMed2001

Structural and functional abnormalities of the hippocampal formation in rats with environmentally induced reductions in prepulse inhibition of acoustic startle.

The effects of social isolation on prepulse inhibition of acoustic startle (PPI), electrophysiology and morphology of subicular pyramidal neurons and the densities of interneuronal sub-types in the hippocampal formation were examined. Wistar rats (male weanlings) were housed socially (socials, n=8) or individually (isolates, n=7). When tested eight weeks later, PPI was lower in isolates. Rats then received terminal anaesthesia before slices of hippocampal formation were made in which the electrophysiological properties of a total of 108 subicular neurons were characterized. There were no differences in neuronal sub-types recorded in socials compared with isolates. Intrinsically burst-firing and regular spiking pyramidal neurons were examined in detail. There were no differences in resting membrane potential or input resistance in isolates compared with socials but action potential height was reduced and action potential threshold raised in isolates. A limited morphological examination of Neurobiotin-filled intrinsically burst-firing neurons did not reveal differences in cell-body area or in number of primary dendrites. Sections from the contralateral hemispheres of the same rats were stained with antibodies to calretinin, parvalbumin and the neuronal isoform of nitric oxide synthase (nNOS). In isolates, the density of calretinin positive neurons was increased in the dentate gyrus but unchanged in areas CA3, CA1 and subiculum. Parvalbumin and nNOS positive neuronal densities were unchanged. Hence in rats with environmentally induced reductions in PPI there are structural and functional abnormalities in the hippocampal formation. If the reduction in PPI stems from these abnormalities, and reduced PPI in rats is relevant to schizophrenia, then drugs that correct the reported electrophysiological changes might have antipsychotic effects.

Acoustic Stimulation↗
PubMed2001

Morphological and neurochemical differentiation of large granular layer interneurons in the adult rat cerebellum.

The granular layer of the cerebellar cortex consists of densely packed neuronal cells, classified into granule cells and large interneurons. In this study, we provide a comparative survey of large granular layer interneurons in the adult rat cerebellum based on both morphological and neurochemical criteria. To this end, double immunofluorescence histochemistry was performed by combining antibodies against the cytoplasmic antigen Rat-303, calretinin, the metabotropic glutamate receptor mGluR2 and somatostatin. Based on Rat-303/calretinin double immunohistochemistry, three distinct populations of large granular layer interneurons could be discerned: cells immunopositive for Rat-303, calretinin or both. Rat-303 or calretinin single-labeled cells represented Golgi cells and unipolar brush cells, respectively. Rat-303/calretinin double-labeled cells located just underneath the Purkinje cell layer represented Lugaro cells. Morphometrical analysis distinguished two populations of Rat-303-positive Golgi cells according to their location: vermis versus hemisphere. Immunostaining for the metabotropic glutamate receptor mGluR2 combined with Rat-303 or calretinin revealed that the majority of Golgi cells (about 90%) appeared to be mGluR2 positive. Lugaro cells were mGluR2 negative. In addition, a limited population of large polymorphous interneurons in the depth of the granular layer with morphological features resembling Golgi cells also displayed Rat-303/calretinin immunoreactivity and were mGluR2 negative. Double immunohistochemistry for Rat-303 and somatostatin revealed three populations of labeled cells in the depth of the granular layer. Besides double-labeled Golgi cells, Rat-303 or somatostatin single-labeled cells were present. Based on mGluR2/somatostatin and calretinin/somatostatin double immunostainings, Rat-303 single-labeled cells were found to correspond to Rat-303/calretinin-positive, mGluR2-negative Golgi-like cells, while the identity of somatostatin single-labeled cells remained unclear. The data presented in this article elaborate previous reports on the morphological and neurochemical differentiation of large interneurons in the rat cerebellar granular layer. In addition, they indicate that the current classification of these cells into Golgi cells, Lugaro cells and unipolar brush cells does not describe the observed neurochemical heterogeneity.

Animals↗
PubMed2001

Postnatal differentiation of unipolar brush cells and mossy fiber-unipolar brush cell synapses in rat cerebellum.

