| 1 | Mol. Psychiatry 2005 Jun 10: 606-12 |
|---|---|
| PMID | 15534618 |
| 标题 | Netrin receptor deficient mice exhibit functional reorganization of dopaminergic systems and do not sensitize to amphetamine. |
| Abstract | Netrins are guidance cues that play a fundamental role in organizing the developing brain. The netrin receptor,DCC（在结直肠癌中删除），由多巴胺能（DA）神经元高度表达。DCCmay therefore participate in the organization of DA circuitry during development and also influence DA function in the adult. Here we show that adultDCCheterozygous mice exhibit a blunted behavioral response to the indirect DA agonist amphetamine and do not develop sensitization to its effects when treated repeatedly. These behavioral alterations are associated with profound changes in DA function. In the medial prefrontal cortex,DCC杂合子表现出增加的酪氨酸羟化酶（Th）蛋白水平，并且DA和DA代谢产物的基础浓度显着增加。相反，在伏隔核中，DCCheterozygotes show no changes in either TH or DA levels, but exhibit decreased concentrations of DA metabolites, suggesting reduced DA activity. In addition,DCCheterozygous mice exhibit a small, but significant reduction in total number of TH-positive neurons in midbrain DA cell body regions. These results demonstrate for the first time that alterations inDCCexpression lead to selective changes in DA function and, in turn, to differences in DA-related behaviors in adulthood. These findings raise the possibility that changes inDCCfunction early in life are implicated in the development of DA dysregulation observed in certain psychiatric disorders, such asschizophrenia, or following chronic use of drugs of abuse. |
| SCZ关键字 | schizophrenia, schizophrenic |
| 2 | 欧元。J. Neurosci。2007 Dec 26: 3215-28 |
| PMID | 18005074 |
| 标题 | Netrin-1 receptor-deficient mice show enhanced mesocortical dopamine transmission and blunted behavioural responses to amphetamine. |
| Abstract | The mesocorticolimbic dopamine (DA) system is implicated in neurodevelopmental psychiatric disorders includingschizophreniabut it is unknown how disruptions in brain development modify this system and increase predisposition to cognitive and behavioural abnormalities in adulthood. Netrins are guidance cues involved in the proper organization of neuronal connectivity during development. We have hypothesized that variations in the function ofDCC(deleted in colorectal cancer), a netrin-1 receptor highly expressed by DA neurones, may result in altered development and organization of mesocorticolimbic DA circuitry, and influence DA function in the adult. To test this hypothesis, we assessed the effects of reducedDCC在DA函数的几个指标上。使用体内微透析，我们表明成年小鼠的发展降低DCCdisplay increased basal DA levels in the medial prefrontal cortex and exaggerated DA release in response to the indirect DA agonist amphetamine. In contrast, these mice exhibit normal levels of DA in the nucleus accumbens but significantly blunted amphetamine-induced DA release. Concomitantly, using conditioned place preference, locomotor activity and prepulse inhibition paradigms, we found that reducedDCCdiminishes the rewarding and behavioural-activating effects of amphetamine and protects against amphetamine-induced deficits in sensorimotor gating. Furthermore, we found that adultDCC-deficient mice exhibit altered dendritic spine density in layer V medial prefrontal cortex pyramidal neurones but not in nucleus accumbens medium spiny neurones. These findings demonstrate that reducedDCCduring development results in a behavioural phenotype opposite to that observed in developmental models ofschizophreniaand identifyDCCas a critical factor in the development of DA function. |
| SCZ关键字 | schizophrenia, schizophrenic |
| 3 | 欧元。J. Neurosci。2009年10月30日：1318-28 |
| PMID | 19788579 |
| 标题 | Post-pubertal emergence of a dopamine phenotype in netrin-1 receptor-deficient mice. |
