Neurite outgrowth and synaptogenesis are critical steps for functional recovery following ischemic stroke.Damaged axons of the central nervous system in adult mammals exhibit limited regenerative capacity,resulting in...Neurite outgrowth and synaptogenesis are critical steps for functional recovery following ischemic stroke.Damaged axons of the central nervous system in adult mammals exhibit limited regenerative capacity,resulting in enduring neurological deficits.Recent findings from our research indicate that inhibition of Rho-associated kinase(ROCK)2 facilitates neuroprotection in different models of central nervous system diseases.In addition,our prior studies have demonstrated that axonal protection enhances the regeneration of injured axons.However,it remains unclear whether the axonal protection mediated by ROCK2 inhibition also facilitates synaptogenesis.In this study,we aimed to investigate the effects of inhibiting ROCK2 expression on synaptogenesis and neurogenesis in ischemic stroke using an shRNA-expressing adeno-associated virus(AAV)vector(AAV-sh.ROCK2).We demonstrated that AAV-sh.ROCK2 increased neurite outgrowth and facilitated synaptogenesis in vivo.Furthermore,AAV-sh.ROCK2 increased neuronal survival and promoted neurogenesis following middle cerebral artery occlusion surgery as well as long-term motor functional recovery after ischemia/reperfusion injury.Notably,AAV-sh.ROCK2 also stimulated serotonergic and dopaminergic axon sprouting after ischemia/reperfusion injury.Mechanistically,AAV-sh.ROCK2 activity resulted in increased anti-collapsin response mediator protein 2 activation and reductions in RhoA and ROCK2 expression.Our study identified ROCK2 as a critical regulator of synaptogenesis and neurogenesis,highlighting it as a promising target to facilitate neuroprotection and regeneration in ischemic stroke.展开更多
Here, we review research on the mechanisms underlying the ability of thrombospondin to promote synaptogenesis and examine its role in central nervous system diseases and drug actions. Thrombospondin secreted by glial ...Here, we review research on the mechanisms underlying the ability of thrombospondin to promote synaptogenesis and examine its role in central nervous system diseases and drug actions. Thrombospondin secreted by glial cells plays a critical role in synaptogenesis and maintains synapse stability. Thrombospondin regulates synaptogenesis through receptor a26-1 and neuroligin 1, and promotes the proliferation and differentiation of neural progenitor cells. It also participates in synaptic remodeling following injury and in the action of some nervous system drugs.展开更多
To investigate the pattern of neural differentiation and synaptogenesis in the mouse retina,immunolabeling,Brd U assay and transmission electron microscopy were used.We show that the neuroblastic cell layer is the ger...To investigate the pattern of neural differentiation and synaptogenesis in the mouse retina,immunolabeling,Brd U assay and transmission electron microscopy were used.We show that the neuroblastic cell layer is the germinal zone for neural differentiation and retinal lamination.Ganglion cells differentiated initially at embryonic day 13(E13),and at E18 horizontal cells appeared in the neuroblastic cell layer.Neural stem cells in the outer neuroblastic cell layer differentiated into photoreceptor cells as early as postnatal day 0(P0),and neural stem cells in the inner neuroblastic cell layer differentiated into bipolar cells at P7.Synapses in the retina were mainly located in the outer and inner plexiform layers.At P7,synaptophysin immunostaining appeared in presynaptic terminals in the outer and inner plexiform layers with button-like structures.After P14,presynaptic buttons were concentrated in outer and inner plexiform layers with strong staining.These data indicate that neural differentiation and synaptogenesis in the retina play important roles in the formation of retinal neural circuitry.Our study showed that the period before P14,especially between P0 and P14,represents a critical period during retinal development.Mouse eye opening occurs during that period,suggesting that cell differentiation and synaptic formation lead to the attainment of visual function.展开更多
Over the past two decades, many investigators have reported how extracellular matrix molecules act to regulate neuroplasticity. The majority of these studies involve proteins which are targets of matrix metalloprotein...Over the past two decades, many investigators have reported how extracellular matrix molecules act to regulate neuroplasticity. The majority of these studies involve proteins which are targets of matrix metalloproteinases. Importantly, these enzyme/substrate interactions can regulate degenerative and regenerative phases of synaptic plasticity, directing axonal and dendritic reorganization after brain insult. The present review first summarizes literature support for the prominent role of matrix metalloproteinases during neuroregeneration, followed by a discussion of data contrasting adaptive and maladaptive neuroplasticity that reveals time-dependent metalloproteinase/substrate regulation of postinjury synaptic recovery. The potential for these enzymes to serve as therapeutic targets for enhanced neuroplasticity after brain injury is illustrated with experiments demonstrating that metalloproteinase inhibitors can alter adaptive and maladaptive outcome. Finally, the complexity of metalloproteinase role in reactive synaptogenesis is revealed in new studies showing how these enzymes interact with immune molecules to mediate cellular response in the local regenerative environment, and are regulated by novel binding partners in the brain extracellular matrix. Together, these different examples show the complexity with which metalloproteinases are integrated into the process of neuroregeneration, and point to a promising new angle for future studies exploring how to facilitate brain plasticity.展开更多
Striatum,as the largest structure of the basal ganglia,serves as a center for information transmission and is critical for motor function and reward perception.However,the genetic mechanisms underlying its development...Striatum,as the largest structure of the basal ganglia,serves as a center for information transmission and is critical for motor function and reward perception.However,the genetic mechanisms underlying its development require further exploration.Here,we found that Sox9,traditionally recognized as a glial marker,is uniquely expressed in striatal medium spiny neurons(MSNs),especially in Drd2-expressing indirect pathway MSNs(D2-MSNs).Intriguingly,Sox9 expression in the striatum,which is conserved in humans,is a dynamic process.It maintains a high level during the perinatal stage,and exhibits low expression levels or vanishes at the embryonic and postnatal stages,respectively.The peak period of Sox9 expression coincides with the transition from neurogenesis to synaptogenesis.Importantly,gene regulatory network analysis and gain-of-function experiments confirmed Sox9 is strongly correlated with synaptogenesis.Moreover,we identified that Sox9 regulates synaptogenesis by repressing Foxp2,a well-known synapse regulator.Furthermore,we demonstrated that the biased expression pattern of Sox9 in D2-MSNs is,at least in part,regulated by another SoxE family member Sox8,which is specifically expressed in Drd1-expressing direct pathway MSNs(D1-MSNs).Taken together,our findings reveal a new marker of D2-MSNs and identify its distinctive function in striatal development.展开更多
