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Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory

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Neural Regeneration Research 2024年第5期19卷 1133-1141页

作者： Baicheng Zhao Hang Zhang Ying Liu Gaoyu Zu Yuxiao Zhang Jiayi Hu Shuai Liu Linya You Department of Human Anatomy&Histoembryology School of Basic Medical SciencesFudan UniversityShanghaiChina shanghai key laboratory of brain functional genomics(ministry of education) Affiliated Mental Health Center(ECNU)School of Psychology and Cognitive ScienceEast China Normal UniversityShanghaiChina shanghai Changning Mental Health Center ShanghaiChina NYU-ECNU Institute of brain and Cognitive Science at NYU shanghai ShanghaiChina key laboratory of Medical Imaging Computing and Computer Assisted Intervention of shanghai ShanghaiChina

Bromodomain and plant homeodomain(PHD)finger containing protein 1(Brpf1)is an activator and scaffold protein of a multiunit complex that includes other components involving lysine acetyltransferase(KAT)6A/6B/7.Brpf1,KAT6A,and KAT6B mutations were identified as the causal genes of neurodevelopmental disorders leading to intellectual disability.Our previous work revealed strong and specific expression of Brpf1 in both the postnatal and adult forebrain,especially the hippocampus,which has essential roles in learning and memory.Here,we hypothesized that Brpf1 plays critical roles in the function of forebrain excitatory neurons,and that its deficiency leads to learning and memory deficits.To test this,we knocked out Brpf1 in forebrain excitatory neurons using CaMKIIa-Cre.We found that Brpf1 deficiency reduced the frequency of miniature excitatory postsynaptic currents and downregulated the expression of genes Pcdhgb1,Slc16a7,Robo3,and Rho,which are related to neural development,synapse function,and memory,thereby damaging spatial and fear memory in mice.These findings help explain the mechanisms of intellectual impairment in patients with BRPF1 mutation.

关键词： behavioral test Brpf1 CAMKIIa-Cre intellectual disability miniature excitatory postsynaptic current mRNA-Seq

Developmental Impairments of Synaptic Refinement in the Thalamus of a Mouse Model of Fragile X Syndrome

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Neuroscience Bulletin 2024年第4期40卷 439-450页

作者： Xiaotong Wu Yali Liu Xiaomeng Wang Lu Zheng Libiao Pan Hao Wang Department of Neurosurgery of Second Affiliated Hospital and School of brain Science and brain Medicine Key Laboratory for Biomedical Engineering of Education MinistryZhejiang University School of MedicineHangzhou310058China Nanhu brain-computer Interface Institute Hangzhou311100China NHC and CAMS key laboratory of Medical Neurobiology MOE Frontier Science Center for Brain Research and Brain Machine IntegrationKey Laboratory of Precise Treatment and Clinical Translational Research of Neurological DiseasesSchool of Brain Science and Brain MedicineZhejiang UniversityHangzhou310058China Lingang laboratory Shanghai200031China

While somatosensory over-reactivity is a common feature of autism spectrum disorders such as fragile X syndrome(FXS),the thalamic mechanisms underlying this remain unclear.Here,we found that the developmental elimination of synapses formed between the principal nucleus of V(PrV)and the ventral posterior medial nucleus(VPm)of the somatosensory system was delayed in fragile X mental retardation 1 gene knockout(Fmr1 KO)mice,while the developmental strengthening of these synapses was disrupted.Immunohistochemistry showed excessive VGluT2 puncta in mutants at P12–13,but not at P7–8 or P15–16,confirming a delay in somatic pruning of PrV-VPm synapses.Impaired synaptic function was associated with a reduction in the frequency of quantal AMPA events,as well as developmental deficits in presynaptic vesicle size and density.Our results uncovered the developmental impairment of thalamic relay synapses in Fmr1 KO mice and suggest that a thalamic contribution to the somatosensory over-reactivity in FXS should be considered.

