Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunohistochemical double-label techniques were used to study the localization of DARPP-32, a phosphoprotein that is enriched in neurons possessing members of the D1 subfamily of dopamine receptors, in several different types of striatal neurons in the rat basal ganglia. The vast majority (94.1%) of striatonigral projection neurons (the vast majority of which contain substance P), identified by retrograde labeling with fluorogold, were observed to contain DARPP-32. Similarly, the vast majority of striatopallidal projection neurons (87.7%), identified by immunofluorescence labeling for enkephalin (ENK), were found to label for DARPP-32. In contrast, cholinergic and neuropeptide Y-containing striatal interneurons were never observed to contain DARPP-32. These results suggest that essentially all major types of striatal medium spiny projection neurons may possess members of the D1 subfamily of dopamine receptors, but that striatal local circuit neurons do not possess members of the D1 subfamily of receptors.
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PMID:Immunohistochemical localization of DARPP-32 in striatal projection neurons and striatal interneurons: implications for the localization of D1-like dopamine receptors on different types of striatal neurons. 183 66

Grafted striatal neurons have previously been shown to receive innervation from both the host cerebral cortex and dopaminergic substantia nigra. In the present study, we have used quantitative in situ hybridization histochemistry for striatal neuropeptide mRNAs, to determine the extent of functional integration exhibited by these two afferent systems. DARPP-32, preproenkephalin (PPE) and preprotachykinin (PPT) mRNAs were all expressed within discrete patches of the graft (termed P-regions) which corresponded well with each other on adjacent sections. Dopamine-depleting 6-OHDA lesions resulted in a marked increase in PPE mRNA levels and a concomitant decrease in PPT mRNA expression both in the remaining host striatum and in the P-regions of the graft. In a previous report [7], we have shown that cortical and dopaminergic afferents to the striatum interact in the regulation of PPE mRNA expression, such that in the absence of functional dopaminergic inputs, intact prefrontal corticostriatal afferents are necessary in order to maintain increased PPE mRNA levels. In the present study, we observed that cortical knife cut lesions placed at the level of the foreceps minor in previously 6-OHDA-lesioned animals resulted in a normalization of PPE mRNA expression, not only in the remaining host striatum but also within the P-regions of striatal grafts. Cellular analysis showed that this normalization was most pronounced in the peripherally situated P-regions (along the graft borders), which are known to receive dense host-derived cortical input. The cortical lesions had no significant effect on the 6-OHDA-induced reduction of PPT mRNA levels neither in the remaining lost striatum nor in the striatal graft. The expression of DARPP-32 mRNA in the remaining host striatum or striatal graft was not affected by either 6-OHDA lesion or cortical transection, demonstrating the specificity of the cortical lesion effect. These results indicate that both cortical and dopaminergic afferents originating in the host, functionally regulate neuropeptide mRNA expression within the striatal grafts, and that the two afferent systems interact with each other in the regulation of enkephalin gene expression in grafted neurons. On basis of recent results [9] showing that the enkephalin-expressing neurons are identical, at least in part, to efferent graft neurons projecting to the host globus pallidus, it is proposed that the cortical-dopamine interaction demonstrated here may play an important role in the recovery of complex motor performance induced by the striatal transplants.
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PMID:Neurotransmitter-related gene expression in intrastriatal striatal transplants. III. Regulation by host cortical and dopaminergic afferents. 760 15