Background The global aging population is increasingly inflicted with Alzheimer’s disease(AD),but a cure is still unavailable.Neurotrophic factor-α1/carboxypeptidase E(NF-α1/CPE)gene therapy has been shown to preve...Background The global aging population is increasingly inflicted with Alzheimer’s disease(AD),but a cure is still unavailable.Neurotrophic factor-α1/carboxypeptidase E(NF-α1/CPE)gene therapy has been shown to prevent and reverse memory loss and pathology in AD mouse models.However,the mechanisms of action of NF-α1/CPE are not fully understood.We investigated if a non-enzymatic form of NF-α1/CPE-E342Q is efficient in reversing AD pathology and carried out a proteomic study to uncover the mechanisms of action of NF-α1/CPE in AD mice.Methods AAV-human NF-α1/CPE or a non-enzymatic form,NF-α1/CPE-E342Q,was delivered into the hippocampus of 3×Tg-AD male mice.The effects on cognitive function,neurodegeneration,synaptogenesis and autophagy were investigated.A quantitative proteomic analysis of the hippocampus was carried out.Results Hippocampal delivery of AAV-NF-α1/CPE-E342Q prevented memory loss,neurodegeneration and microglial activation in 3×Tg-AD mice,indicating that the action is independent of its enzymatic activity.Quantitative proteomic analysis of the hippocampus of 3×Tg-AD mice revealed differential expression of>2000 proteins involving many metabolic pathways after NF-α1/CPE gene therapy.Of these,two new proteins,Snx4 and Trim28,which increase Aβproduction and tau levels,respectively,were down-regulated by NF-α1/CPE.Western blot analysis verified their reduction in AAV-NF-α1/CPE-treated 3×Tg-AD mice compared to untreated mice.Our proteomic analysis indicated synaptic organization as the top signaling pathway altered in response to CPE expression.Synaptic markers PSD95 and Synapsin1 were decreased in 3×Tg-AD mice and were restored with AAV-NF-α1/CPE treatment.Proteomic analysis hypothesized involvement of autophagic signaling pathway.Indeed,multiple protein markers of autophagy were down-regulated in 3×Tg-AD mice,accounting for impaired autophagy.NF-α1/CPE gene therapy upregulated the levels of these proteins in 3×Tg-AD mice,thereby reversing autophagic impairment.Conclusions This study uncovered vast actions of NF-α1/CPE in restoring expression of networks of critical proteins including those necessary for maintaining neuronal survival,synaptogenesis and autophagy,while down-regulating many proteins that promote tau and Aβaccumulation to reverse memory loss and AD pathology in 3×Tg-AD mice.AAV-NF-α1/CPE gene therapy uniquely targets many metabolic levels,offering a promising holistic approach for AD treatment(Graphical Abstract).展开更多
Recent studies have found that the suppression of phosphatase and tensin homolog is one of the most effective single-gene approaches for promoting optic nerve regeneration.This effect is primarily mediated through the...Recent studies have found that the suppression of phosphatase and tensin homolog is one of the most effective single-gene approaches for promoting optic nerve regeneration.This effect is primarily mediated through the activation of the protein kinase B/phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway.The purpose of this article is to elucidate how the downregulation of phosphatase and tensin homolog is involved in each key phase of optic nerve regeneration and to summarize the potential targets for therapeutic interventions in this process.Optic nerve regeneration progresses through five phases:stress response,growth navigation,nerve regeneration,synaptic reconstruction,and remyelination.During the stress response phase,the suppression of phosphatase and tensin homolog enhances the survival of retinal ganglion cells and promotes the proliferation of microglia.In the nerve regeneration phase,reduced levels of phosphatase and tensin homolog facilitate mitochondrial transport,while inhibition of the phosphatase and tensin homolog-L isoform specifically promotes mitophagy.During the synaptic reconstruction phase,the deletion of phosphatase and tensin homolog modulates the synthesis of axon extension-related proteins and stabilizes microglial microtubules,thereby accele rating the clearance of damaged synapses and the fo rmation of new ones.During the remyelination phase,the knockout of phosphatase and tensin homolog promotes the proliferation of oligodendrocyte progenitor cells and the diffe rentiation of oligodendrocytes,relieving myelination obstruction.This paper also discusses current strategies and translational challenges for neuron-specific inhibition of phosphatase and tensin homolog,including off-ta rget effects,delive ry precisio n,and long-term safety.By integrating molecular insights with emerging bioengineering approaches,this paper provides a framework for develo ping targeted therapies for optic nerve regeneration and broader applications in the field of central nervous system regeneration.展开更多
Neuronal nitric oxide synthase （nNOS） is mainly expressed in neurons,to some extent in astrocytes and neuronal stem cells.The alternative splicing of nNOS mRNA generates 5 isoforms of nNOS,including nNOS-,nNOS-,nNOS...Neuronal nitric oxide synthase （nNOS） is mainly expressed in neurons,to some extent in astrocytes and neuronal stem cells.The alternative splicing of nNOS mRNA generates 5 isoforms of nNOS,including nNOS-,nNOS-,nNOS-,nNOS-and nNOS-2.Monomer of nNOS is inactive,and dimer is the active form.Dimerization requires tetrahydrobiopterin （BH 4）,heme and L-arginine binding.Regulation of nNOS expression relies largely on cAMP response element-binding protein （CREB） activity,and nNOS activity is regulated by heat shock protein 90 （HSP90）/HSP70,calmodulin （CaM）,phosphorylation and dephosphorylation at Ser847 and Ser1412,and the protein inhibitor of nNOS （PIN）.There are primarily 9 nNOS-interacting proteins,including post-synaptic density protein 95 （PSD95）,clathrin assembly lymphoid leukemia （CALM）,calcium/calmodulindependent protein kinase II alpha （CAMKIIA）,Disks large homolog 4 （DLG4）,DLG2,6-phosphofructokinase,muscle type （PFK-M）,carboxy-terminal PDZ ligand of nNOS （CAPON） protein,syntrophin and dynein light chain （LC）.Among them,PSD95,CAPON and PFK-M are important nNOS adapter proteins in neurons.The interaction of PSD95 with nNOS controls synapse formation and is implicated in N-methyl-D-aspartic acid-induced neuronal death.nNOS-derived NO is implicated in synapse loss-mediated early cognitive/motor deficits in several neuropathological states,and negatively regulates neurogenesis under physiological and pathological conditions.展开更多
Ephedrine is a prevalent sympathomimetic alkaloid and amphetamine-type stimulant precursor that has become a widespread contaminant in global aquatic ecosystems.While the neurotoxic effects of high-dose ephedrine expo...Ephedrine is a prevalent sympathomimetic alkaloid and amphetamine-type stimulant precursor that has become a widespread contaminant in global aquatic ecosystems.While the neurotoxic effects of high-dose ephedrine exposure are documented in humans and other mammals,its impact on aquatic vertebrates at environmentally realistic concentrations remains poorly understood.Determining how these persistent residues affect neural development and physiological homeostasis is critical for evaluating ecological risks to aquatic life.Here we show that chronic,low-dose ephedrine exposure impairs neurodevelopment in adult zebrafish by simultaneously disrupting synaptogenesis architecture and neurotransmitter balance.Integrated transcriptomic and histopathological analyses reveal that ephedrine targets the synaptogenesis signaling pathway,resulting in reduced presynaptic vesicles and structural abnormalities in the postsynaptic density.Computational docking and biochemical assays further demonstrate that ephedrine engages the vesicular acetylcholine transporter and tyrosine hydroxylase with high affinity,triggering excitotoxic cascades and biphasic neurochemical dysregulation that manifest as anxiety-like phenotypes and cognitive impairments.These findings indicate that environmentally relevant concentrations of stimulant precursors pose a significant threat to the neural circuit integrity of aquatic species,necessitating urgent regulatory attention to pharmaceutical residues in surface waters.展开更多
