| 1 | Neuroscience 2008 Jun 154: 701-9 |
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| PMID | 18495356 |
| Title | Preliminary evidence for a modulation of fetal dopaminergic development by maternal immune activation during pregnancy. |
| Abstract | Maternal infection during pregnancy is an environmental risk factor for the offspring to develop severe brain disorders, including schizophrenia and autism. However, only little is known about the neurodevelopmental mechanisms underlying the association between prenatal exposure to infection and the emergence of brain and behavioral dysfunctions in later life. Using a mouse model of prenatal immune challenge by the viral mimic polyriboinosinic-polyribocytidilic acid (PolyI:C), we explored the acute effects of maternal immune activation during pregnancy on the development of the fetal dopaminergic system, a neurotransmitter system known to be affected in schizophrenia and related disorders. We found that maternal immunological stimulation in early/middle pregnancy increased the number of mesencephalic dopamine neurons in the fetal brain at middle/late and late gestation. This effect was paralleled by changes in fetal expression of several genes known to be involved in dopamine neuron development, including the inductive signals sonic hedgehog (SHH) and fibroblast growth factor 8 (Fgf8), as well as transcription factors Nurr1 and Pitx3. These findings provide initial in vivo evidence for a modulation of fetal dopaminergic development by maternal immune activation during pregnancy. Additional investigations of the neurodevelopmental effects of prenatal immune challenge are thus clearly warranted in order to further validate whether abnormal dopaminergic development may be a critical neuropathological mechanism underlying the precipitation of schizophrenia-like brain and behavioral dysfunctions emerging after in utero exposure to infection. |
| SCZ Keywords | schizophrenia |
| 2 | Cell Tissue Res. 2009 Apr 336: 11-20 |
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| PMID | 19224248 |
| Title | Characterization of primary neurospheres generated from mouse ventral rostral hindbrain. |
| Abstract | Serotonergic (5-HT) neurons of the reticular formation play a key role in the modulation of behavior, and their dysfunction is associated with severe neurological and psychiatric disorders, such as depression and schizophrenia. However, the molecular mechanisms underlying the differentiation of the progenitor cells and the specification of the 5-HT phenotype are not fully understood. A primary neurosphere cell-culture system from mouse ventral rostral hindbrain at embryonic day 12 was therefore established. The generated primary neurospheres comprised progenitor cells and fully differentiated neurons. Bromodeoxyuridine incorporation experiments in combination with immunocytochemistry for neural markers revealed the proliferation capacity of the neural multipotent hindbrain progenitors within neurospheres and their ability to differentiate toward the neuronal lineage and serotonergic phenotype. Gene expression analysis by reverse transcription with the polymerase chain reaction showed that the neurospheres were regionally specified, as reflected by the expression of the transcription factors Gata2 and Pet1. Treatment of dissociated primary neurospheres with exogenous SHH significantly increased the number of 5-HT-immunopositive cells compared with controls, whereas neutralization of endogenous SHH significantly decreased the number of 5-HT neurons. Thus, the primary neurosphere culture system presented here allows the expansion of hindbrain progenitor cells and the experimental control of their differentiation toward the serotonergic phenotype. This culture system is therefore a useful model for in vitro studies dealing with the development of 5-HT neurons. |
| SCZ Keywords | schizophrenia |
| 3 | Proc. Natl. Acad. Sci. U.S.A. 2009 Nov 106: 19185-90 |
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| PMID | 19850875 |
| Title | Spatiotemporally separable Shh domains in the midbrain define distinct dopaminergic progenitor pools. |
| Abstract | Midbrain dopamine neurons (mDA) are important regulators of diverse physiological functions, including movement, attention, and reward behaviors. Accordingly, aberrant function of dopamine neurons underlies a wide spectrum of disorders, such as Parkinson's disease (PD), dystonia, and schizophrenia. The distinct functions of the dopamine system are carried out by neuroanatomically discrete subgroups of dopamine neurons, which differ in gene expression, axonal projections, and susceptibility in PD. The developmental underpinnings of this heterogeneity are undefined. We have recently shown that in the embryonic CNS, mDA originate from the midbrain floor plate, a ventral midline structure that is operationally defined by the expression of the molecule SHH. Here, we develop these findings to reveal that in the embryonic midbrain, the spatiotemporally dynamic SHH domain defines multiple progenitor pools. We deduce 3 distinct progenitor pools, medial, intermediate, and lateral, which contribute to different mDA clusters. The earliest progenitors to express SHH, here referred to as the medial pool, contributes neurons to the rostral linear nucleus and mDA of the ventral tegmental area/interfascicular regions, but remarkably, little to the substantia nigra pars compacta. The intermediate SHH+ progenitors give rise to neurons of all dopaminergic nuclei, including the SNpc. The last and lateral pool of SHH+ progenitors generates a cohort that populates the red nucleus, Edinger Westphal nucleus, and supraoculomotor nucleus and cap. Subsequently, these lateral SHH+ progenitors produce mDA. This refined ontogenetic definition will expand understanding of dopamine neuron biology and selective susceptibility, and will impact stem cell-derived therapies and models for PD. |
| SCZ Keywords | schizophrenia |
| 4 | Cell Stem Cell 2013 May 12: 559-72 |
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| PMID | 23642365 |
| Title | Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. |