| Abstract | During the pubertal period the mesocortical dopamine (DA) system undergoes substantial reorganization of neuronal connectivity and functional refinement. Netrins are guidance cues involved in the organization of neuronal circuitry. We have previously shown that adult mice that develop with reduced levels of the netrin-1 receptor [deleted in colorectal cancer (DCC]]显示中皮质DA回路的选择性重组，显示出增强的中皮层DA功能，并表现出与在动物模型中观察到的行为表型相反的行为表型schizophrenia。Here we assess whether theDCCbehavioural and DA phenotypes are present prior to the maturation of the mesocortical DA system by comparingDCC-heterozygous and wild-type mice at the post-weaning and peri-pubertal periods on various indices of DA function. At both the post-weaning and peri-pubertal ages, but unlike in adulthood,DCC-heterozygous and wild-type mice show no differences in the number of midbrain DA neurones or in tyrosine hydroxylase protein levels in the medial prefrontal cortex. Furthermore, the elevated baseline concentration of mesocortical DA and DA metabolites observed in adultDCC-heterozygous mice is not present in either post-weanling or peri-pubertal mice. Interestingly, post-weanling, but not peri-pubertal,DCC-heterozygous mice show greater baseline concentrations of DA metabolites in the nucleus accumbens, opposite to what was observed in adulthood. Finally, neither post-weanling nor peri-pubertalDCC- 杂合小鼠证明了成年后观察到的钝化苯丙胺诱导的运动反应。因此，这些发现表明“保护”DCCphenotype has a post-pubertal emergence and indicate thatDCC可能在中皮质胶质BID DA系统的正常成熟中发挥作用。 |
| SCZ关键字 | schizophrenia, schizophrenic |
| 4 | Synapse 2009 Jan 63: 54-60 |
| PMID | 18932228 |
| 标题 | Altered netrin-1 receptor expression in dopamine terminal regions following neonatal ventral hippocampal lesions in the rat. |
| Abstract | 大鼠的新生儿腹侧海马（NVH）病变，该病变建模schizophrenia, alter dopamine (DA)-mediated behaviors in adulthood. The precise mechanisms underlying these effects remain elusive; however, neuronal reorganization within the medial prefrontal cortex (mPFC) has been suggested. Netrins are developmental cues that organize brain wiring, including the mesocorticolimbic DA circuitry. We showed recently that the netrin-1 receptorsDCCand UNC5H are highly expressed by DA neurons and that variation inDCClevels during development lead to profound changes in mesocorticolimbic DA function and behavior in adulthood. We hypothesized that changes in netrin-1 receptor function could be one of the mechanisms producing enduring changes in DA function in nVH-lesioned animals. To begin to explore this idea, we examined the effects of nVH lesions onDCC并在大脑区域接收ro UNC5H表达式bust DA innervation; the mPFC, striatum, and nucleus accumbens (NAcc) at three developmental time points; 3 days after lesion, before puberty and during early adulthood. Expression was also examined in the cerebellar simple lobule; a brain region deprived of DA innervation. Neonatal VH lesions produced dynamic changes inDCCMPFC和NACC中的表达。这些变化的方向和幅度取决于所检查的发育年龄和大脑区域，并且特定于接受DA神经的区域。尽管需要进一步的研究来了解这些变化的功能意义，但这些结果提出了有趣的可能性，即NVH病变和围产期损伤通常可以通过调节Netrin-1功能来发挥其神经元重组作用。 |
| SCZ关键字 | schizophrenia, schizophrenic |
| 5 | Schizophr. Res. 2012 May 137: 26-31 |
| PMID | 22418395 |
| 标题 | Association between schizophrenia and genetic variation in DCC: a case-control study. |
| Abstract | schizophreniais a highly heritable neurodevelopmental disorder associated with alterations in synaptic connectivity. Deleted in colorectal cancer (DCC), a receptor for the guidance cue netrin-1, plays a pivotal role in organizing neuronal circuitry by guiding growing axons and dendrites to their correct targets and by influencing synaptic connectivity. Results from experiments we previously conducted inDCC-heterozygous mice show thatDCC在中皮质糖多巴胺（DA）电路的发展组织中起着至关重要的作用。此外，我们已经证明了降低的表达DCCduring development and/or throughout life confers resilience to the development ofschizophrenia-like DA and behavioural abnormalities. Importantly, this "protective" phenotype only emerges after puberty. Here we assess whetherDCCmay contribute to the risk ofschizophrenia。We examined single nucleotide polymorphisms (SNPs) located in theDCC基因与schizophreniausing a case-control sample consisting of 556 unrelatedschizophrenicpatients and 208 healthy controls. We found one SNP, rs2270954, to be nominally associated withschizophrenia; patients were less likely to be heterozygous at this locus and more likely to be homozygous for the minor allele (?(2)=9.84, df=2, nominal p=0.0071). Intriguingly, this SNP is located within the 3' untranslated region, an area known to contain a number of regulatory sequences that determine the stability and translation efficacy of mRNA. These results, together with our previous findings from studies in rodents, point atDCCas a promising novel candidate gene that may contribute to the genetic basis behind individual differences in susceptibility toschizophrenia。 |
| SCZ关键字 | schizophrenia, schizophrenic |
| 6 | Schizophr. Res. 2012 May 137: 26-31 |