In chronic phase of spinal cord injury, functional recovery is more untreatable compared with early intervention in acute phase of spinal cord injury. In the last decade, several combination therapies successfully imp...In chronic phase of spinal cord injury, functional recovery is more untreatable compared with early intervention in acute phase of spinal cord injury. In the last decade, several combination therapies successfully improved motor dysfunction in chronic spinal cord injury. However, their effectiveness is not sufficient. We previously found a new effective compound for spinal cord injury, matrine, which induced axonal growth and functional recovery in acute spinal cord injury mice via direct activation of extracellular heat shock protein 90. Although our previous study clarified that matrine was an activator of extracellular heat shock protein 90, the potential of matrine for spinal cord injury in chronic phase has not been sufficiently evaluated. Thus, this study aimed to investigate whether matrine ameliorates chronic spinal cord injury in mice. Once daily intragastric administration of matrine(100 μmol/kg per day) to spinal cord injury mice were starte at 28 days after injury, and continued for 154 days. Continuous mat rine treatment improved hindlimb motor function in chronic spinal cord injury mice. In injured spinal cords of the matrine-treated mice, the density of neurofilament-H-positive axons was increased. Moreover, matrine treatment increased the density of bassoon-positive presynapses in contact with choline acetyltransferase-positive motor neurons in the lumbar spinal cord. These findings suggest that matrine promotes remodeling and reconnection of neural circuits to regulate hindlimb movement. All protocols were approved by the Committee for Animal Care and Use of the Sugitani Campus of the University of Toyama(approval No. A2013 INM-1 and A2016 INM-3) on May 7, 2013 and May 17, 2016, respectively.展开更多
In the nervous system, neurons contact each other to form neuronal circuits and drive behavior, relying heavily on synaptic connections. The proper development and growth of synapses allows functional transmission of ...In the nervous system, neurons contact each other to form neuronal circuits and drive behavior, relying heavily on synaptic connections. The proper development and growth of synapses allows functional transmission of electrical information between neurons or between neurons and muscle fibers. Defects in synapse-formation or development lead to many diseases. Autophagy, a major determinant of protein turnover, is an essential process that takes place in developing synapses. During the induction of autophagy, proteins and cytoplasmic components are encapsulated in autophagosomes, which fuse with lysosomes to form autolysosomes. The cargoes are subsequently degraded and recycled. However, aberrant autophagic activity may lead to synaptic dysfunction, which is a common pathological characteristic in several disorders. Here, we review the current understanding of autophagy in regulating synaptic development and function. In addition, autophagy-related synaptic dysfunction in human diseases is also summarized.展开更多
Synapses are key structures in neural networks,and are involved in learning and memory in the central nervous system.Investigating synaptogenesis and synaptic aging is important in understanding neural development and...Synapses are key structures in neural networks,and are involved in learning and memory in the central nervous system.Investigating synaptogenesis and synaptic aging is important in understanding neural development and neural degeneration in diseases such as Alzheimer disease and Parkinson’s disease.Our previous study found that synaptogenesis and synaptic maturation were harmonized with brain development and maturation.However,synaptic damage and loss in the aging cerebellum are not well understood.This study was designed to investigate the occurrence of synaptic aging in the cerebellum by observing the ultrastructural changes of dendritic spines and synapses in cerebellar Purkinje cells of aging mice.Immunocytochemistry,Di I diolistic assays,and transmission electron microscopy were used to visualize the morphological characteristics of synaptic buttons,dendritic spines and synapses of Purkinje cells in mice at various ages.With synaptic aging in the cerebellum,dendritic spines and synaptic buttons were lost,and the synaptic ultrastructure was altered,including a reduction in the number of synaptic vesicles and mitochondria in presynaptic termini and smaller thin specialized zones in pre-and post-synaptic membranes.These findings confirm that synaptic morphology and function is disrupted in aging synapses,which may be an important pathological cause of neurodegenerative diseases.展开更多
The prefrontal neocortex is involved in many high cognitive functions in humans.Deficits in neuronal and neurocircuitry development in this part of the cerebrum have been associated with various neuropsychiatric disor...The prefrontal neocortex is involved in many high cognitive functions in humans.Deficits in neuronal and neurocircuitry development in this part of the cerebrum have been associated with various neuropsychiatric disorders in adolescents and adults.There are currently little available data regarding prenatal dendrite and spine formation on projecting neurons in the human prefrontal neocortex.Previous studies have demonstrated that Golgi silver staining can identify neurons in the frontal lobe and visual cortex in human embryos.In the present study,five fetal brains,at 19,20,26,35,and 38 gestational weeks,were obtained via the body donation program at Xiangya School of Medicine,Central South University,China.Golgi-stained pyramidal neurons in layer V of Brodmann area 46 in fetuses were quantitatively analyzed using the Neurolucida morphometry system.Results revealed that somal size,total dendritic length,and branching points of these neurons increased from 26 to 38 gestational weeks.There was also a large increase in dendritic spines from 35 to 38 gestational weeks.These findings indicate that,in the human prefrontal neocortex,dendritic growth in layer V pyramidal neurons occurs rapidly during the third trimester of gestation.The use of human fetal brain tissue was approved by the Animal Ethics Committee of Xiangya School of Medicine,Central South University,China(approval No.2011-045)on April 5,2011.展开更多
Astrocytes(ASTs)and oligodendroglial lineage cells(OLGs)are major macroglial cells in the central nervous system.ASTs communicate with each other through connexin(Cx)and Cx-based network structures,both of which allow...Astrocytes(ASTs)and oligodendroglial lineage cells(OLGs)are major macroglial cells in the central nervous system.ASTs communicate with each other through connexin(Cx)and Cx-based network structures,both of which allow for quick transport of nutrients and signals.Moreover,ASTs interact with OLGs through connexin(Cx)-mediated networks to modulate various physiological processes in the brain.In this article,following a brief description of the infrastructural basis of the glial networks and exocrine factors by which ASTs and OLGs may crosstalk,we focus on recapitulating how the interactions between these two types of glial cells modulate myelination,and how the AST-OLG interactions are involved in protecting the integrity of the blood-brain barrier(BBB)and regulating synaptogenesis and neural activity.Recent studies further suggest that AST-OLG interactions are associated with myelin-related diseases,such as multiple sclerosis.A better understanding of the regulatory mechanisms underlying AST-OLG interactions may inspire the development of novel therapeutic strategies for related brain diseases.展开更多