关键词： Fragile X syndrome Synaptic refinement VPm Sensory over-reactivity

Harnessing innate immune pathways for therapeutic advancement in cancer

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1506-1564页

作者： Ankang Hu Li Sun Hao Lin Yuheng Liao Hui Yang Ying Mao Department of Neurosurgery Huashan HospitalFudan UniversityShanghaiP.R.China Institute for Translational brain Research Shanghai Medical CollegeFudan University ShanghaiPR.China National Center for Neurological Disorders Huashan HospitalShanghai Medical CollegeFudan UniversityShanghaiP.R.China shanghai key laboratory of brain Function Restoration and Neural Regeneration Shanghai Clinical Medical Center of NeurosurgeryNeurosurgical Institute of Fudan UniversityHuashan HospitalShanghai Medical CollegeFudan UniversityShanghaiP.R.China State key laboratory of Medical Neurobiology and MOE Frontiers Center for brain Science and MOE Frontiers Center for brain Science Institutes of Brain ScienceShanghai Medical CollegeFudan UniversityShanghaiP.R.China shanghai key laboratory of Medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism(Ministry of Science and Technology)and Key Laboratory of Metabolism and Molecular Medicine(Ministry of Education)and Molecular and Cell Biology LabInstitutes of Biomedical SciencesShanghai Medical College of Fudan UniversityShanghaiP.R.China

The innate immune pathway is receiving increasing attention in cancer therapy.This pathway is ubiquitous across various cell types,not only in innate immune cells but also in adaptive immune cells,tumor cells,and stromal cells.Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment(TME)and improved tumor prognosis in preclinical studies.However,to date,the clinical success of drugs targeting the innate immune pathway remains limited.Interestingly,recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression.The uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation.In this review,we observe that the role of the innate immune pathway demonstrates heterogeneity,linked to the tumor development stage,pathway status,and specific cell types.We propose that within the TME,the innate immune pathway exhibits multidimensional diversity.This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks.The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways.Refining our understanding of the tumor's innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinicalapplication.

关键词： drugs therapeutic innate

Shedding light on gene therapy of Parkinson’s disease in non-human primates

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The Innovation 2024年第2期5卷 15-16页

作者： Xunyi Yan Xin Jin New Cornerstone Science laboratory Center for Motor Control and DiseaseKey Laboratory of Brain Functional GenomicsEast China Normal University3663 North Zhongshan RoadShanghai 200062China NYU–ECNU Institute of brain and Cognitive Science New York University Shanghai3663 North Zhongshan RoadShanghai 200062China

Parkinson’s disease(PD)is a progressive neurodegeneration disease initially described by James Parkinson.It is typically diagnosed based on clinical features such as bradykinesia,resting tremor,rigidity,and,in later stages,postural instability.Epidemiologically,the prevalence of PD ranges from 5 to over 35 cases per 100,000 population,with the majority affecting individuals aged 50 years or older.The risk increases with age,particularly in males.Various factors,including genetics,lifestyle,specific environmental influences,and geometry,contribute to the disease.

关键词： clinical rigidity initially

Neuronomodulation of Excitable Neurons

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Neuroscience Bulletin 2024年第1期40卷 103-112页

作者： Yizhang Chen Lin Xiao Jian Qiu Institute of Neuroscience Second Military Medical UniversityShanghai 200433China Institute for brain Research and Rehabilitation Key Laboratory of BrainCognition and Education Sciences of Ministry of EducationSouth China Normal UniversityGuangzhou 510631China Department of Chemical Physiology and Biochemistry Oregon Health and Science UniversityPortlandOR 97239USA

Neuronomodulation refers to the modulation of neural conduction and synaptic transmission(i.e.,the conduction process involved in synaptic transmission)of excitable neurons via changes in the membrane potential in response to chemical substances,from spillover neuro-transmitters to paracrine or endocrine hormones circulating in the blood.Neuronomodulation can be direct or indirect,depending on the transduction pathways from the ligand binding site to the ion pore,either on the same molecule,i.***.the ion channel,or through an intermediate step on different molecules.The major players in direct neurono-modulation are ligand-gated or voltage-gated ion channels.The key process of direct neuronomodulation is the binding and chemoactivation of ligand-gated or voltage-gated ion channels,either orthosterically or allosterically,by various ligands.Indirect neuronomodulation involves metabotropic receptor-mediated slow potentials,where steroid hormones,cytokines,and chemokines can implement these actions.Elucidating neuronomodulation is of great significance for understanding the physiological mechanisms of brain function,and the occurrence and treatment of diseases.

