scholarly journals Axon growth and synaptic function: A balancing act for axonal regeneration and neuronal circuit formation in CNS trauma and disease

2020 ◽  
Vol 80 (7-8) ◽  
pp. 277-301
Author(s):  
Conrad Kiyoshi ◽  
Andrea Tedeschi
Keyword(s):  
Axonal Regeneration ◽  
Axon Growth ◽  
Synaptic Function ◽  
Neuronal Circuit ◽  
Cns Trauma ◽  
Circuit Formation

scholarly journals The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair after CNS Injury and Disease

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1078
Author(s):  
Debasish Roy ◽  
Andrea Tedeschi
Keyword(s):  
Nervous System ◽  
Lipid Metabolism ◽  
Lipid Accumulation ◽  
Axon Regeneration ◽  
Axon Growth ◽  
The Body ◽  
Cns Repair ◽  
Cord Injury ◽  
Cns Trauma

Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of new membrane. Of the three major kinds of membrane lipids, phospholipids are the most abundant in all cell membranes, including neurons. Not only immature axons, but also severed axons in the adult require large amounts of lipids for axon regeneration to occur. Lipids also serve as energy storage, signaling molecules and they contribute to tissue physiology, as demonstrated by a variety of metabolic disorders in which harmful amounts of lipids accumulate in various tissues through the body. Detrimental changes in lipid metabolism and excess accumulation of lipids contribute to a lack of axon regeneration, poor neurological outcome and complications after a variety of central nervous system (CNS) trauma including brain and spinal cord injury. Recent evidence indicates that rewiring lipid metabolism can be manipulated for therapeutic gain, as it favors conditions for axon regeneration and CNS repair. Here, we review the role of lipids, lipid metabolism and ectopic lipid accumulation in axon growth, regeneration and CNS repair. In addition, we outline molecular and pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and disease.

scholarly journals Neurosteroid Biosynthesis and Action in the Purkinje Cell

2009 ◽  
Vol 2 ◽  
pp. JEN.S2290 ◽  
Author(s):  
Kazuyoshi Tsutsui
Keyword(s):  
Purkinje Cell ◽  
De Novo ◽  
Current Knowledge ◽  
Neuronal Circuit ◽  
Vertebrate Brain ◽  
Neonatal Life ◽  
Cerebellar Neuron ◽  
Brain Data ◽  
Circuit Formation ◽  
Biological Actions

It is now clearly established that steroids can be synthesized de novo by the vertebrate brain. Such steroids are called neurosteroids. To understand neurosteroid action in the brain, data on the regio- and temporal-specific synthesis of neurosteroids are needed. In the middle 1990s, the Purkinje cell, an important cerebellar neuron, was identified as a major site for neurosteroid formation in vertebrates. This discovery has allowed deeper insights into neuronal neurosteroidogenesis and biological actions of neurosteroids have become clear by the studies using the Purkinje cell as an excellent cellular model, which is known to play an important role in memory and learning processes. From the past 10 years of research on mammals, we now know that the Purkinje cell actively synthesizes progesterone and estradiol de novo from cholesterol during neonatal life, when cerebellar neuronal circuit formation occurs. Both progesterone and estradiol promote dendritic growth, spinogenesis, and synaptogenesis via each cognate nuclear receptor in the developing Purkinje cell. Such neurosteroid actions that may be mediated by neurotrophic factors contribute to the formation of cerebellar neuronal circuit during neonatal life. Allopregnanolone, a progesterone metabolite, is also synthesized in the cerebellum and acts on Purkinje cell survival in the neonate. The aim of this review is to summarize the current knowledge regarding the biosynthesis and biological actions of neurosteroids in the Purkinje cell during development.

scholarly journals ­­STAT3 combines with Rho-ROCK signaling pathway inhibitor, regulate axon growth of ganglion cells derived from retinal Müller cells