Stromal cell-derived factor-1 and its receptor C-X-C chemokine receptor 4(CXCR4) have been shown to regulate neural regeneration after stroke.Howeve r,whether stromal cell-derived factor-1 receptor CXCR7,which is wide...Stromal cell-derived factor-1 and its receptor C-X-C chemokine receptor 4(CXCR4) have been shown to regulate neural regeneration after stroke.Howeve r,whether stromal cell-derived factor-1 receptor CXCR7,which is widely distributed in the develo ping and adult central nervous system,participates in neural regeneration remains poorly unde rstood.In this study,we established rat models of focal cerebral ischemia by injecting endothelin-1 into the cerebral co rtex and striatum.Starting on day 7 after injury,CXCR7-neutralizing antibody was injected into the lateral ventricle using a micro drug delivery system for 6 consecutive days.Our results showed that CXCR7-neutralizing antibody increased the total length and number of sprouting co rticospinal tra ct fibers in rats with cerebral ischemia,increased the expression of vesicular glutamate transporter 1 and growth-related protein 43,marke rs of the denervated spinal cord synapses,and promoted the differentiation and maturation of oligodendrocyte progenitor cells in the striatum.In addition,CXCR7 antibody increased the expression of CXCR4 in the striatum,increased the protein expression of RAS and ERK1/2 associated with the RAS/ERK signaling pathway,and im proved rat motor function.These findings suggest that CXCR7 improved neural functional recovery after ischemic stroke by promoting axonal regeneration,synaptogenesis,and myelin regeneration,which may be achieved by activation of CXCR4 and the RAS/ERK1/2 signaling pathway.展开更多
Contactins are a group of cell adhesion molecules that are mainly expressed in the brain and play pivotal roles in the organization of axonal domains, axonal guidance, neuritogenesis, neuronal development, synapse for...Contactins are a group of cell adhesion molecules that are mainly expressed in the brain and play pivotal roles in the organization of axonal domains, axonal guidance, neuritogenesis, neuronal development, synapse formation and plasticity, axo-glia interactions and neural regeneration. Contactins comprise a family of six members. Their absence leads to malformed axons and impaired nerve conduction. Contactin mediated protein complex formation is critical for the organization of the axon in early central nervous system development. Mutations and differential expression of contactins have been identified in neuro-developmental or neurological disorders. Taken together, contactins are extensively studied in the context of nervous system development. This review summarizes the physiological roles of all six members of the Contactin family in neurodevelopment as well as their involvement in neurological/neurodevelopmental disorders.展开更多
Epilepsy is a neural network disorder caused by uncontrolled neuronal hyperexcitability induced by an imbalance between excitatory and inhibitory networks.Abnormal synaptogenesis plays a vital role in the formation of...Epilepsy is a neural network disorder caused by uncontrolled neuronal hyperexcitability induced by an imbalance between excitatory and inhibitory networks.Abnormal synaptogenesis plays a vital role in the formation of overexcited networks.Recent evidence has confirmed that thrombospondin-1(TSP-1),mainly secreted by astrocytes,is a critical cytokine that regulates synaptogenesis during epileptogenesis.Furthermore,numerous studies have reported that TSP-1 is also involved in other processes,such as angiogenesis,neuroinflammation,and regulation of Ca^(2+)homeostasis,which are closely associated with the occurrence and development of epilepsy.In this review,we summarize the potential contributions of TSP-1 to epilepsy development.展开更多
Background and Purpose: We have previously demonstrated that 2-week treatment of experimental intracerebral hemorrhage (ICH) with a daily dose of 2 mg/kg statin starting 24 hours post-injury exerts a neuroprotective e...Background and Purpose: We have previously demonstrated that 2-week treatment of experimental intracerebral hemorrhage (ICH) with a daily dose of 2 mg/kg statin starting 24 hours post-injury exerts a neuroprotective effect. The present study extends our previous investigation and tests the effect of acute high-dose (within 24 hours) statin therapy on experimental ICH. Material and Methods: Fifty-six male wistar rats were subjected to ICHby stereotactic injection of 100 μl of autologous blood into the striatum. Rats were divided randomly into seven groups: saline control group (n = 8);10, 20 and 40 mg/kg simvastatin-treated groups (n = 8);and 10, 20 and 40 mg/kg atorvastatin-treated groups (n = 8). Simvastatin or atorvastatin were administered orally at 3 and 24 hours after ICH. Neurological functional outcome was evaluated using behavioral tests (mNSS and corner turn test) at multiple time points afterICH. Animals were sacrificed at 28 days after treatment, and histological studies were completed. Results: Acute treatment with simvastatin or atorvastatin at doses of 10 and 20 mg/kg, but not at 40 mg/kg, significantly enhanced recovery of neurological function starting from 2 weeks post-ICH and persisting for up to 4 weeks postICH. In addition, at doses of 10 mg/kg and 20 mg/kg, histological evaluations revealed that simvastatin or atorvastatin reduced tissue loss, increased cell proliferation in the subventricular zone and enhanced vascular density and synaptogenesis in the hematoma boundary zone when compared to salinetreated rats. Conclusions: Treatment with simvastatin or atorvastatin at doses of 10 and 20 mg/kg significantly improves neurological recovery after administration during the first 24 hours after ICH. Decreased tissue loss, increased cell proliferation and vascularity likely contribute to improved functional recovery in rats treated with statins after ICH.展开更多
In the development and regeneration of the nervous system, neurons face the complex task of establishing and/or repairing neuronal connections and contacts. The formation of these neuronal circuits is largely coordina...In the development and regeneration of the nervous system, neurons face the complex task of establishing and/or repairing neuronal connections and contacts. The formation of these neuronal circuits is largely coordinated by tightly regulated temporal and spatial changes in mRNA translation, which enables incredibly precise control over protein expression and localization (Jung and Holt, 2011). Local mRNA translation in specific cellular compartments appears to play a role in many processes that are important to nervous system development and regeneration, including: cell survival, migration, growth cone guidance, and synaptogenesis (Jung and Holt, 2011).展开更多
Proteases comprise a variety of enzymes defined by their ability to catalytically hydrolyze the peptide bonds of other proteins,resulting in protein lysis.Cathepsins,specifically,encompass a class of at least twenty p...Proteases comprise a variety of enzymes defined by their ability to catalytically hydrolyze the peptide bonds of other proteins,resulting in protein lysis.Cathepsins,specifically,encompass a class of at least twenty proteases with potent endopeptidase activity.They are located subcellularly in lysosomes,organelles responsible for the cell’s degradative and autophagic processes,and are vital for normal lysosomal function.Although cathepsins are involved in a multitude of cell signaling activities,this chapter will focus on the role of cathepsins(with a special emphasis on Cathepsin B)in neuronal plasticity.We will broadly define what is known about regulation of cathepsins in the central nervous system and compare this with their dysregulation after injury or disease.Importantly,we will delineate what is currently known about the role of cathepsins in axon regeneration and plasticity after spinal cord injury.It is well established that normal cathepsin activity is integral to the function of lysosomes.Without normal lysosomal function,autophagy and other homeostatic cellular processes become dysregulated resulting in axon dystrophy.Furthermore,controlled activation of cathepsins at specialized neuronal structures such as axonal growth cones and dendritic spines have been positively implicated in their plasticity.This chapter will end with a perspective on the consequences of cathepsin dysregulation versus controlled,localized regulation to clarify how cathepsins can contribute to both neuronal plasticity and neurodegeneration.展开更多
基金supported by the National Natural Science Foundation of China,No.82471327the Natural Science Foundation of ShandongProvince,No.ZR2024MH200(both to SL).
