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AbstractBackgroundSchizophrenia is a psychiatric disorder characterized by positive and negative symptoms and cognitive impairments. Second-and third-generation antipsychotics alleviate not only positive symptoms but also negative symptoms and cognitive impairments, with a lower liability for extrapyramidal symptoms (EPS).Accumulating evidences suggest that dopaminergic mesocorticolimbic and nigrostriatal pathways implicated in the pathophysiology of schizophrenia and the therapeutic and side effects of antipsychotics. However, the detailed mechanism remains unclear.Aims & ObjectivesTo explore them, we investigated the neuronal circuits implicated in the therapeutic and side effects of aripiprazole, a dopamine D2 receptor partial agonist, in the animal model of schizophrenia by using connectome analysis.MethodA mouse model of schizophrenia was prepared by phencyclidine (PCP), s.c. injection to ddY mice for 14 consecutive days.ResultRepeated PCP induced the sensitization of PCP-induced hyperactivity, social deficit and impairment of object recognition memory which associated with increase of dopamine turnover in the nucleus accumbens, but decreases of it in the prefrontal cortex. Aripiprazole (0.3mg/kg) improved these PCP- induced behavioral changes. However, aripiprazole (3.0mg/kg) induced catalepsy such as EPS-like behavior. Connectome analysis using MRI revealed that repeated PCP administration decreased functional connectivity, but aripiprazole (0.3mg/kg) attenuated it. However,aripiprazole (3.0mg/kg) further increased functional connectivity.Discussion & ConclusionThese results suggest that aripiprazole (0.3mg/kg) improves PCP-induced behavioral changes and decreased functional connectivity by attenuating dopaminergic disfunction, but high-dose aripiprazole (3.0mg/kg) induces catalepsy associated with increased functional connectivity induced by excessive dopamine D2 receptor antagonism.

01 Oct 2024·Cell Stem Cell

Marmoset and human trophoblast stem cells differ in signaling requirements and recapitulate divergent modes of trophoblast invasion

Article

Author: Sasaki, Erika ; Reik, Wolf ; Linneberg-Agerholm, Madeleine ; Ellermann, Anna L ; Boroviak, Thorsten E. ; Munger, Clara ; Rawlings, Thomas M. ; Brickman, Joshua M. ; Kohler, Timo N. ; Weberling, Antonia ; Brosens, Jan J. ; Clark, Stephen J. ; Hollfelder, Florian ; Clark, Stephen J ; Siriwardena, Dylan ; Boroviak, Thorsten E ; Ellermann, Anna L. ; Penfold, Christopher ; Kohler, Timo N ; Bergmann, Sophie ; Brosens, Jan J ; Brickman, Joshua M ; Zernicka-Goetz, Magdalena ; Behr, Rüdiger ; Rawlings, Thomas M ; Slatery, Erin

Early human trophoblast development has remained elusive due to the inaccessibility of the early conceptus. Non-human primate models recapitulate many features of human development and allow access to early postimplantation stages. Here, we tracked the pre- to postimplantation transition of the trophoblast lineage in superficially implanting marmoset embryos in vivo. We differentiated marmoset naive pluripotent stem cells into trophoblast stem cells (TSCs), which exhibited trophoblast-specific transcriptome, methylome, differentiation potential, and long-term self-renewal. Notably, human TSC culture conditions failed to support marmoset TSC derivation, instead inducing an extraembryonic mesoderm-like fate in marmoset cells. We show that combined MEK, TGF-β/NODAL, and histone deacetylase inhibition stabilizes a periimplantation trophoblast-like identity in marmoset TSCs. By contrast, these conditions differentiated human TSCs toward extravillous trophoblasts. Our work presents a paradigm to harness the evolutionary divergence in implantation strategies to elucidate human trophoblast development and invasion.

01 Sep 2024·Lab Animal

Production of a heterozygous exon skipping model of common marmosets using gene-editing technology

Article

Author: Morioka, Tomoe ; Kurotaki, Yoko ; Manabe, Ri-ichiroh ; Okazaki, Yasushi ; Inoue, Takashi ; Suematsu, Makoto ; Tagami, Michihira ; Yamamoto, Takashi ; Saido, Takaomi C. ; Sakuma, Tetsushi ; Saido, Takaomi C ; Kumita, Wakako ; Sasaguri, Hiroki ; Nagata, Kenichi ; Mihira, Naomi ; Ozaki, Kokoro ; Sasaki, Erika ; Manabe, Ri-Ichiroh ; Sato, Kenya

Nonhuman primates (NHPs), which are closely related to humans, are useful in biomedical research, and an increasing number of NHP disease models have been reported using gene editing. However, many disease-related genes cause perinatal death when manipulated homozygously by gene editing. In addition, NHP resources, which are limited, should be efficiently used. Here, to address these issues, we developed a method of introducing heterozygous genetic modifications into common marmosets by combining Platinum transcription activator-like effector nuclease (TALEN) and a gene-editing strategy in oocytes. We succeeded in introducing the heterozygous exon 9 deletion mutation in the presenilin 1 gene, which causes familial Alzheimer's disease in humans, using this technology. As a result, we obtained animals with the expected genotypes and confirmed several Alzheimer's disease-related biochemical changes. This study suggests that highly efficient heterozygosity-oriented gene editing is possible using TALEN and oocytes and is an effective method for producing genetically modified animals.

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Pipeline

Pipeline Snapshot as of 04 Jul 2025

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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