| Abstract | Human pluripotent stem cells are a powerful tool for modeling brain development and disease. The human cortex is composed of two major neuronal populations: projection neurons and local interneurons. Cortical interneurons comprise a diverse class of cell types expressing the neurotransmitter GABA. Dysfunction of cortical interneurons has been implicated in neuropsychiatric diseases, including schizophrenia, autism, and epilepsy. Here, we demonstrate the highly efficient derivation of human cortical interneurons in an NKX2.1::GFP human embryonic stem cell reporter line. Manipulating the timing of SHH activation yields three distinct GFP+ populations with specific transcriptional profiles, neurotransmitter phenotypes, and migratory behaviors. Further differentiation in a murine cortical environment yields parvalbumin- and somatostatin-expressing neurons that exhibit synaptic inputs and electrophysiological properties of cortical interneurons. Our study defines the signals sufficient for modeling human ventral forebrain development in vitro and lays the foundation for studying cortical interneuron involvement in human disease pathology. |
| SCZ Keywords | schizophrenia |
| 5 | Stem Cell Res 2013 Jul 11: 647-56 |
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| PMID | 23672829 |
| Title | Enhanced derivation of mouse ESC-derived cortical interneurons by expression of Nkx2.1. |
| Abstract | Forebrain GABAergic interneurons are divided into subgroups based on their neurochemical markers, connectivity and physiological properties. Abnormal interneuron function is implicated in the pathobiology of neurological disorders such as schizophrenia, autism, and epilepsy. Studies on interneuron development and their role in disease would benefit from an efficient mechanism for the production and selection of specific interneuron subgroups. In this study, we engineered a mouse embryonic stem cell (mESC) line for doxycycline-inducible expression of Nkx2.1, a required transcription factor for cortical interneurons derived from the medial ganglionic eminence (MGE). This mESC line was modified to express GFP in Lhx6(+) cells, a marker of newly postmitotic and mature MGE-derived cortical interneurons. The addition of doxycycline to differentiating ESCs efficiently induced Nkx2.1 protein and increased the production of GFP(+) cells. Transplantation of GFP(+) putative interneuron precursors resulted in migratory, morphological, and neurochemical features consistent with cortical interneuron fates. To test the hypothesis that Sonic hedgehog (SHH) primarily influences cortical interneuron fate determination through the induction of Nkx2.1, ESCs were grown with doxycycline and the SHH antagonist cyclopamine. We found induced Nkx2.1 renders SHH signaling dispensable for the generation of MGE-derived interneurons. These results demonstrate that inducible expression of fate determining genes in embryonic stem cells can be used to study fate determination of the developing forebrain. |
| SCZ Keywords | schizophrenia |
| 6 | Stem Cells 2014 Jul 32: 1789-804 |
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| PMID | 24648391 |
| Title | Efficient specification of interneurons from human pluripotent stem cells by dorsoventral and rostrocaudal modulation. |
| Abstract | GABAergic interneurons regulate cortical neural networks by providing inhibitory inputs, and their malfunction, resulting in failure to intricately regulate neural circuit balance, is implicated in brain diseases such as schizophrenia, Autism, and Epilepsy. During early development, GABAergic interneuron progenitors arise from the ventral telencephalic area such as medial ganglionic eminence (MGE) and caudal ganglionic eminence (CGE) by the actions of secreted signaling molecules from nearby organizers, and migrate to their target sites where they form local synaptic connections. In this study, using combinatorial and temporal modulation of developmentally relevant dorsoventral and rostrocaudal signaling pathways (SHH, Wnt, and FGF8), we efficiently generated MGE cells from multiple human pluripotent stem cells. Most importantly, modulation of FGF8/FGF19 signaling efficiently directed MGE versus CGE differentiation. Human MGE cells spontaneously differentiated into Lhx6-expressing GABAergic interneurons and showed migratory properties. These human MGE-derived neurons generated GABA, fired action potentials, and displayed robust GABAergic postsynaptic activity. Transplantation into rodent brains results in well-contained neural grafts enriched with GABAergic interneurons that migrate in the host and mature to express somatostatin or parvalbumin. Thus, we propose that signaling modulation recapitulating normal developmental patterns efficiently generate human GABAergic interneurons. This strategy represents a novel tool in regenerative medicine, developmental studies, disease modeling, bioassay, and drug screening. |
| SCZ Keywords | schizophrenia |
| 7 | Biol Open 2015 -1 4: 1336-43 |
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| PMID | 26405049 |
| Title | Sonic hedgehog functions upstream of disrupted-in-schizophrenia 1 (disc1): implications for mental illness. |
| Abstract | DISRUPTED-IN-schizophrenia (DISC1) has been one of the most intensively studied genetic risk factors for mental illness since it was discovered through positional mapping of a translocation breakpoint in a large Scottish family where a balanced chromosomal translocation was found to segregate with schizophrenia and affective disorders. While the evidence for it being central to disease pathogenesis in the original Scottish family is compelling, recent genome-wide association studies have not found evidence for common variants at the DISC1 locus being associated with schizophrenia in the wider population. It may therefore be the case that DISC1 provides an indication of biological pathways that are central to mental health issues and functional studies have shown that it functions in multiple signalling pathways. However, there is little information regarding factors that function upstream of DISC1 to regulate its expression and function. We herein demonstrate that Sonic hedgehog (SHH) signalling promotes expression of disc1 in the zebrafish brain. Expression of disc1 is lost in smoothened mutants that have a complete loss of SHH signal transduction, and elevated in patched mutants which have constitutive activation of SHH signalling. We previously demonstrated that disc1 knockdown has a dramatic effect on the specification of oligodendrocyte precursor cells (OPC) in the hindbrain and SHH signalling is known to be essential for the specification of these cells. We show that disc1 is prominently expressed in olig2-positive midline progenitor cells that are absent in smo mutants, while cyclopamine treatment blocks disc1 expression in these cells and mimics the effect of disc1 knock down on OPC specification. Various features of a number of psychiatric conditions could potentially arise through aberrant Hedgehog signalling. We therefore suggest that altered SHH signalling may be an important neurodevelopmental factor in the pathobiology of mental illness. |
| SCZ Keywords | schizophrenia |