Ketamine-related expression of glutamatergic postsynaptic density genes: Possible implications in psychosis

Systemic administration of ketamine, a non-competitive antagonist of the N-methyl-d-aspartate receptor (NMDA-R), produces a condition of NMDA-R hypofunction, which is considered one of the putative molecular mechanisms involved in psychosis. In this study, we evaluated the effect of ketamine on glutamatergic markers of the postsynaptic density (PSD), a pivotal site for dopamine–glutamate interaction. We assessed gene expression of Homer1a, α and βCaMKII, and dopamine transporter (DAT) by two different doses of ketamine. These genes were chosen because of their impact on signal transduction and dopamine–glutamate interplay in postsynaptic density. Moreover, Homer1a is modulated by antipsychotics and represents a candidate gene for schizophrenia. Male Sprague–Dawley rats were injected with saline, 12 mg/kg ketamine or 50 mg/kg ketamine, and sacrificed 90 minutes after injections. In situ hybridization histochemistry was used to quantitate the rate of gene expression in rat forebrain. Homer1a was induced by 50 mg/kg ketamine in ventral striatum and by both 50 and 12 mg/kg ketamine in nucleus accumbens, whereas gene expression was not affected in dorsal striatum. αCaMKII was increased by 12 mg/kg ketamine against saline in almost all subregions assessed. βCaMKII was not affected by ketamine. DAT was increased by both doses of ketamine in the ventro-tegmental area and substantia nigra pars compacta. We suggest that these changes may represent molecular adaptations to the perturbation in glutamatergic transmission induced by ketamine blockade of NMDA receptors and may be implicated in molecular alterations occurring in schizophrenia.     

楚海波主任医师辨治脑卒中后抑郁症的经验

目的:总结楚海波主任医师辨治脑卒中后抑郁症的经验。方法:从楚师对本病的病因病机认识,选方用药,典型病例等方面阐述楚师的临床经验。结论:楚师采用血府逐瘀汤加减治疗本病,疗效明显,值得进一步研究总结。     

Differential expression of cytoskeletal regulatory factors in the adolescent prefrontal cortex: Implications for cortical development

The prevalence of depression, anxiety, schizophrenia, and drug and alcohol use disorders peaks during adolescence. Further, up to 50% of “adult” mental health disorders emerge in adolescence. During adolescence, the prefrontal cortex (PFC) undergoes dramatic structural reorganization, in which dendritic spines and synapses are refined, pruned, and stabilized. Understanding the molecular mechanisms that underlie these processes should help to identify factors that influence the development of psychiatric illness. Here we briefly discuss the anatomical connections of the medial and orbital prefrontal cortex (mPFC and OFC, respectively). We then present original findings suggesting that dendritic spines on deep‐layer excitatory neurons in the mouse mPFC and OFC prune at different adolescent ages, with later pruning in the OFC. In parallel, we used Western blotting to define levels of several cytoskeletal regulatory proteins during early, mid‐, and late adolescence, focusing on tropomyosin‐related kinase receptor B (TrkB) and β1‐integrin–containing receptors and select signaling partners. We identified regional differences in the levels of several proteins in early and midadolescence that then converged in early adulthood. We also observed age‐related differences in TrkB levels, both full‐length and truncated isoforms, Rho‐kinase 2, and synaptophysin in both PFC subregions. Finally, we identified changes in protein levels in the dorsal and ventral hippocampus that were distinct from those in the PFC. We conclude with a general review of the manner in which TrkB‐ and β1‐integrin–mediated signaling influences neuronal structure in the postnatal brain. Elucidating the role of cytoskeletal regulatory factors throughout adolescence may identify critical mechanisms of PFC development. © 2016 Wiley Periodicals, Inc.     

