Targeting TrkB–PSD-95 coupling to mitigate neurological disorders

Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory.The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre-or postsynaptic TrkB resulting in the strengthening of synapses,reflected by long-term potentiation.Postsynaptically,the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca^(2+)/calmodulin-dependent protein kinaseⅡand phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation.In this review,we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders.A reduction of TrkB signaling has been observed in neurodegenerative disorders,such as Alzheimer's disease and Huntington's disease,and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression.Treatment with brain-derived neurotrophic factor is problematic,due to poor pharmacokinetics,low brain penetration,and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform.Although TrkB agonists and antibodies that activate TrkB are being intensively investigated,they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions.Targeting TrkB–postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.

Synaptosomal-associated protein 25 may be an intervention target for improving sensory and locomotor functions after spinal cord contusion

Synaptosomal-associated protein 25 k Da（SNAP-25） is localized on the synapse and participates in exocytosis and neurotransmitter release. Decreased expression of SNAP-25 is associated with Alzheimer＇s disease and attention deficit/hyperactivity disorder. However, the expression of SNAP-25 in spinal cord contusion injury is still unclear. We hypothesized that SNAP-25 is associated with sensory and locomotor functions after spinal cord injury. We established rat models of spinal cord contusion injury to detect gene changes with a gene array. A decreased level of SNAP-25 was detected by quantitative real time-polymerase chain reaction and western blot assay at 1, 3, 7, 14 and 28 days post injury. SNAP-25 was localized in the cytoplasm of neurons of the anterior and posterior horns, which are involved in locomotor and sensory functions. Our data suggest that reduced levels of SNAP-25 are associated with sensory and locomotor functions in rats with spinal cord contusion injury.

衰老的脊髓小胶质细胞呈现表型异质并倾向性靶向运动神经元及其突触

研究发现小胶质细胞随着年龄的增长和疾病的不同而获得独特的区域依赖性有害特征,从而导致神经元功能障碍和大脑退化。然而,目前尚不清楚脊髓中的小胶质细胞是否表现出类似的表型异质性。本研究对3、16、23和30个月大的小鼠的脊髓小胶质细胞进行区域分析。我们使用光学和电子显微镜发现脊髓小胶质细胞在衰老过程中获得越来越活跃的表型,且该现象与区域无关。然而,衰老会导致腹侧而非背角的小胶质细胞失去其空间组织。衰老的腹角小胶质细胞也会聚集在运动神经元胞体周围,它们与运动神经元突触的接触增加;而运动神经元突触已被证明会随着年龄的增长而消失。这些发现表明,在衰老过程中小胶质细胞可能会影响运动神经元接收和传递运动命令的能力。为了更深入地研究衰老脊髓小胶质细胞,我们对FACS分离的3、18、22和29个月大小鼠的小胶质细胞进行RNA测序。我们发现,脊髓小胶质细胞在衰老过程中获得与大脑中小胶质细胞相似的转录特性,其中包括在小胶质细胞-神经元相互作用和炎症中发挥作用的基因表达的改变。到29个月大时,脊髓小胶质细胞表现出额外且独特的转录变化,已知并预计会导致衰老并改变溶酶体和核糖体调节。总之,这项工作为靶向小胶质细胞以改善脊髓中与衰老相关的变化,特别是运动回路的变化奠定了基础。

Identification of galectin-3 as a novel potential prognostic/predictive biomarker and therapeutic target for cerebral cavernous malformation disease

cerebrovascular disease of genetic origin characterized by abnormally dilated capillaries and a wide spectrum of symptoms,including headaches,seizures,neurological deficits,and intracerebral hemorrhage.Its unpredictable clinical course and the current lack of therapies make the identification of prognostic and predictive biomarkers an imperative research challenge.1 Herein,we provide evidence that galectin-3(Gal-3),a major tissue and circulating biomarker of oxidative stress and inflammation,is significantly up-regulated both in CCM patients and experimentalmodels.Specifically,wholetranscriptome sequencing,qRT-PCR,and Western blotting studies demonstrated a significant up-regulation of Gal-3 expression levels both in surgical CCM specimens and in blood samples of CCM patients.

Evolutionary diversity as a catalyst for biological discovery

The tremendous diversity of animal behaviors has inspired generations of scientists from an array of biological disciplines.To complement investigations of ecological and evolutionary factors contributing to behavioral evolution,modern sequencing,gene editing,computational and neuroscience tools now provide a means to discover the proximate mechanisms upon which natural selection acts to generate behavioral diversity.Social behaviors are motivated behaviors that can differ tremendously between closely related species,suggesting phylogenetic plasticity in their underlying biological mechanisms.In addition,convergent evolution has repeatedly given rise to similar forms of social behavior and mating systems in distantly related species.Social behavioral divergence and convergence provides an entry point for understanding the neurogenetic mechanisms contributing to behavioral diversity.We argue that the greatest strides in discovering mechanisms contributing to social behavioral diversity will be achieved through integration of interdisciplinary comparative approaches with modern tools in diverse species systems.We review recent advances and future potential for discovering mechanisms underlying social behavioral variation;highlighting patterns of social behavioral evolution,oxytocin and vasopressin neuropeptide systems,genetic/transcriptional“toolkits,”modern experimental tools,and alternative species systems,with particular emphasis on Microtine rodents and Lake Malawi cichlid fishes.

Myelin repair and functional recovery mediated by neural cell transplantation in a mouse model of multiple sclerosis

Cellular therapies are becoming a major focus for the treatment of demyelinating diseases such as multiple sclerosis （MS）, therefore it is important to identify the most effective cell types that promote myelin repair. Several components contribute to the relative benefits of specific cell types including the overall efficacy of the cell therapy, the reproducibility of treatment, the mechanisms of action of distinct cell types and the ease of isolation and generation of therapeutic populations. A range of distinct cell populations promote functional recovery in animal models of MS including neural stem cells and mesenchymal stem cells derived from different tissues. Each of these cell populations has advantages and disadvantages and likely works through distinct mechanisms. The relevance of such mechanisms to myelin repair in the adult central nervous system is unclear since the therapeutic cells are generally derived from developing animals. Here we describe the isolation and characterization of a population of neural cells from the adult spinal cord that are characterized by the expression of the cell surface glycoprotein NG2. In functional studies, injection of adult NG2~ cells into mice with ongoing MOG3~_~5-induced experimental autoimmune encephalomyelitis （EAE） enhanced remyelination in the CNS while the number of CD3＋ T cells in areas of spinal cord demyelination was reduced approximately three-fold. In vivostudies indicated that in EAE, NG2＊ cells stimulated endogenous repair while in vitro they responded to signals in areas of induced inflammation by differentiating into oligodendrocytes. These results suggested that adult NG2~ cells represent a useful cell population for promoting neural repair in a variety of different conditions including demyelinating diseases such as MS.