2020 ◽  
Author(s):  
xuezhi zhou ◽  
Yujue Wang ◽  
Manjuan Peng ◽  
Ye He ◽  
Jingjie Peng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Layer Thickness ◽  
Axonal Regeneration ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Müller Cells ◽  
Control Group ◽  
Marker Genes ◽  
Mrna Levels ◽  
Muller Cells

Abstract BackgroundMüller differentiated RGCs have potential therapeutic value for glaucoma. However, axonal regeneration of differentiated RGCs has been a difficult problem. Studies have confirmed that STAT3 and Y27632 play essential roles in regulating neuronal axon regeneration. Whether STAT3 and Y27632 can induce the Müller differentiated RGCs axon regeneration is still unknown.MethodRetina Müller cells were isolated and purified from Day 21 SD rats’ retina and were differentiated into retinal stem cells. The stem cells were randomly divided into five groups (control group, AAV-STAT3 group, shSTAT3 group, Y27632 group and AAV-STAT3 + Y27632 group). The axon length in each group were measured by ImageJ. Immunofluorescence were used to label the RGCs. The mRNA level of pluripotent associated and differentiation-associated proteins was analysed by qRT-PCR. Stem cells in different groups were injected into mice model of glaucoma. Immunohistochemical, Immunohistochemistry and OCT were performed to access RGC layer thickness in glaucoma model. VEP was used to detect the optic nerve conduction function.ResultsIn this study, we found that overexpression of STAT3 could promote the growth of RGCs axons generated by Müller cell differentiation. Combined with Y27632, axonal regeneration was significantly longer than that of the STAT3 group. However, after STAT3 was knocked out, axonal regeneration significantly decreased or even stopped. The mRNA levels of Esrrb, Prdm14, Sox2, and Rex1 in Müller differentiated RGCs after overexpression STAT3 combined with Y27632 were significantly increased, while the mRNA levels of Nestin, Eomes, Mixl1 and Gata4 were significantly decreased. The mRNA levels of Socs3, Pten, Klf9, and Mdm4 were significantly decreased, while the mRNA levels of Dclk2, Armcx1, C-MYC, and Nrn1 were significantly increased. The mRNA levels of differentiation and pluripotency marker genes showed opposite results after STAT3 deletion. After injecting Müller differentiated RGCs intervened by STAT3 combined with Y27632 into the eyes of the glaucoma model mice, the axon length, OCT displayed RGC layer thickness and the electrophysiology indicated by VEP were superior to those of the glaucoma model group.ConclusionsThese findings suggested that STAT3 combined with Y27632 can significantly improve the axonal growth level of RGCs, and reveal the potential mechanism to induce pluripotency of RGCs.

scholarly journals The Role and Mechanism of AMIGO3 in the Formation of Aberrant Neural Circuits After Status Convulsion in Immature Mice

2021 ◽  
Vol 14 ◽  
Author(s):  
Xue Li ◽  
Yanan Pan ◽  
Jianxiong Gui ◽  
Zhixu Fang ◽  
Dishu Huang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Axonal Regeneration ◽  
Neural Circuits ◽  
Axon Growth ◽  
Demyelinating Diseases ◽  
Reading Frame ◽  
Myelin Sheaths ◽  
Transmission Electron ◽  
Rhoa Signaling ◽  
Myelin Basic Protein Expression

Leucine rich repeat and immunoglobulin-like domain-containing protein 1 (Lingo-1) has gained considerable interest as a potential therapy for demyelinating diseases since it inhibits axonal regeneration and myelin production. However, the results of clinical trials targeted at Lingo-1 have been unsatisfactory. Amphoterin-induced gene and open reading frame-3 (AMIGO3), which is an analog of Lingo-1, might be an alternative therapeutic target for brain damage. In the present study, we investigated the effects of AMIGO3 on neural circuits in immature mice after status convulsion (SC) induced by kainic acid. The expression of both AMIGO3 and Lingo-1 was significantly increased after SC, with levels maintained to 20 days after SC. Following SC, transmission electron microscopy revealed the impaired microstructure of myelin sheaths and Western blot analysis showed a decrease in myelin basic protein expression, and this damage was alleviated by downregulation of AMIGO3 expression. The ROCK/RhoA signaling pathway was inhibited at 20 days after SC by downregulating AMIGO3 expression. These results indicate that AMIGO3 plays important roles in seizure-induced damage of myelin sheaths as well as axon growth and synaptic plasticity via the ROCK/RhoA signaling pathway.