Quantitative analysis of pre‐ and postsynaptic sex differences in the nucleus accumbens

The nucleus accumbens (NAc) plays a central role in motivation and reward. While there is ample evidence for sex differences in addiction‐related behaviors, little is known about the neuroanatomical substrates that underlie these sexual dimorphisms. We investigated sex differences in synaptic connectivity of the NAc by evaluating pre‐ and postsynaptic measures in gonadally intact male and proestrous female rats. We used DiI labeling and confocal microscopy to measure dendritic spine density, spine head size, dendritic length, and branching of medium spiny neurons (MSNs) in the NAc, and quantitative immunofluorescence to measure glutamatergic innervation using pre‐ (vesicular glutamate transporter 1 and 2) and postsynaptic (postsynaptic density 95) markers, as well as dopaminergic innervation of the NAc. We also utilized electron microscopy to complement the above measures. Clear but subtle sex differences were identified, namely, in distal dendritic spine density and the proportion of large spines on MSNs, both of which are greater in females. Sex differences in spine density and spine head size are evident in both the core and shell subregions, but are stronger in the core. This study is the first demonstration of neuroanatomical sex differences in the NAc and provides evidence that structural differences in synaptic connectivity and glutamatergic input may contribute to behavioral sex differences in reward and addiction. J. Comp. Neurol. 518:1330–1348, 2010. © 2009 Wiley‐Liss, Inc.     

树突棘及突触发育障碍诱发自闭症小鼠核心症状的机制

目的 探讨前额叶皮层（PFC）树突棘及突触发育障碍,诱发自闭症（ASD）小鼠核心症状的机制。方法 将C57小鼠按照完全随机设计,分为正常对照组（CON组）,ASD模型组（VPA组）,溶剂对照组（DMSO组）和Wortmannin抑制剂组（Wortmannin组）,10只/组。旷场实验,青年玩耍实验和三箱社交实验评价小鼠的ASD样行为;高尔基染色观察小鼠PFC树突棘密度的变化;Western blot检测小鼠PFC信号通路相关蛋白p-PI3K、PI3K、p-AKT、AKT、p-mTOR、mTOR以及突触相关蛋白PSD95、p-Syn、Syn的表达;免疫荧光染色观察PSD95、p-Syn的变化。结果 与CON组相比,VPA组小鼠出现了ASD样表型,PFC总的、成熟型树突棘密度减少（P<0.05）,未成熟型树突棘密度增加（P<0.01）,信号通路相关蛋白p-PI3K/PI3K、p-AKT/AKT和p-mTOR/mTOR表达上调（P<0.05）,突触相关蛋白PSD95和p-Syn/Syn表达下调（P<0.01或P<0.001）。Wortmannin能改善小鼠ASD样表型,改善树突棘发育,下调PI3K/Akt/mTOR信号通路及上调突触相关蛋白的表达。结论 PI3K/Akt/mTOR信号通路的过度激活和突触相关蛋白PSD95、p-Syn表达降低可能导致VPA诱导的ASD小鼠PFC树突棘损伤和突触发育障碍,最终导致ASD样表型。     

Molecular regulation of dendritic spine dynamics and their potential impact on synaptic plasticity and neurological diseases

The structure and dynamics of dendritic spines reflect the strength of synapses, which are severely affected in different brain diseases. Therefore, understanding the ultra-structure, molecular signaling mechanism(s) regulating dendritic spine dynamics is crucial. Although, since last century, dynamics of spine have been explored by several investigators in different neurological diseases, but despite countless efforts, a comprehensive understanding of the fundamental etiology and molecular signaling pathways involved in spine pathology is lacking. The purpose of this review is to provide a contextual framework of our current understanding of the molecular mechanisms of dendritic spine signaling, as well as their potential impact on different neurodegenerative and psychiatric diseases, as a format for highlighting some commonalities in function, as well as providing a format for new insights and perspectives into this critical area of research. Additionally, the potential strategies to restore spine structure–function in different diseases are also pointed out. Overall, these informations should help researchers to design new drugs to restore the structure–function of dendritic spine, a “hot site” of synaptic plasticity.     

刺五加注射液配合帕罗西汀治疗脑卒中后抑郁症的应用研究

目的 探讨刺五加注射液配合帕罗西汀治疗脑卒中后抑郁症(PSD)的临床疗效.方法将96例PSD患者随机分为治疗组和对照组各48例 ,对照组给予分别给予帕罗西汀治疗 ,治疗组给予刺五加注射液配合帕罗西汀口服治疗 ,4周为1疗程 ,共2个疗程 ,测定并比较分析两组患者治疗前后HAMD得分.结果 治疗2各疗程后两组患者的 HAMD量表评分均降低 ,治疗组评分显著优于对照组( P <0.05).临床疗效优于对照组.结论 刺五加注射液配合帕罗西汀可明显改善PSD患者的抑郁症状 ,提高临床治疗效果和患者的生活质量.     