文摘Neurite outgrowth and synaptogenesis are critical steps for functional recovery following ischemic stroke.Damaged axons of the central nervous system in adult mammals exhibit limited regenerative capacity,resulting in enduring neurological deficits.Recent findings from our research indicate that inhibition of Rho-associated kinase(ROCK)2 facilitates neuroprotection in different models of central nervous system diseases.In addition,our prior studies have demonstrated that axonal protection enhances the regeneration of injured axons.However,it remains unclear whether the axonal protection mediated by ROCK2 inhibition also facilitates synaptogenesis.In this study,we aimed to investigate the effects of inhibiting ROCK2 expression on synaptogenesis and neurogenesis in ischemic stroke using an shRNA-expressing adeno-associated virus(AAV)vector(AAV-sh.ROCK2).We demonstrated that AAV-sh.ROCK2 increased neurite outgrowth and facilitated synaptogenesis in vivo.Furthermore,AAV-sh.ROCK2 increased neuronal survival and promoted neurogenesis following middle cerebral artery occlusion surgery as well as long-term motor functional recovery after ischemia/reperfusion injury.Notably,AAV-sh.ROCK2 also stimulated serotonergic and dopaminergic axon sprouting after ischemia/reperfusion injury.Mechanistically,AAV-sh.ROCK2 activity resulted in increased anti-collapsin response mediator protein 2 activation and reductions in RhoA and ROCK2 expression.Our study identified ROCK2 as a critical regulator of synaptogenesis and neurogenesis,highlighting it as a promising target to facilitate neuroprotection and regeneration in ischemic stroke.
基金supported by the Natural Science Foundation of Guangdong Province,No.S2011010004096the Medical Scientific Research Foundation of Guangdong Province,No.A2010431 A2009477
文摘Here, we review research on the mechanisms underlying the ability of thrombospondin to promote synaptogenesis and examine its role in central nervous system diseases and drug actions. Thrombospondin secreted by glial cells plays a critical role in synaptogenesis and maintains synapse stability. Thrombospondin regulates synaptogenesis through receptor a26-1 and neuroligin 1, and promotes the proliferation and differentiation of neural progenitor cells. It also participates in synaptic remodeling following injury and in the action of some nervous system drugs.
基金supported by the National Natural Science Foundation of China,No.31070952 and U1204311the Scientific Research Foundation of Henan University of China,No.0000A40475 and 0000A40356
文摘To investigate the pattern of neural differentiation and synaptogenesis in the mouse retina,immunolabeling,Brd U assay and transmission electron microscopy were used.We show that the neuroblastic cell layer is the germinal zone for neural differentiation and retinal lamination.Ganglion cells differentiated initially at embryonic day 13(E13),and at E18 horizontal cells appeared in the neuroblastic cell layer.Neural stem cells in the outer neuroblastic cell layer differentiated into photoreceptor cells as early as postnatal day 0(P0),and neural stem cells in the inner neuroblastic cell layer differentiated into bipolar cells at P7.Synapses in the retina were mainly located in the outer and inner plexiform layers.At P7,synaptophysin immunostaining appeared in presynaptic terminals in the outer and inner plexiform layers with button-like structures.After P14,presynaptic buttons were concentrated in outer and inner plexiform layers with strong staining.These data indicate that neural differentiation and synaptogenesis in the retina play important roles in the formation of retinal neural circuitry.Our study showed that the period before P14,especially between P0 and P14,represents a critical period during retinal development.Mouse eye opening occurs during that period,suggesting that cell differentiation and synaptic formation lead to the attainment of visual function.
文摘Over the past two decades, many investigators have reported how extracellular matrix molecules act to regulate neuroplasticity. The majority of these studies involve proteins which are targets of matrix metalloproteinases. Importantly, these enzyme/substrate interactions can regulate degenerative and regenerative phases of synaptic plasticity, directing axonal and dendritic reorganization after brain insult. The present review first summarizes literature support for the prominent role of matrix metalloproteinases during neuroregeneration, followed by a discussion of data contrasting adaptive and maladaptive neuroplasticity that reveals time-dependent metalloproteinase/substrate regulation of postinjury synaptic recovery. The potential for these enzymes to serve as therapeutic targets for enhanced neuroplasticity after brain injury is illustrated with experiments demonstrating that metalloproteinase inhibitors can alter adaptive and maladaptive outcome. Finally, the complexity of metalloproteinase role in reactive synaptogenesis is revealed in new studies showing how these enzymes interact with immune molecules to mediate cellular response in the local regenerative environment, and are regulated by novel binding partners in the brain extracellular matrix. Together, these different examples show the complexity with which metalloproteinases are integrated into the process of neuroregeneration, and point to a promising new angle for future studies exploring how to facilitate brain plasticity.
基金supported by the National Natural Science Foundation of China(42307063)the China Postdoctoral Science Foundation(2024M760122)the Yunnan Provincial Science and Technology Project at Southwest United Graduate School(202302AO370015).
文摘Striatum,as the largest structure of the basal ganglia,serves as a center for information transmission and is critical for motor function and reward perception.However,the genetic mechanisms underlying its development require further exploration.Here,we found that Sox9,traditionally recognized as a glial marker,is uniquely expressed in striatal medium spiny neurons(MSNs),especially in Drd2-expressing indirect pathway MSNs(D2-MSNs).Intriguingly,Sox9 expression in the striatum,which is conserved in humans,is a dynamic process.It maintains a high level during the perinatal stage,and exhibits low expression levels or vanishes at the embryonic and postnatal stages,respectively.The peak period of Sox9 expression coincides with the transition from neurogenesis to synaptogenesis.Importantly,gene regulatory network analysis and gain-of-function experiments confirmed Sox9 is strongly correlated with synaptogenesis.Moreover,we identified that Sox9 regulates synaptogenesis by repressing Foxp2,a well-known synapse regulator.Furthermore,we demonstrated that the biased expression pattern of Sox9 in D2-MSNs is,at least in part,regulated by another SoxE family member Sox8,which is specifically expressed in Drd1-expressing direct pathway MSNs(D1-MSNs).Taken together,our findings reveal a new marker of D2-MSNs and identify its distinctive function in striatal development.
基金supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development(NICHD),National Institutes of Health,USA.