The unipolar brush cells are excitatory, cerebellar granular layer interneurons that receive mossy fiber input on their dendritic brushes in the form of a giant glutamatergic synapse. We investigated the postnatal development of the brush of the unipolar brush cell in lobules IX and X by light microscopy and defined the maturation of mossy fiber-unipolar brush cell synapses and mossy fiber-granule cell synapses by electron microscopy using calretinin immunocytochemistry to identify unipolar brush cells. During the first postnatal week, unipolar brush cells possessed one or two short, branched dendrites. The brush differentiated primarily during the successive 21 postnatal (P) days, during which it underwent progressive maturation. This developmental process was subdivided into stages 1-4, which were descriptively termed protodendritic unipolar brush cell (P2-12), filopodial brush (P12-16), intermediate brush (P16-21), and dendriolar brush (P21-28) stages. Electron microscopic measurements of individual mossy fiber-unipolar brush cell and mossy fiber-granule cell synaptic junctions were made at P12, 16, 21, and 28. While the average length of mossy fiber-unipolar brush cell synapses increased during development, that of mossy fiber-granule cell synapses decreased. Comparisons of the lengths of mossy fiber-unipolar brush cell and mossy fiber-granule cell synapses demonstrated that mossy fiber-unipolar brush cell synapses were longer on average than mossy fiber-granule cell synapses for all ages. Frequency distribution histograms also showed that the percentage of mossy fiber-unipolar brush cell synapses longer than 0.5 microm was lower in the pooled P12-P16 groups than in the pooled P21-P28 groups (8 versus 20%). In contrast, mossy fiber-granule cell synapses longer than 0.5 microm were a small minority at P12, 16, and 21, and occurred rarely at P28. The present study indicates that mossy fiber-unipolar brush cell synapses increase in length with the differentiation of the brush dendrioles, while that of mossy fiber-granule cell synapses decrease with differentiation of the granule cell dendritic claws. The finding that mossy fiber-unipolar brush cell synapses were generally longer than mossy fiber-granule cell synapses may indicate that the properties of the postsynaptic targets play a major role in shaping synaptic appositions within cerebellar glomeruli.

Aging↗
PubMed2001

The mammalian retinal degeneration B2 gene is not required for photoreceptor function and survival.

The retinal degeneration B (rdgB) gene in Drosophila is essential for photoreceptor function and survival. The rdgB mutant fly exhibits an abnormal electroretinogram and a light-dependent photoreceptor degeneration. The function of RdgB is not fully understood, but the presence of a phosphatidylinositol transfer protein domain suggests a possible role in phosphatidylinositol metabolism and signaling. Two mammalian homologs, M-RdgB1 and M-RdgB2, are known. While M-RdgB1 is widely expressed, M-RdgB2 is found primarily in the retina and the dentate gyrus. Functional conservation between the Drosophila and mammalian RdgBs was demonstrated by the ability of both M-RdgBs to rescue the photoreceptor phenotype in rdgB mutant flies through transgenic expression. To investigate the role of M-RdgB2 in the mammalian retina, we disrupted the m-rdgB2 gene in mice by gene targeting. The homozygous knockout mice are fertile and apparently healthy. By light microscopy, immunocytochemistry and electroretinograms, mice up to 18 months of age showed normal photoreceptor function and survival. The inner retinal neurons were also examined by immunolabeling with a number of cell-specific markers and no apparent defects were found in the major cell populations. We conclude that M-rdgB2 is not essential for phototransduction and photoreceptor survival. Thus, m-rdgB2 is not a candidate gene for human retinal degenerations. Whether M-rdgB2 has a role in visual processing in the inner retina, or whether it is required for hippocampal function, remains to be determined.

Amacrine Cells↗
PubMed1997

Distribution of calretinin-containing neurons relative to other neurochemically identified cell types in the medial septum of the rat.