Emerging roles for HOX proteins in synaptogenesis

2018 ◽  
Vol 62 (11-12) ◽  
pp. 807-818 ◽  
Author(s):  
Françoise Gofflot ◽  
Benoit Lizen
Keyword(s):  
Cell Fate ◽  
Synapse Formation ◽  
Neural Circuit ◽  
Target Selection ◽  
Axon Growth ◽  
Current Data ◽  
Cell Fate Specification ◽  
Hox Proteins ◽  
Circuit Formation ◽  
Vertebrate Central Nervous System

Neural circuit formation requires the intricate orchestration of multiple developmental events including cell fate specification, cell migration, axon guidance, dendritic growth, synaptic target selection, and synaptogenesis. The HOX proteins are well-known transcriptional regulators that control embryonic development. Investigations into their action in the vertebrate central nervous system have demonstrated pivotal roles in specifying neural subpopulations, but also in several successive steps required for the assembly of neuronal circuitry, such as neuron migration, axon growth and pathfinding and synaptic target selection. Several lines of evidence suggest that the HOX transcription factors could also regulate synaptogenesis processes even after the process of axonal and dendritic guidance has concluded. Here we will review the current data on HOX proteins in neural circuit formation in order to evaluate their potential roles in establishing neuronal connectivity with specific emphasis on synapse formation and maturation.

scholarly journals Functional Implications of Neurotransmitter Expression during Axonal Regeneration: Serotonin, But Not Peptides, Auto-Regulate Axon Growth of an Identified Central Neuron

2001 ◽  
Vol 21 (15) ◽  
pp. 5597-5606 ◽  
Author(s):  
Cornelis E. Koert ◽  
Gaynor E. Spencer ◽  
Jan van Minnen ◽  
Ka Wan Li ◽  
Wijnand P. M. Geraerts ◽  
...  
Keyword(s):  
Axonal Regeneration ◽  
Axon Growth ◽  
Central Neuron ◽  
Functional Implications

scholarly journals On Myelinated Axon Plasticity and Neuronal Circuit Formation and Function

2017 ◽  
Vol 37 (42) ◽  
pp. 10023-10034 ◽  
Author(s):  
Rafael G. Almeida ◽  
David A. Lyons
Keyword(s):  
Myelinated Axon ◽  
Neuronal Circuit ◽  
And Function ◽  
Circuit Formation

scholarly journals Akt1-Inhibitor of DNA binding2 is essential for growth cone formation and axon growth and promotes central nervous system axon regeneration

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Hyo Rim Ko ◽  
Il-Sun Kwon ◽  
Inwoo Hwang ◽  
Eun-Ju Jin ◽  
Joo-Ho Shin ◽  
...  
Keyword(s):  
Growth Cone ◽  
Axonal Regeneration ◽  
Potential Role ◽  
Axon Regeneration ◽  
Hippocampal Slices ◽  
Axon Growth ◽  
Mechanistic Studies ◽  
Cone Formation ◽  
Growth Promoting ◽  
Inhibitor Of Dna Binding

Mechanistic studies of axon growth during development are beneficial to the search for neuron-intrinsic regulators of axon regeneration. Here, we discovered that, in the developing neuron from rat, Akt signaling regulates axon growth and growth cone formation through phosphorylation of serine 14 (S14) on Inhibitor of DNA binding 2 (Id2). This enhances Id2 protein stability by means of escape from proteasomal degradation, and steers its localization to the growth cone, where Id2 interacts with radixin that is critical for growth cone formation. Knockdown of Id2, or abrogation of Id2 phosphorylation at S14, greatly impairs axon growth and the architecture of growth cone. Intriguingly, reinstatement of Akt/Id2 signaling after injury in mouse hippocampal slices redeemed growth promoting ability, leading to obvious axon regeneration. Our results suggest that Akt/Id2 signaling is a key module for growth cone formation and axon growth, and its augmentation plays a potential role in CNS axonal regeneration.