文摘Background The global aging population is increasingly inflicted with Alzheimer’s disease(AD),but a cure is still unavailable.Neurotrophic factor-α1/carboxypeptidase E(NF-α1/CPE)gene therapy has been shown to prevent and reverse memory loss and pathology in AD mouse models.However,the mechanisms of action of NF-α1/CPE are not fully understood.We investigated if a non-enzymatic form of NF-α1/CPE-E342Q is efficient in reversing AD pathology and carried out a proteomic study to uncover the mechanisms of action of NF-α1/CPE in AD mice.Methods AAV-human NF-α1/CPE or a non-enzymatic form,NF-α1/CPE-E342Q,was delivered into the hippocampus of 3×Tg-AD male mice.The effects on cognitive function,neurodegeneration,synaptogenesis and autophagy were investigated.A quantitative proteomic analysis of the hippocampus was carried out.Results Hippocampal delivery of AAV-NF-α1/CPE-E342Q prevented memory loss,neurodegeneration and microglial activation in 3×Tg-AD mice,indicating that the action is independent of its enzymatic activity.Quantitative proteomic analysis of the hippocampus of 3×Tg-AD mice revealed differential expression of>2000 proteins involving many metabolic pathways after NF-α1/CPE gene therapy.Of these,two new proteins,Snx4 and Trim28,which increase Aβproduction and tau levels,respectively,were down-regulated by NF-α1/CPE.Western blot analysis verified their reduction in AAV-NF-α1/CPE-treated 3×Tg-AD mice compared to untreated mice.Our proteomic analysis indicated synaptic organization as the top signaling pathway altered in response to CPE expression.Synaptic markers PSD95 and Synapsin1 were decreased in 3×Tg-AD mice and were restored with AAV-NF-α1/CPE treatment.Proteomic analysis hypothesized involvement of autophagic signaling pathway.Indeed,multiple protein markers of autophagy were down-regulated in 3×Tg-AD mice,accounting for impaired autophagy.NF-α1/CPE gene therapy upregulated the levels of these proteins in 3×Tg-AD mice,thereby reversing autophagic impairment.Conclusions This study uncovered vast actions of NF-α1/CPE in restoring expression of networks of critical proteins including those necessary for maintaining neuronal survival,synaptogenesis and autophagy,while down-regulating many proteins that promote tau and Aβaccumulation to reverse memory loss and AD pathology in 3×Tg-AD mice.AAV-NF-α1/CPE gene therapy uniquely targets many metabolic levels,offering a promising holistic approach for AD treatment(Graphical Abstract).
基金National Natural Science Foundation of China,Nos.82260279,31960169the Natural Science Foundation of Jiangxi Province,Nos.20202ACB206002,20213BCJ22057a grant from School of Basic Medical Sciences,Nanchang University。
文摘Recent studies have found that the suppression of phosphatase and tensin homolog is one of the most effective single-gene approaches for promoting optic nerve regeneration.This effect is primarily mediated through the activation of the protein kinase B/phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway.The purpose of this article is to elucidate how the downregulation of phosphatase and tensin homolog is involved in each key phase of optic nerve regeneration and to summarize the potential targets for therapeutic interventions in this process.Optic nerve regeneration progresses through five phases:stress response,growth navigation,nerve regeneration,synaptic reconstruction,and remyelination.During the stress response phase,the suppression of phosphatase and tensin homolog enhances the survival of retinal ganglion cells and promotes the proliferation of microglia.In the nerve regeneration phase,reduced levels of phosphatase and tensin homolog facilitate mitochondrial transport,while inhibition of the phosphatase and tensin homolog-L isoform specifically promotes mitophagy.During the synaptic reconstruction phase,the deletion of phosphatase and tensin homolog modulates the synthesis of axon extension-related proteins and stabilizes microglial microtubules,thereby accele rating the clearance of damaged synapses and the fo rmation of new ones.During the remyelination phase,the knockout of phosphatase and tensin homolog promotes the proliferation of oligodendrocyte progenitor cells and the diffe rentiation of oligodendrocytes,relieving myelination obstruction.This paper also discusses current strategies and translational challenges for neuron-specific inhibition of phosphatase and tensin homolog,including off-ta rget effects,delive ry precisio n,and long-term safety.By integrating molecular insights with emerging bioengineering approaches,this paper provides a framework for develo ping targeted therapies for optic nerve regeneration and broader applications in the field of central nervous system regeneration.
基金supported by the National Natural Science Foundation of China(No. 30971021,81030023 and 30901550)
文摘Neuronal nitric oxide synthase （nNOS） is mainly expressed in neurons,to some extent in astrocytes and neuronal stem cells.The alternative splicing of nNOS mRNA generates 5 isoforms of nNOS,including nNOS-,nNOS-,nNOS-,nNOS-and nNOS-2.Monomer of nNOS is inactive,and dimer is the active form.Dimerization requires tetrahydrobiopterin （BH 4）,heme and L-arginine binding.Regulation of nNOS expression relies largely on cAMP response element-binding protein （CREB） activity,and nNOS activity is regulated by heat shock protein 90 （HSP90）/HSP70,calmodulin （CaM）,phosphorylation and dephosphorylation at Ser847 and Ser1412,and the protein inhibitor of nNOS （PIN）.There are primarily 9 nNOS-interacting proteins,including post-synaptic density protein 95 （PSD95）,clathrin assembly lymphoid leukemia （CALM）,calcium/calmodulindependent protein kinase II alpha （CAMKIIA）,Disks large homolog 4 （DLG4）,DLG2,6-phosphofructokinase,muscle type （PFK-M）,carboxy-terminal PDZ ligand of nNOS （CAPON） protein,syntrophin and dynein light chain （LC）.Among them,PSD95,CAPON and PFK-M are important nNOS adapter proteins in neurons.The interaction of PSD95 with nNOS controls synapse formation and is implicated in N-methyl-D-aspartic acid-induced neuronal death.nNOS-derived NO is implicated in synapse loss-mediated early cognitive/motor deficits in several neuropathological states,and negatively regulates neurogenesis under physiological and pathological conditions.
基金funded by the National Science Fund for Distinguished Young Scholars(42325706)the National Natural Science Foundation of China(42177382,42307366).
文摘Ephedrine is a prevalent sympathomimetic alkaloid and amphetamine-type stimulant precursor that has become a widespread contaminant in global aquatic ecosystems.While the neurotoxic effects of high-dose ephedrine exposure are documented in humans and other mammals,its impact on aquatic vertebrates at environmentally realistic concentrations remains poorly understood.Determining how these persistent residues affect neural development and physiological homeostasis is critical for evaluating ecological risks to aquatic life.Here we show that chronic,low-dose ephedrine exposure impairs neurodevelopment in adult zebrafish by simultaneously disrupting synaptogenesis architecture and neurotransmitter balance.Integrated transcriptomic and histopathological analyses reveal that ephedrine targets the synaptogenesis signaling pathway,resulting in reduced presynaptic vesicles and structural abnormalities in the postsynaptic density.Computational docking and biochemical assays further demonstrate that ephedrine engages the vesicular acetylcholine transporter and tyrosine hydroxylase with high affinity,triggering excitotoxic cascades and biphasic neurochemical dysregulation that manifest as anxiety-like phenotypes and cognitive impairments.These findings indicate that environmentally relevant concentrations of stimulant precursors pose a significant threat to the neural circuit integrity of aquatic species,necessitating urgent regulatory attention to pharmaceutical residues in surface waters.