The topographic distribution of calretinin-immunoreactive neurons was studied in the medial septum diagonal band of Broca complex of the rat, in relation to the localization of other neurochemically identified cell groups containing choline acetyltransferase, parvalbumin or calbindin D28k. Double-labelling experiments revealed that these four antigen-containing cells formed distinct dorsoventrally running lamellae overlayed on top of each other similar to onion leaves. There was only a slight overlapping of the various cell groups. None of the four antigens were co-localized in the same cells. The lamella occupied by calretinin-positive neurons is situated at the border of the medial septum and the intermediolateral septal nucleus, and shows some overlap with the area occupied by cholinergic neurons. Retrograde transport of horseradish peroxidase from the hippocampus combined with immunostaining for calretinin revealed that calretinin-containing neurons do not participate in the septohippocampal projection. The lack of projection to the amygdala was also confirmed. Thus, calretinin-containing neurons represent a distinct cell group in the medial septal region, which either projects to subcortical areas, or may function as interneurons relaying hippocampal feedback to the medial septal projection neurons.

Animals↗
PubMed1996

Distinct preganglionic neurons innervate noradrenaline and adrenaline cells in the cat adrenal medulla.

Calretinin immunoreactivity was present in a subset of preganglionic neurons retrogradely labelled from the cat adrenal gland. Overall, one-third of adrenal preganglionic neurons showed calretinin immunoreactivity, and their proportion increased in the more caudal spinal cord segments. Calretinin-immunoreactive nerve terminals were prominent within the adrenal gland, but were found only in areas of noradrenergic chromaffin cells (approximately one-third of the area of the adrenal medulla). Synaptophysin immunoreactivity was used to label terminals with and without calretinin immunoreactivity. Nerve terminals lacking calretinin immunoreactivity were present among the adrenergic chromaffin-cells and also comprised 20% of the nerve terminals innervating noradrenergic chromaffin cells. Calretinin immunoreactivity thus labels a subpopulation of cat adrenal preganglionic neurons that innervate the noradrenergic chromaffin cells.

Adrenal Medulla↗
PubMed1997

The expression pattern of somatostatin and calretinin by postnatal hippocampal interneurons is regulated by activity-dependent and -independent determinants.

Hippocampal interneurons form distinct populations identified on the basis of their projection pattern and neurochemical characteristics, which includes the expression of specific neuropeptides and/or calcium-binding proteins. The neurochemical maturation of hippocampal interneurons is largely a postnatal event, and factors which govern this maturation are presently unknown. Using slice cultures, we have investigated the role of neuronal activity in regulating the expression of somatostatin and calretinin during the postnatal maturation of hippocampal interneurons. Blocking inhibitory activity with bicuculline, or excitatory activity with 6,7-dinitroquinoxaline-2,3-dione, for 14 days in slice cultures from seven-day-old rat increased and decreased, respectively, the number of somatostatin-immunoreactive neurons. Withdrawal of the blocking agents resulted in a reversal of the effects on somatostatin immunoreactivity. In addition, bicuculline slightly increased the number of calretinin-positive neurons, while 6,7-dinitroquinoxaline-2,3-dione exerted no effect. However, bicuculline and 6,7-dinitroquinoxaline-2,3-dione markedly increased and decreased, respectively, the number of calretinin-labelled axons. Despite activity-linked modifications of immunoreactivity levels, no change in the organotypic location of somatostatin-labelled neurons was observed, whatever the treatment. Double labelling studies demonstrated that somatostatin and calretinin were expressed by different neurons, even when the number of labelled cells was highly increased. These results show that the levels of expression of somatostatin and calretinin in maturing hippocampal interneurons are tuned to the endogenous balance of excitatory and inhibitory activity. In contrast, the neurochemical specificity of each subtype of interneurons does not depend upon variations in neuronal activity.

Animals↗
PubMed1998

Distribution of calretinin immunoreactivity in the mouse dentate gyrus: II. Mossy cells, with special reference to their dorsoventral difference in calretinin immunoreactivity.

