Qingjun Huang

Chemotherapy-related cognitive impairment (CRCI) or “chemo brain” is a devastating neurotoxic sequela of cancer-related treatments, especially for the elderly individuals. Here we show that PTPRO, a tyrosine phosphatase, is highly enriched in the hippocampus, and its level is tightly associated with neurocognitive function but declined significantly during aging. To understand the protective role of PTPRO in CRCI, a mouse model was generated by treating Ptpro ^–/– female mice with doxorubicin (DOX) because Ptpro ^–/– female mice are more vulnerable to DOX, showing cognitive impairments and neurodegeneration. By analyzing PTPRO substrates that are neurocognition-associated tyrosine kinases, we found that SRC and EPHA4 are highly phosphorylated/activated in the hippocampi of Ptpro ^–/– female mice, with increased sensitivity to DOX-induced CRCI. On the other hand, restoration of PTPRO in the hippocampal CA3 region significantly ameliorate CRCI in Ptpro ^–/– female mice. In addition, we found that the plant alkaloid berberine (BBR) is capable of ameliorating CRCI in aged female mice by upregulating hippocampal PTPRO. Mechanistically, BBR upregulates PTPRO by downregulating miR-25-3p, which directly targeted PTPRO. These findings collectively demonstrate the protective role of hippocampal PTPRO against CRCI.

Recent studies have shown that multiple sclerosis (MS) and schizophrenia share similarities in some respects, including white matter damage and neuroinflammation. On the other hand, adenosine was reported to promote oligodendrocyte precursor maturation and remyelinating while influencing microglia activation. The aim of the present study was to examine possible beneficial effects of adenosine on the recovery of cuprizone (CPZ)-exposed mouse which has been used as an animal model of MS and schizophrenia as the CPZ-exposed mouse presents demyelination, oligodendrocyte loss, microglia accumulation, as well as behavioral changes. As reported previously, C57BL/6 mice, after fed CPZ for 5 weeks, showed salient demyelination and oligodendrocyte loss in the cerebral cortex (CTX) and hippocampus, in addition to displaying anxiety-like behavior, spatial working memory deficit, and social interaction impairment. Administration of adenosine for 7 days during the recovery period after CPZ withdrawal promoted the behavioral recovery of CPZ-exposed mice and accelerated the remyelinating process in the brains of mice after CPZ withdrawal in a dose-dependent manner. In addition, the effective dose (10 mg/kg) of adenosine inhibited microglia activation and suppressed abnormal elevation of the pro-inflammatory cytokines IL-1β and TNF-α in CTX and hippocampus, but increased levels of the anti-inflammatory cytokines IL-4 or IL-10 in the same brain regions during the remyelinating process. These results provided an evidence-based rationale for the application of adenosine or its analogues as add-on therapy for schizophrenia.

Although emerging evidence has suggested an association between the Val66Met (rs6265) polymorphisms in brain‐derived neurotrophic factor (BDNF) gene and the panic disorder, the conclusion is inclusive given the mixed results. This meta‐analysis reviewed and analyzed the recent studies addressing the potential association between the Val66Met polymorphisms and panic disorder susceptibility. Related case–control studies were retrieved by database searching and selected according to established inclusion criteria. Six articles were identified, which explored the association between the BDNF Val66Met polymorphism and panic disorder. Statistical analyses revealed no association for the allele contrast and the dominant model. However, the recessive model showed a significant association between the BDNF Val66Met polymorphism and panic disorder (odds ratio = 1.26, 95% confidence interval = 1.04–1.52, z = 2.39, P = 0.02). Despite of some limitations, this meta‐analysis suggests that the Val66Met polymorphism of BDNF gene is a susceptibility factor for panic disorder.

Studies have implicated astrocytic dysfunction in Alzheimer's disease (AD). However, the role of astrocytes in the pathophysiology and treatment of the disease is poorly characterized. Here, we identified astrocytes as independent key factors involved in several Alzheimer‐like phenotypes in an APP/PS1 mouse model, including amyloid pathology, altered neuronal and synaptic properties, and impaired cognition. In vitro astrocytes from APP/PS1 mice induced synaptotoxicity as well as reduced dendritic complexity and axonal branching of hippocampal neurons. These astrocytes produced high levels of soluble β‐amyloid (Aβ) which could be significantly inhibited by fluoxetine (FLX) via activating serotonin 5‐HT₂ receptors. FLX could also protect hippocampal neurons against astrocyte‐induced neuronal damage in vitro. In the same APP/PS1 mice, FLX inhibited activation of astrocytes, lowered Aβ products, ameliorated neurotoxicity, and improved behavioral performance. These findings may provide a basis for the clinical application of FLX in patients, and may also lay the groundwork for exploration of other novel astrocyte‐based therapies of AD. GLIA 2016;64:240–254

