- 作者列表："Aikawa K","Yoshida T","Ohmura Y","Lyttle K","Yoshioka M","Morimoto Y
:Juvenile stress, like that caused by childhood maltreatment, is a significant risk factor for psychiatric disorders such as depression later in life. Recently, the antidepressant effect of ketamine, a noncompetitive N-methyl-d-aspartate receptor antagonist, has been widely investigated. However, little is known regarding its efficacy against depressive-like alterations caused by juvenile stress, which is clinically relevant in human depression. In the present study, we evaluated the antidepressant-like effect of ketamine in adult rats that had been subjected to juvenile stress. Depressive-like behavior was assessed using the forced swim test (FST), and electrophysiological and morphological alterations in the layer V pyramidal cells of the prelimbic cortex were examined using whole-cell patch-clamp recordings and subsequent recording-cell specific fluorescence imaging. We demonstrated that ketamine (10 mg/kg) attenuated the increased immobility time caused by juvenile stress in the FST, restored the diminished excitatory postsynaptic currents, and caused atrophic changes in the apical dendritic spines. Ketamine's effects reversing impaired excitatory/inhibitory ratio of postsynaptic currents were also revealed. These results indicated that ketamine could be effective in reversing the depression-like alterations caused by juvenile stress.
: 青少年压力，就像儿童期虐待引起的压力一样，是以后生活中抑郁症等精神疾病的重要危险因素。最近，非竞争性 N-甲基-d-天冬氨酸受体拮抗剂氯胺酮的抗抑郁作用已被广泛研究。然而，关于其对青少年应激引起的抑郁样改变的疗效知之甚少，这在人类抑郁症中具有临床意义。在本研究中，我们评价了氯胺酮在经历幼年应激的成年大鼠中的抗抑郁样作用。使用强迫游泳测试 (FST) 评估抑郁样行为,使用全细胞膜片钳记录和随后的记录细胞特异性荧光成像检查边缘前皮质 V 层锥体细胞的电生理和形态学改变。我们证明氯胺酮 (10 mg/kg) 减弱了 FST 中幼年应激引起的不动时间增加，恢复了兴奋性突触后电流减少，并引起了顶端树突棘的萎缩性变化。氯胺酮逆转突触后电流受损的兴奋性/抑制性比值的作用也被揭示。这些结果表明，氯胺酮可有效逆转青少年应激引起的抑郁样改变。
METHODS::The adipocyte-derived hormone adiponectin has a broad spectrum of functions beyond metabolic control. We previously reported that adiponectin acts in the brain to regulate depression-related behaviors. However, its underlying neural substrates have not been identified. Here we show that adiponectin receptor 1 (AdipoR1) is expressed in the dorsal raphe nucleus (DRN) and colocalized with tryptophan hydroxylase 2 (TPH2), a marker of serotonin (5-HT) neurons. Selective deletion of AdipoR1 in 5-HT neurons induced anhedonia in male mice, as indicated by reduced female urine sniffing time and saccharin preference, and behavioral despair in female mice and enhanced stress-induced decrease in sucrose preference in both sexes. The expression levels of TPH2 were downregulated with a concurrent reduction of 5-HT-immunoreactivity in the DRN and its two major projection regions, the hippocampus and medial prefrontal cortex (mPFC), in male but not female mice lacking AdipoR1 in 5-HT neurons. In addition, serotonin transporter (SERT) expression was upregulated in both DRN projection fields of male mice but only in the mPFC of female mice. These changes presumably lead to decreased 5-HT synthesis and/or increased 5-HT reuptake, thereby reducing 5-HT transmission. The augmented behavioral responses to the selective serotonin reuptake inhibitor fluoxetine but not desipramine, a selective norepinephrine reuptake inhibitor, observed in conditional knockout male mice supports deficient 5-HT transmission underlying depression-related phenotypes. Our results indicate that adiponectin acts on 5-HT neurons through AdipoR1 receptors to regulate depression-related behaviors in a sex-dependent manner.