In our previous study we revealed the presence of clustered large calretinin-immunoreactive multipolar cells in the ventral hilus of the mouse dentate gyrus and indicated that they might be mossy cells, the principal neurons in the dentate hilus. In the present study we confirmed this identification with several methods and analysed further in detail. In Golgi-impregnated samples mossy cells were easily identified by their locations and characteristic thorny excrescences on their proximal dendrites. Golgi-impregnated mossy cells were observed not only in the ventral hilus but also in the dorsal hilus, where no calretinin-immunoreactive large multipolar cells were encountered. Interestingly, mossy cells exhibited dorsoventral differences in the size and complexity of thorny excrescences; mossy cells at the dorsal and middle levels had larger and more complex thorny excrescences, which covered dendritic shafts for a longer distance, while ventral mossy cells had smaller, simpler and shorter thorny excrescences. Confocal laser scanning light microscopic observations at a high magnification showed that the vast majority of calretinin-immunoreactive large neurons in the ventral hilus displayed the thorny excrescences characteristic to mossy cells. Mossy cells identified with the intracellular injection of Lucifer Yellow were calretinin-immunoreactive. Electron microscopic observations clearly revealed that calretinin-immunoreactive elements showed structural features of mossy cells such as thorny excrescences receiving typical synapses from mossy fibre terminals. At the supragranular zone, a well-known target zone of mossy cell axons, a dense calretinin-immunoreactive band was seen, where numerous calretinin-immunoreactive punctae and fibres were packed. Electron microscopic observations revealed that these calretinin-immunoreactive axon terminals in the supragranular zone made asymmetrical synapses on presumed granule cell dendritic spines. Tracer injection studies and lesion experiments indicated that the supragranular calretinin-immunoreactive axon terminals mainly originated from the large calretinin-immunoreactive multipolar cells in the ipsilateral ventral hilus. Fluorescent double immunostaining for calretinin and glutamate receptor 2/3 (GluR2/3) revealed that all large calretinin-immunoreactive hilar cells in the ventral level were GluR2/3-immunoreactive and almost all intensely GluR2/3-immunoreactive hilar cells in the ventral level were calretinin-immunoreactive. In addition intensely GluR2/3-immunoreactive but calretinin-negative large cells were encountered in the dentate hilus at the dorsal level. On the basis of these observations, we concluded that large calretinin-immunoreactive cells in the ventral hilus of the mouse dentate gyrus were really mossy cells and that mossy cells at the dorsal level were calretinin negative. The present study revealed that mouse mossy cells show the dorsoventral difference in the calretinin immunoreactivity and thus they are chemically heterogeneous.

Animals↗
PubMed1998

Calcium-binding protein immunoreactivity in the piriform cortex of the guinea-pig: selective staining of subsets of non-GABAergic neurons by calretinin.

Selective immunostaining for calcium-binding proteins identifies subpopulations of neurons with hypothetical distinct functional roles. The neuronal localization of calcium-binding proteins calretinin, parvalbumin and calbindin is here correlated to GABA and glutamate immunoreactivity in the guinea-pig piriform cortex. In the external border of the molecular layer, neurons positive for calretinin with morphological features of Cajal-Retzius cells were found. Rare GABA immunoreactive cells were observed in the same subpial region, whereas neurons containing GABA were abundant within layers Ia and Ib. Aspartate- and glutamate-immunoreactive cells were also found in the outer Ia layer. A distinct band of calretinin-immunoreactive fibres and terminals localized in layer Ia, where the afferent fibres originating from the olfactory bulb are segregated. In layer II the number of cells containing calretinin exceeded the number of neurons positive for the anti-GABA antibody. Part of the layer II calretinin-positive neurons with pyramidal shape and large apical dendrites directed toward the surface were found to be immunoreactive for the anti-glutamate antibody on adjacent sections. Neurons in layer II immunoreactive for either parvalbumin or calbindin showed morphological features of interneurons, and their number matched the count of GABA containing cells. Calretinin-positive neurons with the general morphological features of interneurons were scarcely represented in the deep piriform cortical layers, where large multipolar and small bipolar calbindin-positive cells prevailed. The present data show that in the piriform cortex of the guinea-pig calretinin, although expressed in Cajal-Retzius-like cells as in other cortical areas, also marks a subpopulation of glutamate containing pyramidal-like neurons in layer II.

Animals↗
PubMed1998

Calretinin immunoreactivity in the developing thalamus of the rat: a marker of early generated thalamic cells.