| PMID | 22418395 |
| 标题 | Association between schizophrenia and genetic variation in DCC: a case-control study. |
| Abstract | schizophreniais a highly heritable neurodevelopmental disorder associated with alterations in synaptic connectivity. Deleted in colorectal cancer (DCC), a receptor for the guidance cue netrin-1, plays a pivotal role in organizing neuronal circuitry by guiding growing axons and dendrites to their correct targets and by influencing synaptic connectivity. Results from experiments we previously conducted inDCC-heterozygous mice show thatDCC在中皮质糖多巴胺（DA）电路的发展组织中起着至关重要的作用。此外，我们已经证明了降低的表达DCCduring development and/or throughout life confers resilience to the development ofschizophrenia-like DA and behavioural abnormalities. Importantly, this "protective" phenotype only emerges after puberty. Here we assess whetherDCCmay contribute to the risk ofschizophrenia。We examined single nucleotide polymorphisms (SNPs) located in theDCC基因与schizophreniausing a case-control sample consisting of 556 unrelatedschizophrenicpatients and 208 healthy controls. We found one SNP, rs2270954, to be nominally associated withschizophrenia; patients were less likely to be heterozygous at this locus and more likely to be homozygous for the minor allele (?(2)=9.84, df=2, nominal p=0.0071). Intriguingly, this SNP is located within the 3' untranslated region, an area known to contain a number of regulatory sequences that determine the stability and translation efficacy of mRNA. These results, together with our previous findings from studies in rodents, point atDCCas a promising novel candidate gene that may contribute to the genetic basis behind individual differences in susceptibility toschizophrenia。 |
| SCZ关键字 | schizophrenia, schizophrenic |
| 7 | Immunopharmacol Immunotoxicol 2013 Oct 35: 581-93 |
| PMID | 23981041 |
| 标题 | Prenatal activation of maternal TLR3 receptors by viral-mimetic poly(I:C) modifies GluN2B expression in embryos and sonic hedgehog in offspring in the absence of kynurenine pathway activation. |
| Abstract | 我怀孕期间的激活免疫系统s believed to lead to psychiatric and neurological disorders in the offspring, but the molecular changes responsible are unknown. Polyinosinic:polycytidylic acid (poly(I:C)) is a viral-mimetic double-stranded RNA complex which activates Toll-Like-Receptor-3 and can activate the metabolism of tryptophan through the oxidative kynurenine pathway to compounds that modulate activity of glutamate receptors. The aim was to determine whether prenatal administration of poly(I:C) affects the expression of neurodevelopmental proteins in the offspring and whether such effects were mediated via the kynurenine pathway. Pregnant rats were treated with poly(I:C) during late gestation and the offspring were allowed to develop to postnatal day 21 (P21). Immunoblotting of the brains at P21 showed decreased expression of sonic hedgehog, a key protein in dopaminergic neuronal maturation. Expression of ?-synuclein was decreased, while tyrosine hydroxylase was increased. Disrupted inschizophrenia-1 (DISC-1) and 5-HT2C receptor levels were unaffected, as were the dependence receptors Unc5H1, Unc5H3 and Deleted in Colorectal Cancer (DCC), the inflammation-related transcription factor NFkB and the inducible oxidative enzyme cyclo-oxygenase-2 (COX-2). An examination of embryo brains 5?h after maternal poly(I:C) showed increased expression of GluN2B, with reduced doublecortin andDCCbut no change in NFkB. Despite altered protein expression, there were no changes in the kynurenine pathway. The results show that maternal exposure to poly(I:C) alters the expression of proteins in the embryos and offspring which may affect the development of dopaminergic function. The oxidation of tryptophan along the kynurenine pathway is not involved in these effects. |
| SCZ关键字 | schizophrenia, schizophrenic |
| 8 | 欧元。J. Neurosci。2013 Sep 38: 2853-63 |
| PMID | 23738838 |
| 标题 | UNC5C单倍型表型：与DCC单倍度不足模型的惊人相似之处。 |