Changes in proinflammatory cytokines and white matter in chronically stressed rats Ping Yang,1 Zhenyong Gao,1 Handi Zhang,1 Zeman Fang,1 Cairu Wu,1 Haiyun Xu,1,2 Qing-Jun Huang1 1Mental Health Center, 2Department of Anatomy, Shantou University Medical College, Shantou, Guangdong, People’s Republic of China Although the pathogenesis of depression, an incapacitating psychiatric ailment, remains largely unknown, previous human and animal studies have suggested that both proinflammatory cytokines and altered oligodendrocytes play important roles in the condition. This study examined these two factors in the brains of rats following unpredictable chronic mild stress for 4 weeks, with the hypothesis that chronic stress may affect oligodendrocytes and elevate proinflammatory cytokines in the brain. After suffering unpredictable stressors for 4 weeks, the rats showed depression-like behaviors, including decreased locomotion in the open field, increased immobility time in the forced swim test, and decreased sucrose consumption and less sucrose preference when compared with controls. Immunohistochemical staining of brain sections showed higher immunoreactivity of proinflammatory cytokines in certain brain regions of stressed rats compared with controls; lower immunoreactivity of myelin basic protein and fewer mature oligodendrocytes were seen in the prefrontal cortex, but no demyelination was detected. These results are interpreted and discussed in the context of recent findings from human and animal studies. Keywords: cytokines, depression, myelination, oligodendrocytes, stress

Alzheimer’s disease (AD) is the most common neurodegenerative disorder of the central nervous system. Current approaches for AD treatment only ameliorate symptoms. Therapeutic strategies that target the pathological processes of the disease remain elusive. Fluoxetine (FLX) is one of the most widely used antidepressants for the treatment of depression and anxiety associated with AD, however, it is unknown if the drug affects the pathogenesis of the disease. We showed that FLX improved spatial memory, learning and emotional behaviors of APP/PS1 mice, a well characterized model of AD. In the same mice, FLX effectively prevented the protein loss of synaptophysin (SYP) and microtubuleassociated protein 2 (MAP2). FLX was unable to prevent plaque formation, but significantly lowered high levels of soluble β-amyloid (Aβ) in brain tissue, cerebrospinal fluid (CSF) and blood sera. FLX also effectively inhibited the phosphorylation of amyloid precursor protein (APP) at T668, which may be a possible mechanism of the reduced Aβ production in APP/PS1 mouse after treatment.

Serotonin/norepinephrine reuptake inhibitors antidepressants exert their effects by increasing serotonin and norepinephrine in the synaptic cleft. Studies show it takes 2–3 weeks for the mood‐enhancing effects, which indicate other mechanisms may underlie their treatment effects. Here, we investigated the role of white matter in treatment and pathogenesis of depression using an unpredictable chronic mild stress (UCMS) mouse model. Desvenlafaxine (DVS) was orally administrated to UCMS mice at the dose of 10 mg/kg/day 1 week before they went through a 7‐week stress procedure and lasted for over 8 weeks before the mice were killed. No significant changes were found for protein markers of neurons and astrocytes in UCMS mice. However, myelin and oligodendrocyte‐related proteins were significantly reduced in UCMS mice. DVS prevented the stress‐induced injury to white matter and the decrease of phosphorylated 5′‐AMP‐activated protein kinase and 3‐hydroxy‐3‐methyl‐glutaryl‐CoA reductase protein expression. DVS increased open arm entries in an elevated plus‐maze test, sucrose consumption in the sucrose preference test and decreased immobility in tail suspension and forced swimming tests. These findings suggest that stress induces depression‐like behaviors and white matter deficits in UCMS mice. DVS may ameliorate the oligodendrocyte dysfunction by affecting cholesterol synthesis, alleviating the depression‐like phenotypes in these mice. image We examined the possible role of oligodendrocyte and myelin in the pathological changes of depression with an unpredictable chronic mild stress (UCMS) mouse model. Oligodendrocyte‐related proteins in the mouse brain were specifically changed during the stress period. The depressive‐like behaviors and oligodendrocyte deficits could be prevented by the administration of desvenlafaxine. Oligodendrocyte and myelin may be an essential target of desvenlafaxine for the treatment of depression.

Previous studies have demonstrated that quetiapine (QTP) may have neuroprotective properties; however, the underlying mechanisms have not been fully elucidated. In this study, we identified a novel mechanism by which QTP increased the synthesis of ATP in astrocytes and protected GABAergic neurons from aging‐induced death. In 12‐month‐old mice, QTP significantly improved cell number of GABAegic neurons in the cortex and ameliorated anxiety‐like behaviors compared to control group. Complimentary in vitro studies showed that QTP had no direct effect on the survival of aging GABAergic neurons in culture. Astrocyte‐conditioned medium (ACM) pretreated with QTP (ACM_QTP) for 24 h effectively protected GABAergic neurons against aging‐induced spontaneous cell death. It was also found that QTP boosted the synthesis of ATP from cultured astrocytes after 24 h of treatment, which might be responsible for the protective effects on neurons. Consistent with the above findings, a Rhodamine 123 test showed that ACM_QTP, not QTP itself, was able to prevent the decrease in mitochondrial membrane potential in the aging neurons. For the first time, our study has provided evidence that astrocytes may be the conduit through which QTP is able to exert its neuroprotective effects on GABAergic neurons. image The neuroprotective properties of quetiapine (QTP) have not been fully understood. Here, we identify a novel mechanism by which QTP increases the synthesis of ATP in astrocytes and protects GABAergic neurons from aging‐induced death in a primary cell culture model. In 12‐month‐old mice, QTP significantly improves cell number of GABAegic neurons and ameliorates anxiety‐like behaviors. Our study indicates that astrocytes may be the conduit through which QTP exerts its neuroprotective effects on GABAergic neurons.