The present work was aimed to study the immunocytochemical localization of the calcium-binding protein, calretinin, in the rat thalamus from embryonic day 14 to the third postnatal week. In the adult rat thalamus, calretinin immunoreactivity is intensely expressed in some intralaminar and midline nuclei, as well as in selected regions of the reticular nucleus. At embryonic day 14, calretinin was expressed by immature and migrating neurons and fibres laterally to the neuroepithelium of the diencephalic vesicle in the region identified as reticular neuroepithelium. At embryonic day 16, immunoreactive neurons were present in the primordium of the reticular nucleus and in the region of the reticular thalamic migration, where neurons showed the morphology of migratory cells. At the end of embryonic development and in the first postnatal week, calretinin-positive neurons were observed in selected region of the reticular nucleus and it was intensely expressed in some intralaminar and midline nuclei. Bands of immunopositive fibres were also observed crossing the thalamus. During the second postnatal week, the immunolabelling in the reuniens, rhomboid, paraventricular and central medial thalamic nuclei remains very intense while a decrease of immunoreactivity in mediodorsal, centrolateral and laterodorsal nuclei was observed. The immunostaining of fibres, particularly evident in the perinatal period, progressively decreased and it was no longer visible by the end of the second postnatal week when the distribution and intensity of calretinin immunostaining was similar to that observed in the adult rat thalamus. The present findings indicate that the immunolocalization of calretinin can be used to identify subsets of thalamic neuronal population during pre- and postnatal maturation allowing also the detection of the migratory pattern of early generated reticular thalamic neurons.

Aging↗
PubMed1998

Calretinin-immunoreactive neurons in the human thalamus.

The distribution of the calcium-binding protein calretinin in the thalamus of normal human individuals was studied with immunohistochemistry. Calretinin immunoreactivity was weak in the geniculate bodies and in nuclei of the ventral and posterior groups, moderate in the reticular nucleus and in nuclei of the anterior, medial, and lateral groups, and strong in nuclei of the midline group and anterior intralaminar nuclei. The mediodorsal nucleus was unique among thalamic nuclei because it contained a wide variety of intensely immunostained perikarya embedded in a moderately-labelled neuropil. The reticular nucleus displayed several small and uniformly distributed neuronal clusters composed of immunostained perikarya lying in a moderately-labelled neuropil. Intense and uniform immunostaining was observed in all midline nuclei and in the anterior intralaminar nuclei, including the paracentral and central lateral nuclei. These nuclei, which harboured numerous intensely-stained perikarya lying in a dense immunoreactive neuropil, were the most strongly-immunoreactive structures of the entire human thalamus. At the level of the posterior intralaminar nuclei, the central median nucleus was virtually free of immunostaining whereas the parafascicular nucleus was moderately labelled. The nucleus submedius located just beneath the central median/parafascicular complex displayed a very intense calretinin immunostaining. This study has provided evidence for the presence of the protein calretinin in the human thalamus. The pattern of distribution of calretinin, as delineated in the present study, suggests that this calcium-binding protein may participate in various subcortical and cortical thalamic systems involved in the modulation of emotional and motivational states.

Aged↗
PubMed1998

Simultaneous expression of brain-derived neurotrophic factor and neurotrophin-3 in Cajal-Retzius, subplate and ventricular progenitor cells during early development stages of the rat cerebral cortex.

To identify production sites and action targets of neurotrophins during neurogenesis, we investigated immunoreactivities of neurotrophins and their tyrosine kinase receptors in the cerebral cortex of rat embryos. Two sets of ligand-receptor systems, brain-derived neurotrophic factor/TrkB and neurotrophin-3/TrkC, were expressed simultaneously in Cajal-Retzius, subplate neurons and ventricular multipotent stem cells at embryonic days 13 and 15. Intraventricular administration of brain-derived neurotrophic factor or neurotrophin-3 at embryonic day 16 markedly modulated microtubule-associated protein II and/or Hu protein expression in different ways in the cortical plate cells by embryonic day 20. These observations indicate the involvement of autocrine and/or local paracrine action of brain-derived neurotrophic factor and/or neurotrophin-3 during formation of the cerebral cortex.

Aging↗
PubMed1999

Calretinin-immunoreactive neurons in primate pedunculopontine and laterodorsal tegmental nuclei.