METHODS::Multiple schizophrenia (SCZ) risk loci may be involved in gene co-regulation mechanisms, and analysis of coexpressed gene networks may help to clarify SCZ molecular basis. We have previously identified a dopamine D2 receptor (DRD2) coexpression module enriched for SCZ risk genes and associated with cognitive and neuroimaging phenotypes of SCZ, as well as with response to treatment with antipsychotics. Here we aimed to identify regulatory factors modulating this coexpression module and their relevance to SCZ. We performed motif enrichment analysis to identify transcription factor (TF) binding sites in human promoters of genes coexpressed with DRD2. Then, we measured transcript levels of a group of these genes in primary mouse cortical neurons in basal conditions and upon overexpression and knockdown of predicted TFs. Finally, we analyzed expression levels of these TFs in dorsolateral prefrontal cortex (DLPFC) of SCZ patients. Our in silico analysis revealed enrichment for NURR1 and ERR1 binding sites. In neuronal cultures, the expression of genes either relevant to SCZ risk (Drd2, Gatad2a, Slc28a1, Cnr1) or indexing coexpression in our module (Btg4, Chit1, Osr1, Gpld1) was significantly modified by gain and loss of Nurr1 and Err1. Postmortem DLPFC expression data analysis showed decreased expression levels of NURR1 and ERR1 in patients with SCZ. For NURR1 such decreased expression is associated with treatment with antipsychotics. Our results show that NURR1 and ERR1 modulate the transcription of DRD2 coexpression partners and support the hypothesis that NURR1 is involved in the response to SCZ treatment.SIGNIFICANCE STATEMENT In the present study, we provide in silico and experimental evidence for a role of the TFs NURR1 and ERR1 in modulating the expression pattern of genes coexpressed with DRD2 in human DLPFC. Notably, genetic variations in these genes is associated with SCZ risk and behavioral and neuroimaging phenotypes of the disease, as well as with response to treatment. Furthermore, this study presents novel findings on a possible interplay between D2 receptor-mediated dopamine signaling involved in treatment with antipsychotics and the transcriptional regulation mechanisms exerted by NURR1. Our results suggest that coexpression and co-regulation mechanisms may help to explain some of the complex biology of genetic associations with SCZ.
METHODS::Abnormal neurotransmission is central to schizophrenia (SZ). Alterations across multiple neurotransmitter systems in SZ suggest that this illness may be associated with dysregulation of core intracellular processes such as signaling pathways that underlie the regulation and integration of these systems. The AKT-mTOR signaling cascade has been implicated in SZ by gene association, postmortem brain and animal studies. AKT and mTOR are serine/threonine kinases which play important roles in cell growth, proliferation, survival, and differentiation. Both AKT and mTOR require phosphorylation at specific sites for their complete activation. mTOR forms two functionally distinct multiprotein complexes, mTOR Complex 1 (mTORC1) and Complex 2 (mTORC2). mTORC1 mediates ribosome biogenesis, protein translation, and autophagy, whereas mTORC2 contributes to actin dynamics. Altered protein synthesis and actin dynamics can lead to an abnormal neuronal morphology resulting in deficits in learning and memory. Currently, there is a lack of direct evidence to support the hypothesis of disrupted mTOR signaling in SZ, and we have addressed this by characterizing this signaling pathway in SZ brain. We found a reduction in AKT and mTOR protein expression and/or phosphorylation state in dorsolateral prefrontal cortex (DLPFC) from 22 pairs of SZ and matched comparison subjects. We also found reduced protein expression of GβL, a subunit protein common to both mTOR complexes. We further investigated mTOR complex-specific subunit composition and phosphorylation state, and found abnormal mTOR expression in both complexes in SZ DLPFC. These findings provide evidence that proteins associated with the AKT-mTOR signaling cascade are downregulated in SZ DLPFC.