In the present study, we have re-examined the heterogeneous nature of intrastriatal striatal transplants derived from embryonic day 14-15 rat striatal primordia implanted into the previously excitotoxically lesioned striatum of adult rats, using in situ hybridization histochemistry to localize neurotransmitter-related messenger RNAs. These grafts are characterized by discrete patches of DARPP-32 messenger RNA expression, which cover approximately one-third of the cross-sectional graft area. The messenger RNAs encoding for preproenkephalin (the enkephalin precursor), preprotachykinin (precursor to substance P), choline acetyltransferase, as well as the D1 and D2 dopamine receptors, which are abundant in the normal striatum, were all present in the striatal grafts and were expressed almost exclusively in the DARPP-32-positive graft regions. In these graft regions, the expression of the neurotransmitter-related messenger RNAs was generally similar to that seen in the intact striatum, although the level of expression of preproenkephalin and preprotachykinin messenger RNAs varied notably among the patches of expression. Cellular analysis performed on individual patches showed that the expression per cell of preproenkephalin and preprotachykinin messenger RNAs was inversely related, such that patches with higher than normal preproenkephalin messenger RNA levels displayed lower than normal preprotachykinin messenger RNA levels, and vice versa. Moreover, messenger RNA expression for the dopamine D2 receptor was overall lower than that for the dopamine D1 receptor, both with respect to the level per cell and the number of positive cells within the DARPP-32 patches. Glutamate decarboxylase messenger RNA was expressed throughout the grafts, in 98% of all neurons located in the DARPP-32-positive regions and in 75% of all neurons in the non-DARPP-32 regions of the graft. Interestingly, the cellular expression of glutamate decarboxylase messenger RNA was considerably higher in the non-DARPP-32 expressing regions than that in the DARPP-32 messenger RNA-rich areas, where it approximated that of the intact striatum. Furthermore, grafted neurons located outside the DARPP-32-expressing regions displayed similar levels of expression to those found in the overlying cortex and in the closely adjacent globus pallidus. To further characterize the DARPP and non-DARPP graft compartments, messenger RNAs encoding the alpha 1 and beta 2 subunits of the GABAA receptor were studied. These receptor subunits, which exhibit a high expression in the host cortex and pallidum but little in the intact striatum, were found in discrete patches situated outside, but often closely associated with, the DARPP-32-rich areas of the graft.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neurotransmitter-related gene expression in intrastriatal striatal transplants--I. Phenotypical characterization of striatal and non-striatal graft regions. 770 3

The phenotypic characteristics of identified graft neurons in intrastriatal striatal transplants which give rise to efferent projections innervating the host brain were examined using a combination of in situ hybridization histochemistry and fluorescent retrograde tracing. Cell suspension grafts of embryonic day 14-15 rat striatal primordia (including both the medial and lateral ganglionic eminences) were implanted into the previously excitotoxically lesioned striatum of adult rats, and after longer than one year the retrograde tracer Fluoro-Gold was injected bilaterally into either the globus pallidus or the substantia nigra. Injections into the globus pallidus resulted in significant retrograde labelling of graft neurons within most of the experimental animals, whereas very few graft cells were labelled after the nigral injections. The vast majority of the neurons retrogradely labelled from the globus pallidus occurred in clusters or patches in the caudal half of the transplants, which corresponded well with DARPP-32 messenger RNA expressing (i.e. striatal) regions of the grafts. Indeed, within these Fluoro-Gold-labelled graft patches, the proportion of retrogradely labelled cells found to contain DARPP-32 messenger RNA was identical to that observed in the intact striatum after similar pallidal injections (93%). In addition, some Fluoro-Gold-labelled cells were found scattered outside the DARPP-32-positive cell clusters; these cells were overall larger and rarely (c. 9%) DARPP-32 messenger RNA-positive. Messenger RNA encoding for glutamate decarboxylase (which was found in 95% of Fluoro-Gold-labelled neurons in the intact striatum) was detected in almost all retrogradely labelled graft neurons located in both the DARPP-32-positive patches of retrograde labelling (93%) and in the DARPP-32-negative regions (82%). In the intact striatum, neurons labelled after pallidal injections of Fluoro-Gold were observed to express preproenkephalin messenger RNA to a greater extent than preprotachykinin messenger RNA (81% vs 21%). Conversely, within the grafts, retrogradely labelled neurons in the patches of Fluoro-Gold-labelled cells were more often found to contain preprotachykinin messenger RNA (50%) than preproenkephalin messenger RNA (21%). The Fluoro-Gold-labelled cells scattered outside the patches of retrograde labelling rarely expressed either preproenkephalin or preprotachykinin messenger RNA. Fluoro-Gold injections into the host substantia nigra resulted in very few retrogradely labelled graft neurons; however, many (85%) of these cells were observed to express glutamate decarboxylase messenger RNA, while only rarely were they observed to contain either DARPP-32, preproenkephalin or preprotachykinin messenger RNAs (c. 10%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neurotransmitter-related gene expression in intrastriatal striatal transplants--II. Characterization of efferent projecting graft neurons. 770 12