Single- and double-antigen localization procedures were used to study the distribution, morphological characteristics and chemical phenotype of neurons containing the calcium-binding protein calretinin in the pedunculopontine and laterodorsal tegmental nuclei of the cynomolgus monkey (Macaca fascicularis). Calretinin was detected in neurons that belonged to a highly heteromorphic and widely distributed subpopulation of the pedunculopontine and laterodorsal tegmental nuclei in the cynomolgus monkey. Double-immunostaining experiments revealed that about 12% of these calretinin-containing neurons displayed immunoreactivity for another calcium-binding protein, Calbindin-D28k. The calretinin/Calbindin-D28k double-labeled neurons had small to medium-sized perikarya, from which emerged a bipolar or multipolar dendritic arborization. Calretinin was also present in approximately 8% of the cholinergic neurons of the pedunculopontine/laterodorsal nuclear complex, as visualized on single sections immunostained for both calretinin and choline acetyltransferase. These calretinin/choline acetyltransferase double-labeled neurons displayed markedly different sizes and shapes, and occurred preferentially in the pars compacta and dissipata of the pedunculopontine tegmental nucleus. Numerous calretinin-immunoreactive fibers were also present within and around the superior cerebellar peduncle. Some of these varicose fibers closely surrounded large non-immunoreactive neurons, as well as large neurons staining positively for choline acetyltransferase. This study provides the first evidence for the existence of calretinin-immunoreactive neurons within the primate pedunculopontine and laterodorsal tegmental nuclei. Our data suggest that calretinin may play a role in the function of the pedunculopontine/laterodorsal nuclear complex by acting either alone or in conjunction with acetylcholine or Calbindin-D28k.

Animals↗
PubMed1999

The entorhino-septo-supramammillary nucleus connection in the rat: morphological basis of a feedback mechanism regulating hippocampal theta rhythm.

Recent electrophysiological observations suggest that, in addition to the medial septal area pacemaker system, several alternative or additional mechanisms are involved in the generation/regulation of hippocampal theta activity. Discharging neurons phase-locked to hippocampal theta waves have been observed in the dorsal raphe, nucleus reticularis pontis oralis and especially in the supramammillary region of rats. Since these areas are reciprocally interconnected with the hippocampal formation, including the entorhinal cortex, it would aid our understanding of limbic function to elucidate the location and neurochemical content of the entorhino-septal and septo-supramammillary projection neurons, as well as that of their postsynaptic targets. Light and electron microscopic immunostaining for calretinin, in combination with antero- and retrograde tracer techniques, postembedding immunostaining for GABA and the transmitter specific [3H]D-aspartate retrograde radiolabeling, as well as a co-localization experiment for calretinin and glutamate decarboxylase in rat supramammillary and septal neurons, demonstrated that: (i) a large population of entorhinal cells that forms asymmetric synaptic contacts on calretinin-containing neurons located at the border between the medial and lateral septal areas contains calretinin and are aspartate/glutamatergic; (ii) the overwhelming majority of calretinin-immunoreactive cells located at the border between the lateral and medial septal area are GABAergic; (iii) these neurons can be retrogradely labeled from the supramammillary area; (iv) anterogradely labeled axons originating in the border between the medial and lateral septum are GABAergic and (v) terminate on supramammillary area non-GABAergic, calretinin-containing neurons, which are known to project to the septal complex and hippocampus. These observations indicate that a large population of cells participating in the hippocampal feedback regulation of theta regulation/generation contain the same calcium-binding protein. Furthermore, entorhinal excitatory transmitter-containing neurons can depress the activity of supramammillary theta generating/regulating cells via septal inhibitory neurons.

Animals↗
PubMed1999

Administration of recombinant human Activin-A has powerful neurotrophic effects on select striatal phenotypes in the quinolinic acid lesion model of Huntington's disease.