scholarly journals Chondroitinase ABC Promotes Axon Regeneration and Reduces Retrograde Apoptosis Signaling in Lamprey

2021 ◽  
Vol 9 ◽  
Author(s):  
Jianli Hu ◽  
William Rodemer ◽  
Guixin Zhang ◽  
Li-Qing Jin ◽  
Shuxin Li ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Axonal Regeneration ◽  
Neuronal Apoptosis ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Chondroitinase Abc ◽  
Apoptotic Signaling ◽  
Akt Activation ◽  
Collateral Sprouting ◽  
Cord Injury

Paralysis following spinal cord injury (SCI) is due to failure of axonal regeneration. It is believed that axon growth is inhibited by the presence of several types of inhibitory molecules in central nervous system (CNS), including the chondroitin sulfate proteoglycans (CSPGs). Many studies have shown that digestion of CSPGs with chondroitinase ABC (ChABC) can enhance axon growth and functional recovery after SCI. However, due to the complexity of the mammalian CNS, it is still unclear whether this involves true regeneration or only collateral sprouting by uninjured axons, whether it affects the expression of CSPG receptors such as protein tyrosine phosphatase sigma (PTPσ), and whether it influences retrograde neuronal apoptosis after SCI. In the present study, we assessed the roles of CSPGs in the regeneration of spinal-projecting axons from brainstem neurons, and in the process of retrograde neuronal apoptosis. Using the fluorochrome-labeled inhibitor of caspase activity (FLICA) method, apoptotic signaling was seen primarily in those large, individually identified reticulospinal (RS) neurons that are known to be “bad-regenerators.” Compared to uninjured controls, the number of all RS neurons showing polycaspase activity increased significantly at 2, 4, 8, and 11 weeks post-transection (post-TX). ChABC application to a fresh TX site reduced the number of polycaspase-positive RS neurons at 2 and 11 weeks post-TX, and also reduced the number of active caspase 3-positive RS neurons at 4 weeks post-TX, which confirmed the beneficial role of ChABC treatment in retrograde apoptotic signaling. ChABC treatment also greatly promoted axonal regeneration at 10 weeks post-TX. Correspondingly, PTPσ mRNA expression was reduced in the perikaryon. Previously, PTPσ mRNA expression was shown to correlate with neuronal apoptotic signaling at 2 and 10 weeks post-TX. In the present study, this correlation persisted after ChABC treatment, which suggests that PTPσ may be involved more generally in signaling axotomy-induced retrograde neuronal apoptosis. Moreover, ChABC treatment caused Akt activation (pAkt-308) to be greatly enhanced in brain post-TX, which was further confirmed in individually identified RS neurons. Thus, CSPG digestion not only enhances axon regeneration after SCI, but also inhibits retrograde RS neuronal apoptosis signaling, possibly by reducing PTPσ expression and enhancing Akt activation.

scholarly journals Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Laura J Wagstaff ◽  
Jose A Gomez-Sanchez ◽  
Shaline V Fazal ◽  
Georg W Otto ◽  
Alastair M Kilpatrick ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Axonal Regeneration ◽  
Nerve Repair ◽  
Axon Growth ◽  
Common Mechanism ◽  
Molecular Pathways ◽  
Chronic Denervation ◽  
Clinical Problems ◽  
Molecular Framework

After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during chronic denervation that results from slow axon growth. This impairs axonal regeneration and causes significant clinical problems. In mice, we find that repair cells express reduced c-Jun protein as regenerative support provided by these cells declines during aging and chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to control levels. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, suggesting molecular pathways that can be targeted to promote repair in the PNS.

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