关键词： Neuron Membrane potential Excitability Chemoactivation Neuronomodulation

Comparative transcriptome analysis between rhesus macaques(Macaca mulatta) and crab-eating macaques(M. fascicularis)

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Zoological Research 2024年第2期45卷 299-310页

作者： Yu-Xiang Mao Yamei Li Zikun Yang Ning Xu Shilong Zhang Xuankai Wang Xiangyu Yang Qiang Sun Yafei Mao Institute of Neuroscience State Key Laboratory of NeuroscienceCenter for Excellence in Brain Science&Intelligence TechnologyChinese Academy of SciencesShanghai 200031China shanghai Center for brain Science and brain-Inspired Intelligence Technology Shanghai 201210China University of Chinese Academy of Sciences Beijing 100049China key laboratory of Genetic Evolution&Animal Models Chinese Academy of SciencesKunmingYunnan 650201China Bio-X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric DisordersMinistry of EducationShanghai Jiao Tong UniversityShanghai 200030China Zhiyuan College Shanghai Jiao Tong UniversityShanghai 200240China Center for Genomic Research International Institutes of MedicineFourth Affiliated HospitalZhejiang UniversityYiwuZhejiang 322000China

Understanding gene expression variations between species is pivotal for deciphering the evolutionary diversity in phenotypes. Rhesus macaques(Macaca mulatta, MMU)and crab-eating macaques(M. fascicularis, MFA) serve as crucial nonhuman primate biomedical models with different phenotypes. To date, however, large-scale comparative transcriptome research between these two species has not yet been fully explored. Here, we conducted systematic comparisons utilizing newly sequenced RNA-seq data from84 samples(41 MFA samples and 43 MMU samples)encompassing 14 common tissues. Our findings revealed a small fraction of genes(3.7%) with differential expression between the two species, as well as 36.5% of genes with tissue-specific expression in both macaques. Comparison of gene expression between macaques and humans indicated that 22.6% of orthologous genes displayed differential expression in at least two tissues. Moreover,19.41% of genes that overlapped with macaque-specific structural variants showed differential expression between humans and macaques. Of these, the FAM220A gene exhibited elevated expression in humans compared to macaques due to lineage-specific duplication. In summary,this study presents a large-scale transcriptomic comparison between MMU and MFA and between macaques and humans. The discovery of gene expression variations not only enhances the biomedical utility of macaque models but also contributes to the wider field of primate genomics.

关键词： Crab-eating macaques Rhesus macaques Comparative transcriptomics Biomedical models Nonhuman primates RNA-seq Duplicated genes

Effects of acupuncture on hypothalamic–pituitary–adrenal axis:Current status and future perspectives

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Journal of Integrative Medicine 2024年第4期22卷 445-458页

作者： Jia-yuan Zheng Jing Zhu Yu Wang Zhan-zhuang Tian Department of Integrative Medicine and Neurobiology School of Basic Medical SciencesState Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain ScienceInstitutes of Brain ScienceInstitute of Acupuncture ResearchAcademy of Integrative MedicineShanghai Key Laboratory for Acupuncture Mechanism and Acupoint FunctionShanghai Medical CollegeFudan University Department of Human Anatomy School of Integrative MedicineShanghai University of Traditional Chinese Medicine

The hypothalamic–pituitary–adrenal(HPA) axis is a critical component of the neuroendocrine system,playing a central role in regulating the body's stress response and modulating various physiological processes. Dysregulation of HPA axis function disrupts the neuroendocrine equilibrium, resulting in impaired physiological functions. Acupuncture is recognized as a non-pharmacological type of therapy which has been confirmed to play an important role in modulating the HPA axis and thus favorably targets diseases with abnormal activation of the HPA axis. With numerous studies reporting the promising efficacy of acupuncture for neuroendocrine disorders, a comprehensive review in terms of the underlying molecular mechanism for acupuncture, especially in regulating the HPA axis, is currently in need. This review fills the need and summarizes recent breakthroughs, from the basic principles and the pathological changes of HPA axis dysfunction, to the molecular mechanisms by which acupuncture regulates the HPA axis. These mechanisms include the modulation of multiple neurotransmitters and their receptors, neuropeptides and their receptors, and microRNAs in the paraventricular nucleus,hippocampus, amygdala and pituitary gland, which alleviate the hyperfunctioning of the HPA axis.This review comprehensively summarizes the mechanism of acupuncture in regulating HPA axis dysfunction for the first time, providing new targets and prospects for further exploration of acupuncture.Please cite this article as: Zheng JY, Zhu J, Wang Y, Tian ZZ. Effects of acupuncture on hypothalamic–pituitary–adrenal axis: Current status and future perspectives. J Integr Med. 2024; 22(4): 445–458.