DARPP32 is a D1-receptor associated signaling protein found in striatal projection neurons in mammals, including both substance P-containing (SP+) neurons and enkephalinergic (ENK+) projection neurons. The present study used immunohistochemical single- and double-labeling to examine the cellular localization of DARPP32 in pigeon striatum. Single-label studies revealed that DARPP32 is present in numerous medium-sized striatal perikarya and DARPP32+ axons and terminals were seen to profusely innervate the two major striatal projection targets, the pallidum and the substantia nigra. The single-labeling studies indicated that about 60% of all striatal perikarya labeled for DARPP32+ in striatum, which exceeds the abundance of either SP+ or ENK+ perikarya. Single-labeling studies also showed that the abundance of DARPP32+ fibers and terminals in pallidum exceeds that of either SP+ or ENK+ fibers and terminals in pallidum. Double-labeling found that 30-50% of striatal SP+ perikarya and 7-24% of ENK+ striatal perikarya labeled for DARPP32 in pigeon, and confirmed that DARPP32 was found in both SP+ and ENK+ fibers and terminals in pallidum. In contrast to its prevalence in striatal projection neurons, DARPP32 was virtually absent from cholinergic and NPY+ striatal interneurons, as also true in mammals. Our data are consistent with the interpretation that many SP+ neurons and many ENK+ neurons in avian striatum possess D1-type dopamine receptors and use a DARPP32 signalling pathway, although this may be more common for SP+ than for ENK+ neurons.
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PMID:Immunohistochemical localization of DARPP32 in striatal projection neurons and striatal interneurons in pigeons. 992 70

The role of the dopamine- and cyclic AMP-regulated phosphoprotein of M(r) 32,000 (DARPP-32) in dopaminergic regulation of gene transcription in striatum and globus pallidus was examined. Mice with targeted disruption of the gene encoding DARPP-32, its homologue, inhibitor-1, or both, were used. Pharmacological characterization showed that mutant mice had normal basal levels of dopamine D(1) and D(2) receptors and adenosine A(2A) receptors. Basal expression levels of the striatonigral-specific neuropeptides substance P and prodynorphin and the immediate early genes c-fos and NGFI-A were also unaltered in mutant mice. A full D(1) receptor agonist, SKF 82958, up-regulated the expression of these neuropeptides and immediate early genes significantly more in wild-type mice than in mice lacking DARPP-32. Moreover, the additive stimulation of SKF 82958 and quinelorane, a D(2) receptor agonist, on c-fos mRNA in globus pallidus was significantly decreased in DARPP-32 and DARPP-32/I-1 knockout mice. No changes in dopamine receptor-induced gene expression were found in I-1 knockout mice. These results demonstrate an important involvement of DARPP-32 in dopamine receptor-mediated regulation of gene expression both in striatal neurons, which are enriched in DARPP-32, and in pallidal neurons, which do not contain DARPP-32.
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PMID:Dopamine D(1) receptor-induced gene transcription is modulated by DARPP-32. 1085 68

