Prefrontal cortex-specific Dcc deletion induces schizophrenia-related behavioral phenotypes and fail to be rescued by olanzapine treatment.

Multiple genome studies have discovered that variation in deleted in colorectal carcinoma (Dcc) at transcription and translation level were associated with the occurrences of psychiatric disorders. Yet, little is known about the function of Dcc in schizophrenia (SCZ)-related behavioral abnormalities and the efficacy of antipsychotic drugs in vivo. Here, we used an animal model of prefrontal cortex-specific knockdown (KD) of Dcc in adult C57BL/6 mice to study the attention deficits and impaired locomotor activity. Our results supported a critical role of Dcc deletion in SCZ-related behaviors. Notably, olanzapine rescued the SCZ-related behaviors in the MK801-treated mice but not in the cortex-specific Dcc KD mice, indicating that Dcc play a critical in the mechanism of antipsychotic effects of olanzapine. Knockdown of Dcc in prefrontal cortex results in glutamatergic dysfunction, including defects in glutamine synthetase and postsynaptic maturation. As one of the major risk factors of the degree of antipsychotic response, Dcc deletion-induced glutamatergic dysfunction may be involved in the underlying mechanism of treatment resistance of olanzapine. Our findings identified Dcc deletion-mediated SCZ-related behavioral defects, which serve as a valuable animal model for study of SCZ and amenable to targeted investigations in mechanistic hypotheses of the mechanism underlying glutamatergic dysfunction-induced antipsychotic treatment resistance.

miR143-3p-Mediated NRG-1-Dependent Mitochondrial Dysfunction Contributes to Olanzapine Resistance in Refractory Schizophrenia.

BACKGROUND: Olanzapine is an effective antipsychotic medication for treatment-resistant schizophrenia (TRS); however, the therapeutic effectiveness of olanzapine has been found to vary in individual patients. It is imperative to unravel its resistance mechanisms and find reliable targets to develop novel precise therapeutic strategies. METHODS: Unbiased RNA sequencing analysis was performed using homogeneous populations of neural stem cells derived from induced pluripotent stem cells in 3 olanzapine responder (reduction of Positive and Negative Syndrome Scale score ≥25%) and 4 nonresponder (reduction of Positive and Negative Syndrome Scale score <25%) inpatients with TRS. We also used a genotyping study from patients with TRS to assess the candidate genes associated with the olanzapine response. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9-mediated genome editing, neurologic behavioral tests, RNA silencing, and microRNA sequencing were used to investigate the phenotypic mechanisms of an olanzapine resistance gene in patients with TRS. RESULTS: Neuregulin-1 (NRG-1) deficiency-induced mitochondrial dysfunction is associated with olanzapine treatment outcomes in TRS. NRG-1 knockout mice showed schizophrenia-relevant behavioral deficits and yielded olanzapine resistance. Notably, miR143-3p is a critical NRG-1 target related to mitochondrial dysfunction, and miR143-3p levels in neural stem cells associate with severity to olanzapine resistance in TRS. Meanwhile, olanzapine resistance in NRG-1 knockout mice could be rescued by treatment with miR143-3p agomir via intracerebral injection. CONCLUSIONS: Our findings provide direct evidence of olanzapine resistance resulting from NRG-1 deficiency-induced mitochondrial dysfunction, and they link olanzapine resistance and NRG-1 deficiency-induced mitochondrial dysfunction to an NRG-1/miR143-3p axis, which constitutes a novel biomarker and target for TRS.

Generation of refractory schizophrenia patient-derived induced pluripotent stem cell line UJSi001-A.

Schizophrenia is considered one of the most serious mental disorders nowadays. Approximately 30-60% of people with schizophrenia do not present adequate response to drug treatment and persist with symptoms of the disease; they are known as refractory schizophrenic people. We generated induced pluripotent stem cells (iPSCs) from a refractory schizophrenia patient by electroporation of peripheral blood mononuclear cells (PBMC) with episomal plasmids encoding OCT 4, SOX 2, NANOG, LIN 28, KLF 4 and LMYC. The resulting iPSCs had normal karyotype, were free of genomically integrated episomal plasmids, expressed pluripotency markers, and could differentiate into the three germ layers in vivo.

Asiatic Acid Protects Dopaminergic Neurons from Neuroinflammation by Suppressing Mitochondrial Ros Production.

This study sought to evaluate the effects of Asiatic acid in LPS-induced BV2 microglia cells and 1-methyl-4-phenyl-pyridine (MPP+)-induced SH-SY5Y cells, to investigate the potential anti-inflammatory mechanisms of Asiatic acid in Parkinson’s disease (PD). SH-SY5Y cells were induced using MPP+ to establish as an in vitro model of PD, so that the effects of Asiatic acid on dopaminergic neurons could be examined. The NLRP3 inflammasome was activated in BV2 microglia cells to explore potential mechanisms for the neuroprotective effects of Asiatic acid. We showed that Asiatic acid reduced intracellular production of mitochondrial reactive oxygen species and altered the mitochondrial membrane potential to regulate mitochondrial dysfunction, and suppressed the NLRP3 inflammasome in microglia cells. We additionally found that treatment with Asiatic acid directly improved SH-SY5Y cell viability and mitochondrial dysfunction induced by MPP+. These data demonstrate that Asiatic acid both inhibits the activation of the NLRP3 inflammasome by downregulating mitochondrial reactive oxygen species directly to protect dopaminergic neurons from, and improves mitochondrial dysfunction in SH-SY5Y cells, which were established as a model of Parkinson’s disease. Our finding reveals that Asiatic acid protects dopaminergic neurons from neuroinflammation by suppressing NLRP3 inflammasome activation in microglia cells as well as protecting dopaminergic neurons directly. This suggests a promising clinical use of Asiatic acid for PD therapy.