Characterization of physiological phenotypes of dentate gyrus synapses of PDZ1/2 domain‐deficient PSD‐95‐knockin mice

The hippocampal formation is involved in several important brain functions of animals, such as memory formation and pattern separation, and the synapses in the dentate gyrus (DG) play critical roles as the first step in the hippocampal circuit. Previous studies have reported that mice with genetic modifications of the PDZ1/2 domains of postsynaptic density (PSD)‐95 exhibit altered synaptic properties in the DG and impaired hippocampus‐dependent behaviors. Based on the involvement of the DG in the regulation of behaviors, these data suggest that the abnormal behavior of these knockin (KI) mice is due partly to altered DG function. Precise understanding of the phenotypes of these mutant mice requires characterization of the synaptic properties of the DG, and here we provide detailed studies of DG synapses. We have demonstrated global changes in the PSD membrane‐associated guanylate kinase expression pattern in the DG of mutant mice, and DG synapses in these mice exhibited increased long‐term potentiation under a wide range of stimulus intensities, although the N‐methyl‐d ‐aspartic acid receptor dependence of the long‐term potentiation was unchanged. Furthermore, our data also indicate increased silent synapses in the DG of the KI mice. These findings suggest that abnormal protein expression and physiological properties disrupt the function of DG neurons in these KI mice.     

五行辩证针刺治疗对卒中后抑郁患者生活质量的影响

目的：观察五行辩证针刺治疗对卒中后抑郁患者抑郁情绪及生活质量的影响。方法将150例卒中后抑郁患者按随机数字表法分为3组,每组50例,均予以神经内科常规治疗及康复训练,西药组予以盐酸帕罗西汀治疗,针刺组予以盐酸帕罗西汀联合常规针刺治疗,五行针刺组予以盐酸帕罗西汀联合五行辩证针刺治疗。治疗4周,观察3个月。于治疗前后采用抑郁自评量表及脑卒中患者生活质量量表评定抑郁情绪及生活质量。结果治疗4周末起3组抑郁自评量表评分均较治疗前显著降低(P <0.01);五行针刺组显著低于西药组及针刺组(P <0.05或0.01)。治疗1周末起3组脑卒中患者生活质量量表评分均较治疗前显著升高(P <0.05或0.01);治疗4周末五行针刺组显著高于西药组及针刺组(P <0.05或0.01),治疗3个月末仍显著高于西药组(P <0.01)。结论抗抑郁剂联合五行辩证针刺治疗卒中后抑郁具有增效作用,有利于改善患者的抑郁情绪及生活质量。     

针灸联合体感音乐治疗对脑卒中后抑郁患者康复的影响

目的观察针灸联合体感音乐治疗对脑卒中后抑郁(PSD)患者康复的影响。方法回顾分析2011年3月—2013年1月间我院收治且确诊为PSD的患者90例,依据治疗方案不同分为观察组及对照组,观察组患者采用针灸联合体感音乐治疗,对照组仅给予针灸治疗,2组均以2周为1疗程,对比治疗前及治疗1疗程后汉密顿抑郁量表(HAMD)评分、匹兹堡睡眠质量指数(PSQI)、生活满意指数A(LSIA)、ADL评定Barthel指数、客观生活质量评定(QLI)、功能独立性量表(FIM)及简化Fugl-Meyer运动功能评分改善情况。结果观察组治疗后HAMD、PSQI较治疗前显著下降,LSIA较治疗前显著上升(P0.05);对照组治疗后HAMD、PSQI、LSIA与治疗前比较无明显差异(P0.05);观察组治疗后HAMD、PSQI、LSIA改善显著优于对照组(P0.05);观察组治疗后QLI、ADL、Fugl-Meyer评分改善显著优于对照组(P0.05);2组治疗后FIM评分比较差异无统计学意义。结论针灸联合体感音乐可有效改善PSD患者抑郁情绪、睡眠质量及运动功能障碍,提高患者生活质量,促进PSD患者康复作用显著。