Area X is a nucleus within songbird basal ganglia that is part of the anterior forebrain song learning circuit. It receives cortical song-related input and projects to the dorsolateral medial nucleus of thalamus (DLM). We carried out single- and double-labeled immunohistochemical and pathway tracing studies in male zebra finch to characterize the cellular organization and circuitry of area X. We found that 5.4% of area X neuronal perikarya are relatively large, possess aspiny dendrites, and are rich in the pallidal neuron/striatal interneuron marker Lys8-Asn9-neurotensin8-13 (LANT6). Many of these perikarya were found to project to the DLM, and their traits suggest that they are pallidal. Area X also contained several neuron types characteristic of the striatum, including interneurons co-containing LANT6 and the striatal interneuron marker parvalbumin (2% of area X neurons), interneurons containing parvalbumin but not LANT6 (4.8%), cholinergic interneurons (1.4%), and neurons containing the striatal spiny projection neuron marker dopamine- and adenosine 3',5'-monophosphate-regulated phosphoprotein (DARPP-32) (30%). Area X was rich in substance P (SP)-containing terminals, and many ended on area X neurons projecting to the DLM with the woolly fiber morphology characteristic of striatopallidal terminals. Although SP+ perikarya were not detected in area X, prior studies suggest it is likely that SP-synthesizing neurons are present and the source of the SP+ input to area X neurons projecting to the DLM. Area X was poor in enkephalinergic fibers and perikarya. The present data support the premise that area X contains both striatal and pallidal neurons, with the striatal neurons likely to include SP+ neurons that project to the pallidal neurons.
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PMID:An immunohistochemical and pathway tracing study of the striatopallidal organization of area X in the male zebra finch. 1469 37

Identifying genes for bipolar mood disorders through classic genetics has proven difficult. Here, we present a comprehensive convergent approach that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a stimulant--methamphetamine, and a mood stabilizer--valproate), with human data (linkage loci from human genetic studies, changes in postmortem brains from patients), as a bayesian strategy of crossvalidating findings. Topping the list of candidate genes, we have DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) located at 17q12, PENK (preproenkephalin) located at 8q12.1, and TAC1 (tachykinin 1, substance P) located at 7q21.3. These data suggest that more primitive molecular mechanisms involved in pleasure and pain may have been recruited by evolution to play a role in higher mental functions such as mood. The analysis also revealed other high-probability candidates genes (neurogenesis, neurotrophic, neurotransmitter, signal transduction, circadian, synaptic, and myelin related), pathways and mechanisms of likely importance in pathophysiology.
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PMID:Candidate genes, pathways and mechanisms for bipolar (manic-depressive) and related disorders: an expanded convergent functional genomics approach. 1531 10

Ependymal overexpression of brain-derived neurotrophic factor (BDNF) stimulates neuronal addition to the adult striatum, from subependymal progenitor cells. Noggin, by suppressing subependymal gliogenesis and increasing progenitor availability, potentiates this process. We asked whether BDNF/Noggin overexpression might be used to recruit new striatal neurons in R6/2 huntingtin transgenic mice. R6/2 mice injected with adenoviral BDNF and adenoviral Noggin (AdBDNF/AdNoggin) recruited BrdU(+)betaIII-tubulin(+) neurons, which developed as DARPP-32(+) and GABAergic medium spiny neurons that expressed either enkephalin or substance P and extended fibers to the globus pallidus. Only AdBDNF/AdNoggin-treated R6/2 mice harbored migrating doublecortin-defined neuroblasts in their striata, and the new neurons expressed p27 as a marker of mitotic quiescence after parenchymal integration. AdBDNF/AdNoggin-treated R6/2 mice sustained their rotarod performance and open-field activity and survived longer than did AdNull-treated and untreated controls. Neither motor performance nor survival improved in R6/2 mice treated only with AdBDNF, and intraventricular infusion of the mitotic inhibitor Ara-C completely blocked the performance and survival effects of AdBDNF/AdNoggin, suggesting that the benefits of AdBDNF/AdNoggin derived from neuronal addition. Thus, BDNF and Noggin induced striatal neuronal regeneration, delayed motor impairment, and extended survival in R6/2 mice, suggesting a new therapeutic strategy in Huntington disease.
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PMID:Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease. 1788 87