基金supported by a Grant-in-Aid for Challenging Exploratory Research(No.26670044)from the Ministry of Education,Culture,Sports,Science,and Technology of Japan(to CT)a Grant-in-Aid for a Cooperative Research Project from the Institute of Natural Medicine,University of Toyama,in 2014 and 2015(to CT)+1 种基金discretionary funds of the President of the University of Toyama,in 2014,2015,and 2016(to CT)the Natural Medicine and Biotechnology Research of Toyama Prefecture,Japan(to CT)
文摘In chronic phase of spinal cord injury, functional recovery is more untreatable compared with early intervention in acute phase of spinal cord injury. In the last decade, several combination therapies successfully improved motor dysfunction in chronic spinal cord injury. However, their effectiveness is not sufficient. We previously found a new effective compound for spinal cord injury, matrine, which induced axonal growth and functional recovery in acute spinal cord injury mice via direct activation of extracellular heat shock protein 90. Although our previous study clarified that matrine was an activator of extracellular heat shock protein 90, the potential of matrine for spinal cord injury in chronic phase has not been sufficiently evaluated. Thus, this study aimed to investigate whether matrine ameliorates chronic spinal cord injury in mice. Once daily intragastric administration of matrine(100 μmol/kg per day) to spinal cord injury mice were starte at 28 days after injury, and continued for 154 days. Continuous mat rine treatment improved hindlimb motor function in chronic spinal cord injury mice. In injured spinal cords of the matrine-treated mice, the density of neurofilament-H-positive axons was increased. Moreover, matrine treatment increased the density of bassoon-positive presynapses in contact with choline acetyltransferase-positive motor neurons in the lumbar spinal cord. These findings suggest that matrine promotes remodeling and reconnection of neural circuits to regulate hindlimb movement. All protocols were approved by the Committee for Animal Care and Use of the Sugitani Campus of the University of Toyama(approval No. A2013 INM-1 and A2016 INM-3) on May 7, 2013 and May 17, 2016, respectively.
基金supported by the National Natural Science Foundation of China (81401043 and 81273491)Zhejiang Provincial Natural Science Foundation of China (LQ13H310004 and LY12H31010)+3 种基金the Health Bureau of Zhejiang Province (2013KYA147)a Key Laboratory of Hangzhou City Project (20090233T12)the Science Foundation of Hangzhou Normal University (2012QDL048)the Program of "Xinmiao" Talents in Zhejiang Province,China (2015R423054)
文摘In the nervous system, neurons contact each other to form neuronal circuits and drive behavior, relying heavily on synaptic connections. The proper development and growth of synapses allows functional transmission of electrical information between neurons or between neurons and muscle fibers. Defects in synapse-formation or development lead to many diseases. Autophagy, a major determinant of protein turnover, is an essential process that takes place in developing synapses. During the induction of autophagy, proteins and cytoplasmic components are encapsulated in autophagosomes, which fuse with lysosomes to form autolysosomes. The cargoes are subsequently degraded and recycled. However, aberrant autophagic activity may lead to synaptic dysfunction, which is a common pathological characteristic in several disorders. Here, we review the current understanding of autophagy in regulating synaptic development and function. In addition, autophagy-related synaptic dysfunction in human diseases is also summarized.
基金supported by the Science and Technology Projects of Henan Province of China,No.172102310001the Biology Advantage Discipline Fund of Henan Province of China
文摘Synapses are key structures in neural networks,and are involved in learning and memory in the central nervous system.Investigating synaptogenesis and synaptic aging is important in understanding neural development and neural degeneration in diseases such as Alzheimer disease and Parkinson’s disease.Our previous study found that synaptogenesis and synaptic maturation were harmonized with brain development and maturation.However,synaptic damage and loss in the aging cerebellum are not well understood.This study was designed to investigate the occurrence of synaptic aging in the cerebellum by observing the ultrastructural changes of dendritic spines and synapses in cerebellar Purkinje cells of aging mice.Immunocytochemistry,Di I diolistic assays,and transmission electron microscopy were used to visualize the morphological characteristics of synaptic buttons,dendritic spines and synapses of Purkinje cells in mice at various ages.With synaptic aging in the cerebellum,dendritic spines and synaptic buttons were lost,and the synaptic ultrastructure was altered,including a reduction in the number of synaptic vesicles and mitochondria in presynaptic termini and smaller thin specialized zones in pre-and post-synaptic membranes.These findings confirm that synaptic morphology and function is disrupted in aging synapses,which may be an important pathological cause of neurodegenerative diseases.
基金supported by the National Natural Science Foundation of China,No.81873780(to DHL)grants from the Department of Education of Hunan Province of China,No.16C1577(to LXH)the Xiangtan Medicine and Health Vocational College of China
文摘The prefrontal neocortex is involved in many high cognitive functions in humans.Deficits in neuronal and neurocircuitry development in this part of the cerebrum have been associated with various neuropsychiatric disorders in adolescents and adults.There are currently little available data regarding prenatal dendrite and spine formation on projecting neurons in the human prefrontal neocortex.Previous studies have demonstrated that Golgi silver staining can identify neurons in the frontal lobe and visual cortex in human embryos.In the present study,five fetal brains,at 19,20,26,35,and 38 gestational weeks,were obtained via the body donation program at Xiangya School of Medicine,Central South University,China.Golgi-stained pyramidal neurons in layer V of Brodmann area 46 in fetuses were quantitatively analyzed using the Neurolucida morphometry system.Results revealed that somal size,total dendritic length,and branching points of these neurons increased from 26 to 38 gestational weeks.There was also a large increase in dendritic spines from 35 to 38 gestational weeks.These findings indicate that,in the human prefrontal neocortex,dendritic growth in layer V pyramidal neurons occurs rapidly during the third trimester of gestation.The use of human fetal brain tissue was approved by the Animal Ethics Committee of Xiangya School of Medicine,Central South University,China(approval No.2011-045)on April 5,2011.
基金supported by the Ministry of Science and Technology of China(2021ZD0201700)the National Natural Science Foundation of China(31921003).
文摘Astrocytes(ASTs)and oligodendroglial lineage cells(OLGs)are major macroglial cells in the central nervous system.ASTs communicate with each other through connexin(Cx)and Cx-based network structures,both of which allow for quick transport of nutrients and signals.Moreover,ASTs interact with OLGs through connexin(Cx)-mediated networks to modulate various physiological processes in the brain.In this article,following a brief description of the infrastructural basis of the glial networks and exocrine factors by which ASTs and OLGs may crosstalk,we focus on recapitulating how the interactions between these two types of glial cells modulate myelination,and how the AST-OLG interactions are involved in protecting the integrity of the blood-brain barrier(BBB)and regulating synaptogenesis and neural activity.Recent studies further suggest that AST-OLG interactions are associated with myelin-related diseases,such as multiple sclerosis.A better understanding of the regulatory mechanisms underlying AST-OLG interactions may inspire the development of novel therapeutic strategies for related brain diseases.