Huntington disease is characterized by the selective loss of striatal neurons, particularly of medium-sized spiny glutamate decarboxylase67 staining/GABAergic projection neurons which co-contain the calcium binding protein calbindin. Lesioning of the adult rat striatum by intrastriatal injection of the N-methyl-D-aspartate receptor agonist quinolinic acid (100 nmol) results in a pattern of striatal neuropathology seven days later that resembles that seen in the Huntington brain. Using this animal model of human Huntington's disease we investigated the effect of daily intrastriatal infusion of the nerve cell survival molecule ActivinA (single bolus dose of 0.73 microg daily for seven days) on the quinolinic acid-induced degeneration of various striatal neuronal phenotypes. By seven days, unilateral intrastriatal infusion of quinolinic acid produced a partial but significant loss (P < 0.01) in the number of striatal neurons immunoreactive for glutamate decarboxylase (to 51.0+/-5.8% of unlesioned levels), calbindin (to 58.7+/-5.1%), choline acetyltransferase (to 68.6+/-6.1%), NADPH-diaphorase (to 47.4+/-5.4%), parvalbumin (to 58.8+/-4.1%) and calretinin (to 60.6+/-8.6%) in adult rats that were administered intrastriatal phosphate-buffered saline for seven days following quinolinic acid. In contrast, in rats that received intrastriatal recombinant human ActivinA once daily for seven days following quinolinic acid, phenotypic degeneration was significantly attenuated in several populations of striatal neurons. Treatment with ActivinA had the most potent protective effect on the striatal cholinergic interneuron population almost completely preventing the lesion induced decline in choline acetyltransferase expression (to 95.1+/-5.8% of unlesioned levels, P < 0.01). ActivinA also conferred a significant protective effect on parvalbumin (to 87.5+/-7.7%, P < 0.01) and NADPH-diaphorase (to 77.5+/-7.5%, P < 0.01) interneuron populations but failed to prevent the phenotypic degeneration of calretinin neurons (to 56.6+/-5.5%). Glutamate decarboxylase67 and calbindin-staining nerve cells represent largely overlapping populations and both identify striatal GABAergic projection neurons. We found that ActivinA significantly attenuated the loss in the numbers of neurons staining for calbindin (to 79.7+/-6.6%, P < 0.05) but not glutamate decarboxylase67 (to 61.1+/-5.9%) at seven days following quinolinic acid lesioning. Taken together these results suggest that exogenous administration of ActivinA can rescue both striatal interneurons (labelled with choline acetyltransferase, parvalbumin, NADPH-diaphorase) and striatal projection neurons (labelled by calbindin) from excitotoxic lesioning with quinolinic acid. Longer-term studies will be required to determine whether these surviving calbindin-expressing projection neurons recover their ability to express the glutamate decarboxylase67/GABAergic phenotype. These results therefore suggest that treatment with ActivinA may help to prevent the degeneration of vulnerable striatal neuronal populations in Huntington's disease.

Activins↗
PubMed1999

Evidence for a deficit in cholinergic interneurons in the striatum in schizophrenia.

Neurochemical and functional abnormalities of the striatum have been reported in schizophrenic brains, but the cellular substrates of these changes are not known. We hypothesized that schizophrenia may involve an abnormality in one of the key modulators of striatal output, the cholinergic interneuron. We measured the densities of cholinergic neurons in the striatum in schizophrenic and control brains in a blind analysis, using as a marker of this cell population immunoreactivity for choline acetyltransferase, the synthetic enzyme of acetylcholine. As an independent marker, we used immunoreactivity for calretinin, a protein which is co-localized with choline acetyltransferase in virtually all of the cholinergic interneurons of the striatum. A significant decrease in choline acetyltransferase-positive and calretinin-positive cell densities was found in the schizophrenic cases compared with controls in the striatum as a whole [for the choline acetyltransferase-positive cells: controls: 3.21 +/- 0.48 cells/mm2 (mean +/- S.D.), schizophrenics: 2.43 +/- 0.68 cells(mm2; P < 0.02]. The decrease was patchy in nature and most prominent in the ventral striatum (for the choline acetyltransferase-positive cells: controls: 3.47 +/- 0.59 cells/mm2, schizophrenics: 2.52 +/- 0.64 cells/ mm2; P < 0.005) which included the ventral caudate nucleus and nucleus accumbens region. Three of the schizophrenic cases with the lowest densities of cholinergic neurons had not been treated with neuroleptics for periods from more than a month to more than 20 years. A decrease in the number or function of the cholinergic interneurons of the striatum may disrupt activity in the ventral striatal-pallidal-thalamic-prefrontal cortex pathway and thereby contribute to abnormalities in function of the prefrontal cortex in schizophrenia.

Adult↗