| 1 | Development 2010 Sep 137: 3089-97 |
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| PMID | 20702565 |
| Title | An SNP in an ultraconserved regulatory element affects Dlx5/Dlx6 regulation in the forebrain. |
| Abstract | Dlx homeobox genes play a crucial role in the migration and differentiation of the subpallial precursor cells that give rise to various subtypes of gamma-aminobutyric acid (GABA)-expressing neurons of the forebrain, including local-circuit cortical interneurons. Aberrant development of GABAergic interneurons has been linked to several neurodevelopmental disorders, including epilepsy, schizophrenia, Rett syndrome and autism. Here, we report in mice that a single-nucleotide polymorphism (SNP) found in an autistic proband falls within a functional protein binding site in an ultraconserved cis-regulatory element. This element, I56i, is involved in regulating DLX5/Dlx6 homeobox gene expression in the developing forebrain. We show that the SNP results in reduced I56i activity, predominantly in the medial and caudal ganglionic eminences and in streams of neurons tangentially migrating to the cortex. Reduced activity is also observed in GABAergic interneurons of the adult somatosensory cortex. The SNP affects the affinity of Dlx proteins for their binding site in vitro and reduces the transcriptional activation of the enhancer by Dlx proteins. Affinity purification using I56i sequences led to the identification of a novel regulator of Dlx gene expression, general transcription factor 2 I (Gtf2i), which is among the genes most often deleted in Williams-Beuren syndrome, a neurodevelopmental disorder. This study illustrates the clear functional consequences of a single nucleotide variation in an ultraconserved non-coding sequence in the context of developmental abnormalities associated with disease. |
| SCZ Keywords | schizophrenia |
| 2 | Neuroscience 2014 Mar 261: 107-17 |
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| PMID | 24374327 |
| Title | Neuregulin 1/ErbB4 enhances synchronized oscillations of prefrontal cortex neurons via inhibitory synapses. |
| Abstract | Both neuregulin 1 (NRG1) and its receptor ErbB4 are susceptibility genes for schizophrenia. Reduced synchronization of evoked oscillations in several cortical regions, especially in the prefrontal cortex, is associated with the core symptoms of schizophrenia. Recent studies have reported that NRG1 may affect the hippocampal oscillations. However, the role of NRG1/ErbB4 signaling in the synchronization of neurons in the prefrontal cortex is unclear. Here, we found that NRG1 enhanced the synchrony of pyramidal neurons via presynaptic interneurons. Meanwhile, NRG1 also increased the synchrony between pairs of fast-spiking interneurons and pairs of fast-spiking and non-fast-spiking interneurons in the prefrontal cortex, and this effect was mediated by ErbB4 receptors. Moreover, the NRG1-enhanced synchrony of interneurons was through their mutually-inhibitory synapses but not electrical coupling. Furthermore, kainate-induced gamma oscillations in vivo were enhanced by NRG1 and did not change in DLX5/6-ErbB4(-/-) mice in which the ErbB4 receptors were specifically knocked out in interneurons of the frontal brain. Overall, our findings suggested that NRG1/ErbB4 signaling plays an important role in the synchronized oscillations of the whole network in the prefrontal cortex that are impaired in schizophrenia. |
| SCZ Keywords | schizophrenia |
| 3 | Neuron 2015 Mar 85: 1332-43 |
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| PMID | 25754826 |
| Title | Gamma rhythms link prefrontal interneuron dysfunction with cognitive inflexibility in Dlx5/6(+/-) mice. |
| Abstract | Abnormalities in GABAergic interneurons, particularly fast-spiking interneurons (FSINs) that generate gamma (?; ?30-120 Hz) oscillations, are hypothesized to disrupt prefrontal cortex (PFC)-dependent cognition in schizophrenia. Although ? rhythms are abnormal in schizophrenia, it remains unclear whether they directly influence cognition. Mechanisms underlying schizophrenia's typical post-adolescent onset also remain elusive. We addressed these issues using mice heterozygous for DLX5/6, which regulate GABAergic interneuron development. In DLX5/6(+/-) mice, FSINs become abnormal following adolescence, coinciding with the onset of cognitive inflexibility and deficient task-evoked ? oscillations. Inhibiting PFC interneurons in control mice reproduced these deficits, whereas stimulating them at ?-frequencies restored cognitive flexibility in adult DLX5/6(+/-) mice. These pro-cognitive effects were frequency specific and persistent. These findings elucidate a mechanism whereby abnormal FSIN development may contribute to the post-adolescent onset of schizophrenia endophenotypes. Furthermore, they demonstrate a causal, potentially therapeutic, role for PFC interneuron-driven ? oscillations in cognitive domains at the core of schizophrenia. |
| SCZ Keywords | schizophrenia |
| 4 | Schizophr. Res. 2016 Mar -1: -1 |
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| PMID | 26972474 |
| Title | Altered expression of developmental regulators of parvalbumin and somatostatin neurons in the prefrontal cortex in schizophrenia. |
| Abstract | Dysfunction of prefrontal cortex (PFC) inhibitory neurons that express the calcium-binding protein parvalbumin or the neuropeptide somatostatin in schizophrenia may be related to disturbances in the migration, phenotypic specification, and/or maturation of these neurons. These pre- and postnatal developmental stages are regulated in a cell type-specific manner by various transcription factors and co-activators, fibroblast growth factor receptors (FgfR), and other molecular markers. Consequently, we used quantitative PCR to quantify mRNA levels for these developmental regulators in the PFC of 62 schizophrenia subjects in whom parvalbumin and somatostatin neuron disturbances were previously reported, and in antipsychotic-exposed monkeys. Relative to unaffected comparison subjects, subjects with schizophrenia exhibited elevated mRNA levels for 1) the transcription factor MafB, which is expressed by parvalbumin and somatostatin neurons as they migrate from the medial ganglionic eminence to the cortex, 2) the transcriptional coactivator PGC-1?, which is expressed postnatally by parvalbumin neurons to maintain parvalbumin levels and inhibitory function, and 3) FgfR1, which is required for the migration and phenotypic specification of parvalbumin and somatostatin neurons. Elevations in these markers were most prominent in younger schizophrenia subjects and were not present in antipsychotic-exposed monkeys. Finally, expression levels of other important developmental regulators (i.e. Dlx1, DLX5, Dlx6, SATB1, Sip1/Zeb2, ST8SIA4, cMaf, Nkx6.2, and Arx) were not altered in schizophrenia. The over-expression of a subset of molecular markers with distinct roles in the pre- and postnatal development of parvalbumin and somatostatin neurons might reflect compensatory mechanisms to sustain the development of these neurons in the face of other insults. |
| SCZ Keywords | schizophrenia |