基金supported by the National Natural Science Foundation of China,Nos.81401002 (to SSZ),81801 053 (to XQZ)。
文摘Stromal cell-derived factor-1 and its receptor C-X-C chemokine receptor 4(CXCR4) have been shown to regulate neural regeneration after stroke.Howeve r,whether stromal cell-derived factor-1 receptor CXCR7,which is widely distributed in the develo ping and adult central nervous system,participates in neural regeneration remains poorly unde rstood.In this study,we established rat models of focal cerebral ischemia by injecting endothelin-1 into the cerebral co rtex and striatum.Starting on day 7 after injury,CXCR7-neutralizing antibody was injected into the lateral ventricle using a micro drug delivery system for 6 consecutive days.Our results showed that CXCR7-neutralizing antibody increased the total length and number of sprouting co rticospinal tra ct fibers in rats with cerebral ischemia,increased the expression of vesicular glutamate transporter 1 and growth-related protein 43,marke rs of the denervated spinal cord synapses,and promoted the differentiation and maturation of oligodendrocyte progenitor cells in the striatum.In addition,CXCR7 antibody increased the expression of CXCR4 in the striatum,increased the protein expression of RAS and ERK1/2 associated with the RAS/ERK signaling pathway,and im proved rat motor function.These findings suggest that CXCR7 improved neural functional recovery after ischemic stroke by promoting axonal regeneration,synaptogenesis,and myelin regeneration,which may be achieved by activation of CXCR4 and the RAS/ERK1/2 signaling pathway.
基金funded by the Center for Nanoscale Microscopy and Molecular Physiology and the European Neuroscience Campus Network,an Erasmus Mundus Joint Doctoral Program(cycle 5/2014/P-04)(to MC)
文摘Contactins are a group of cell adhesion molecules that are mainly expressed in the brain and play pivotal roles in the organization of axonal domains, axonal guidance, neuritogenesis, neuronal development, synapse formation and plasticity, axo-glia interactions and neural regeneration. Contactins comprise a family of six members. Their absence leads to malformed axons and impaired nerve conduction. Contactin mediated protein complex formation is critical for the organization of the axon in early central nervous system development. Mutations and differential expression of contactins have been identified in neuro-developmental or neurological disorders. Taken together, contactins are extensively studied in the context of nervous system development. This review summarizes the physiological roles of all six members of the Contactin family in neurodevelopment as well as their involvement in neurological/neurodevelopmental disorders.
基金supported by the Natural Science Foundation of Shandong Province(ZR2021MH034 and ZR2022MH059)the National Natural Science Foundation of China(81573412).We’d like to thank Editage for English language editing.
文摘Epilepsy is a neural network disorder caused by uncontrolled neuronal hyperexcitability induced by an imbalance between excitatory and inhibitory networks.Abnormal synaptogenesis plays a vital role in the formation of overexcited networks.Recent evidence has confirmed that thrombospondin-1(TSP-1),mainly secreted by astrocytes,is a critical cytokine that regulates synaptogenesis during epileptogenesis.Furthermore,numerous studies have reported that TSP-1 is also involved in other processes,such as angiogenesis,neuroinflammation,and regulation of Ca^(2+)homeostasis,which are closely associated with the occurrence and development of epilepsy.In this review,we summarize the potential contributions of TSP-1 to epilepsy development.
文摘Background and Purpose: We have previously demonstrated that 2-week treatment of experimental intracerebral hemorrhage (ICH) with a daily dose of 2 mg/kg statin starting 24 hours post-injury exerts a neuroprotective effect. The present study extends our previous investigation and tests the effect of acute high-dose (within 24 hours) statin therapy on experimental ICH. Material and Methods: Fifty-six male wistar rats were subjected to ICHby stereotactic injection of 100 μl of autologous blood into the striatum. Rats were divided randomly into seven groups: saline control group (n = 8);10, 20 and 40 mg/kg simvastatin-treated groups (n = 8);and 10, 20 and 40 mg/kg atorvastatin-treated groups (n = 8). Simvastatin or atorvastatin were administered orally at 3 and 24 hours after ICH. Neurological functional outcome was evaluated using behavioral tests (mNSS and corner turn test) at multiple time points afterICH. Animals were sacrificed at 28 days after treatment, and histological studies were completed. Results: Acute treatment with simvastatin or atorvastatin at doses of 10 and 20 mg/kg, but not at 40 mg/kg, significantly enhanced recovery of neurological function starting from 2 weeks post-ICH and persisting for up to 4 weeks postICH. In addition, at doses of 10 mg/kg and 20 mg/kg, histological evaluations revealed that simvastatin or atorvastatin reduced tissue loss, increased cell proliferation in the subventricular zone and enhanced vascular density and synaptogenesis in the hematoma boundary zone when compared to salinetreated rats. Conclusions: Treatment with simvastatin or atorvastatin at doses of 10 and 20 mg/kg significantly improves neurological recovery after administration during the first 24 hours after ICH. Decreased tissue loss, increased cell proliferation and vascularity likely contribute to improved functional recovery in rats treated with statins after ICH.
基金supported by grants from the Natural Sciences and Engineering Research Council of Canada(2015-03780,to GES and 2017-00008,to RLC)
文摘In the development and regeneration of the nervous system, neurons face the complex task of establishing and/or repairing neuronal connections and contacts. The formation of these neuronal circuits is largely coordinated by tightly regulated temporal and spatial changes in mRNA translation, which enables incredibly precise control over protein expression and localization (Jung and Holt, 2011). Local mRNA translation in specific cellular compartments appears to play a role in many processes that are important to nervous system development and regeneration, including: cell survival, migration, growth cone guidance, and synaptogenesis (Jung and Holt, 2011).
基金JS was funded by NINDS(NS25713)Brumagin-Nelson Fund+1 种基金Kaneko Family Fundthe Hong Kong Spinal Cord Injury Fund.
文摘Proteases comprise a variety of enzymes defined by their ability to catalytically hydrolyze the peptide bonds of other proteins,resulting in protein lysis.Cathepsins,specifically,encompass a class of at least twenty proteases with potent endopeptidase activity.They are located subcellularly in lysosomes,organelles responsible for the cell’s degradative and autophagic processes,and are vital for normal lysosomal function.Although cathepsins are involved in a multitude of cell signaling activities,this chapter will focus on the role of cathepsins(with a special emphasis on Cathepsin B)in neuronal plasticity.We will broadly define what is known about regulation of cathepsins in the central nervous system and compare this with their dysregulation after injury or disease.Importantly,we will delineate what is currently known about the role of cathepsins in axon regeneration and plasticity after spinal cord injury.It is well established that normal cathepsin activity is integral to the function of lysosomes.Without normal lysosomal function,autophagy and other homeostatic cellular processes become dysregulated resulting in axon dystrophy.Furthermore,controlled activation of cathepsins at specialized neuronal structures such as axonal growth cones and dendritic spines have been positively implicated in their plasticity.This chapter will end with a perspective on the consequences of cathepsin dysregulation versus controlled,localized regulation to clarify how cathepsins can contribute to both neuronal plasticity and neurodegeneration.