关键词： Acupuncture Electroacupuncture Hypothalamic-pituitary-adrenal axis Mechanism Neurotransmitter microRNA

Two ABCI family transporters,OsABCI15 and OsABCI16,are involved in grain-filling in rice

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Journal of Genetics and genomics 2024年第5期51卷 492-506页

作者： Bin Ma Xiubiao Cao Xiaoyuan Li Zhong Bian Qi-Qi Zhang Zijun Fang Jiyun Liu Qun Li Qiaoquan Liu Lin Zhang Zuhua He Jiangsu key laboratory of Crop genomics and Molecular Breeding/Zhongshan Biological Breeding laboratory/key laboratory of Plant functional genomics of the ministry of education/Jiangsu key laboratory of Crop Genetics and Physiology Agricultural College of Yangzhou UniversityYangzhouJiangsu 225009China Jiangsu Co-Innovation Center for Modern Production Technology of Grain Crops Jiangsu Key Laboratory of Crop Genetics and PhysiologyYangzhou UniversityYangzhouJiangsu 225009China National key laboratory of Plant Molecular Genetics CAS Center for Excellence in Molecular Plant SciencesInstitute of Plant Physiology&EcologyChinese Academy of SciencesShanghai 200032China Institute of Biotechnology Hangzhou Academy of Agricultural SciencesHangzhouZhejiang 310024China Joint International Research laboratory of Agriculture and Agri-Product Safety of the ministry of education Yangzhou UniversityYangzhouJiangsu 225009China

Seed development is critical for plant reproduction and crop yield,with panicle seed-setting rate,grain-filling,and grain weight being key seed characteristics for yield improvement.However,few genes are known to regulate grain filling.Here,we identify two adenosine triphosphate(ATP)-binding cassette(ABC)I-type transporter genes,OsABCI15 and OsABCI16,involved in rice grain-filling.Both genes are highly expressed in developing seeds,and their proteins are localized to the plasma membrane and cytosol.Interestingly,knockout of OsABCI15 and OsABCI16 results in a significant reduction in seed-setting rate,caused predominantly by the severe empty pericarp phenotype,which differs from the previously reported low seed-setting phenotype resulting from failed pollination.Further analysis indicates that OsABCI15 and OsABCI16 participate in ion homeostasis and likely export ions between filial tissues and maternal tissues during grain filling.Importantly,overexpression of OsABCI15 and OsABCI16 enhances the seed-setting rate and grain yield in transgenic plants and decreases ion accumulation in brown rice.Moreover,the OsABCI15/16 orthologues in maize exhibit a similar role in kernel development,as demonstrated by their disruption in transgenic maize.Therefore,ourﬁndings reveal the important roles of two ABC transporters in cereal grain filling,highlighting their value in crop yield improvement.

关键词： ABC transporters Rice Grain filling Ion homeostasis Grain yield

DNA bridging of FOXP3 ladder-like multimer: Unveiling a novel transcriptional regulation paradigm

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The Innovation 2024年第3期5卷 15-16页

作者： Ying Lu Lanfang Li Hanting Yang Bin Li Zuoyun Wang key laboratory of Metabolism and Molecular Medicine of the ministry of education Shanghai Xuhui Central Hospital and School of Basic Medical SciencesFudan UniversityShanghai 200032China Institute for Translational brain Research State Key Laboratory of Medical NeurobiologyMOE Frontiers Center for Brain ScienceDepartment of NeurologyZhongshan HospitalFudan UniversityShanghai 200032China Center for Immune-Related Diseases at shanghai Institute of Immunology Department of Immunology and MicrobiologyShanghai Jiao Tong University School of MedicineShanghai 200025China

In the latest issue of Nature,Zhang et al.characterized a novel ladder-like structure of FOXP3-DNA interaction involving FOXP3 multimerization and remote DNA bridging through a combination of biochemistry,structural biology,cell biology,and bioinformatics analyses.1 In this commentary,we highlight their key findings and provide our insights into the research paradigm for further exploration of a novel transcriptional regulation mode as well as a therapeutic strategy from the structural aspects of the FOXP3 complex(Figure 1).

关键词： FOXP3 bridging