Depletion of microglia with PLX3397 attenuates MK-801-induced hyperactivity associated with regulating inflammation-related genes in the brain

Acute administration of MK-801(dizocilpine),an N-methyl-D-aspartate receptor(NMDAR)antagonist,can establish animal models of psychiatric disorders.However,the roles of microglia and inflammation-related genes in these animal models of psychiatric disorders remain unknown.Here,we found rapid elimination of microglia in the prefrontal cortex(PFC)and hippocampus(HPC)of mice following administration of the dual colony-stimulating factor 1 receptor(CSF1R)/c-Kit kinase inhibitor PLX3397(pexidartinib)in drinking water.Single administration of MK-801 induced hyperactivity in the open-field test(OFT).Importantly,PLX3397-induced depletion of microglia prevented the hyperactivity and schizophrenia-like behaviors induced by MK-801.However,neither repopulation of microglia nor inhibition of microglial activation by minocycline affected MK-801-induced hyperactivity.Importantly,microglial density in the PFC and HPC was significantly correlated with behavioral changes.In addition,common and distinct glutamate-,GABA-,and inflammation-related gene(116 genes)expression patterns were observed in the brains of PLX3397-and/or MK-801-treated mice.Moreover,10 common inflammation-related genes(CD68,CD163,CD206,TMEM119,CSF3R,CX3CR1,TREM2,CD11b,CSF1R,and F4/80)with very strong correlations were identified in the brain using hierarchical clustering analysis.Further correlation analysis demonstrated that the behavioral changes in the OFT were most significantly associated with the expression of inflammation-related genes(NLRP3,CD163,CD206,F4/80,TMEM119,and TMEM176a),but not glutamate-or GABA-related genes in PLX3397-and MK-801-treated mice.Thus,our results suggest that microglial depletion via a CSF1R/c-Kit kinase inhibitor can ameliorate the hyperactivity induced by an NMDAR antagonist,which is associated with modulation of immune-related genes in the brain.

Social avoidance behavior in male tree shrews and prosocial behavior in male mice toward unfamiliar conspecifics in the laboratory

Adult male tree shrews vigorously defend against intruding male conspecifics. However, the characteristics of social behavior have not been entirely explored in these males. In this study, male wild-type tree shrews(Tupaia belangeri chinensis)and C57 BL/6 J mice were first allowed to familiarize themselves with an open-field apparatus. The tree shrews exhibited a short duration of movement(moving) in the novel environment, whereas the mice exhibited a long duration of movement. In the 30 min social preference-avoidance test, target animals significantly decreased the time spent by the experimental tree shrews in the social interaction(SI)zone, whereas experimental male mice exhibited the opposite. In addition, experimental tree shrews displayed a significantly longer latency to enter the SI zone in the second 15 min session(targetpresent) than in the first 15 min session(targetabsent), which was different from that found in mice.Distinct behavioral patterns in response to a conspecific male were also observed in male tree shrews and mice in the first, second, and third 5 min periods. Thus, social behaviors in tree shrews and mice appeared to be time dependent. In summary,our study provides results of a modified social preference-avoidance test designed for the assessment of social behavior in tree shrews. Our findings demonstrate the existence of social avoidance behavior in male tree shrews and prosocial behavior in male mice toward unfamiliar conspecifics. The tree shrew may be a new animal model, which differs from mice, for the study of social avoidance and prosocial behaviors.

Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway

Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder(BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex(mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase(PI3K)-protein kinase B(AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206(40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania.Furthermore, selective knockdown of AKT via AAVAKT-sh RNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly,pharmacological activation of AKT signaling by SC79(40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002(25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin(mTOR)signaling with rapamycin(10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.

Morphological changes in gray matter volume correlate with catechol-O-methyl transferase gene Val158Met polymorphism in first-episode treatment-nave patients with schizophrenia

The catechol-O-methyltransferase（COMT） gene is a schizophrenia susceptibility gene. A common functional polymorphism of this gene,Val158/158 Met,has been proposed to influence gray matter volume（GMV）. However,the effects of this polymorphism on cortical thickness/surface area in schizophrenic patients are less clear. In this study,we explored the relationship between the Val158 Met polymorphism of the COMT gene and the GMV/ cortical thickness/cortical surface area in 150 firstepisode treatment-nave patients with schizophrenia and 100 healthy controls. Main effects of diagnosis were found for GMV in the cerebellum and the visual,medial temporal,parietal,and middle frontal cortex. Patients with schizophrenia showed reduced GMVs in these regions. And main effects of genotype were detected for GMV in the left superior frontal gyrus. Moreover,a diagnosis × genotype interaction was found for the GMV of the left precuneus,and the effect of the COMT gene on GMV was due mainly to cortical thickness rather than cortical surface area. In addition,a pattern ofincreased GMV in the precuneus with increasing Met dose found in healthy controls was lost in patients with schizophrenia. These findings suggest that the COMTMet variant is associated with the disruption of dopaminergic influence on gray matter in schizophrenia,and the effect of the COMT gene on GMV in schizophrenia is mainly due to changes in cortical thickness rather than in cortical surface area.

Apolipoprotein E gene polymorphisms associated with processing speed and executive functions in healthy Han Chinese

Dear Editor,A few studies have focused on exploring APOE gene- related effects on cognitive functions and brain activities in healthy populations. Bondi et aL found that ε4 carriers perform significantly worse on the California Verbal Learning Test than non-carriers in non-demented old subjects （mean age, 72 years）ε11. But the results are not entirely consistent. For example, Scarmeas et aL found no effect of the E4 allele on neuropsychological performance[2] in young adults, and Jochemsen et al. found that the ε4 allele is associated with age-related cognitive decline[3]. Furthermore, protective and negative effects of the E2 allele on cognition are inconsistent[4＇ s]. APOE E2 is thought to be a protective allele for AD in the elderly population due to its role in the superior cognitive performance of ε2 carriers compared to E3 or E4 carriers[5]. However, the ε2 allele has also been found to have a negative effect on AD pathology[4].