| Abstract | DCCand UNC5 homologs (UNC5H) are guidance cue receptors highly expressed by mesocorticolimbic dopamine neurons. We have shown thatDCCheterozygous mice exhibit increased dopamine, but not norepinephrine, innervation and function in medial prefrontal cortex. Concomitantly,DCC杂合子表现出钝性的中唇糖多巴胺释放和对刺激药物的行为反应。这些变化仅在成年期才出现。最近，我们发现多巴胺神经元的UNC5H表达的青春期出现和共表达DCCand UNC5H by single dopamine cells. Here, we demonstrate selective expression of unc5 homolog c mRNA by dopamine neurons in adulthood. We show that unc5c haploinsufficiency results in diminished amphetamine-induced locomotion in male and female mice. This phenotype is identical to that produced byDCChaploinsufficiency and is observed after adolescence. Notably, and similar toDCC单倍不足，UNC5C单倍不足导致内侧前额叶皮层中酪氨酸羟化酶表达的急剧增加，但在伏隔核中不会显着增加。相反，内侧前额叶皮层多巴胺 - ？ - 羟化酶表达没有改变。我们确认UNC5C蛋白在UNC5C杂合小鼠的腹侧换段区域降低，但DCCexpression in this region remains unchanged. UNC5C receptors may also play a role in dopamine function and influence sensitivity to behavioral effects of stimulant drugs of abuse, at least upon first exposure. The striking similarities between theDCCand the unc5c haploinsufficient phenotypes raise the possibility that functions mediated byDCC/UNC5C complexes may be at play. |
| SCZ关键字 | schizophrenia, schizophrenic |
| 9 | Neurosci. Lett. 2014 Jul 575: 58-62 |
| PMID | 24861518 |
| 标题 | Haloperidol treatment downregulates DCC expression in the ventral tegmental area. |
| Abstract | 病理生理学的核心特征schizophreniais abnormal development and function of mesocorticolimbic dopamine (DA) circuitry. We have previously shown that variations in the function of the netrin-1 receptor, deleted in colorectal cancer (DCC), result in changes to the development, organization and ongoing plasticity of DA circuitry. In rodents, repeated exposure to the indirect DA-agonist, amphetamine upregulatesDCCexpression in the ventral tegmental area (VTA), but not in DA terminal regions. This elevation inDCCexpression is associated with increased vulnerability to developing and maintaining sensitized mesolimbic DA function. Antipsychotic medications remain the best treatment option for managing the symptoms inschizophrenia。The peak effects of these medications are gradual, suggesting that a therapeutic component of antipsychotic treatment involves structural reorganization. Here we assessed whether repeated exposure to typical and atypical antipsychotics could also regulateDCC。Adult mice were orally administered haloperidol, clozapine, or risperidone via their drinking water for 4 weeks. Levels ofDCCwere measured by Western blot analysis of tissue punches of the VTA, medial prefrontal cortex, nucleus accumbens, and dorsal striatum. Haloperidol decreasedDCClevels by approximately 50% in the VTA, but not in DA targets. Furthermore, haloperidol did not alter UNC-5 homologue levels, another family of netrin-1 receptors, confirming that its effects targetDCC-mediated netrin-1 signaling specifically. The atypical antipsychotics did not alterDCCexpression. These results suggest that typical antipsychotics induce selective functional reorganization in the VTA viaDCC-mediated netrin-1 signaling. |
| SCZ关键字 | schizophrenia, schizophrenic |
| 10 | J. Mol. Neurosci. 2016 Apr -1: -1 |
| PMID | 27055860 |
| 标题 | An Association Study Between Genetic Polymorphisms in Functional Regions of Five Genes and the Risk of Schizophrenia. |
| Abstract | schizophreniais a severe mental disorder that is likely to be strongly determined by genetic factors. To identify markers of disks, large homolog 2 (DLG2), FAT atypical cadherin 3 (FAT3), kinectin1 (KTN1), deleted in colorectal carcinoma (DCC), and glycogen synthase kinase-3? (GSK3?) that contribute to the genetic susceptibility toschizophrenia,我们系统地polymorphi筛查sms in the functional regions of these genes. A total of 22 functional single-nucleotide polymorphisms (SNPs) in 940 Chinese subjects were genotyped using SNaPshot. The results first suggested that the allelic and genotypic frequencies of theDCCpolymorphism rs2229080 were nominally associated withschizophrenia。患者的可能性较小的CC纯合可能（p = =�0.005，优势比[或] = = �0.635，95％置信区间[95％CI] = 0.0.462-0.873）和schizophreniasubjects exhibited lower frequency of the C allele (P�=�0.024, OR�=�0.811, 95�% CI�=�0.676-0.972). Regarding GSK3?, there was a significant difference in genotype distribution of rs3755557 betweenschizophreniaand healthy control subjects (P�=�0.009). The patients exhibited a significantly lower frequency of the T allele of rs3755557 (P�=�0.002, OR�=�0.654, 95�% CI�=�0.498-0.860). Our results point to the polymorphisms ofDCCand GSK3? as contributors to the genetic basis of individual differences in the susceptibility toschizophrenia。 |
| SCZ关键字 | schizophrenia, schizophrenic |