Connexin: a potential novel target for protecting the central nervous system?

Connexin subunits are proteins that form gap junction channels, and play an important role in communication between adjacent cells. This review article discusses the function of connexins/hemichannels/gap junctions under physiological conditions, and summarizes the findings regarding the role of connexins/hemichannels/gap junctions in the physiological and pathological mechanisms underlying central nervous system diseases such as brain ischemia, traumatic brain and spinal cord injury, epilepsy, brain and spinal cord tumor, migraine, neuroautoimmune disease, Alzheimer’s disease, Parkinson’s disease, X-linked Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher-like disease, spastic paraplegia and maxillofacial dysplasia. Connexins are considered to be a potential novel target for protecting the central nervous system.     

Astroglial heterogeneity:merely a neurobiological question? Or an opportunity for neuroprotection and regeneration after brain injury?

正Pioneer studies by Ramon y Cajal in the early nineteenth century evidenced that astrocytes are a heterogeneous cell population.The initial division of the glial family proposed by Rudolf Albert von Kolliker and William Lloyd Andriezen that separated glia into two groups,fibrous glia and protoplasmic glia,was further refined by Ramon y Cajal,who adopted the term astrocyte for both populations.The term astrocyte was originally coined by Michael von Lenhossek     

Role of neuronal gap junctions in NMDA receptor-mediated excitotoxicity and ischemic neuronal death

正In the mammalian central nervous system(CNS)coupling of neurons by gap junctions and the expression of neuronal gap junction protein,connexin 36(Cx36)rapidly increases(usually during 1–2 hours)following a wide range of neuronal injuries,including ischemia,traumatic brain injury(TBI),spinal cord injury and epilepsy(reviewed in Belousov and Fontes,2013).Pharmacological blockade or genetic elimi-     

The unfolded protein response signaling and retinal Müller cell metabolism

The retina is one of the most energy demanding tissues in the body. Like most neurons in the central nervous system, retinal neurons consume high amounts of adenosine-5′-triphosphate(ATP) to generate visual signal and transmit the information to the brain. Disruptions in retinal metabolism can cause neuronal dysfunction and degeneration resulting in severe visual impairment and even blindness. The homeostasis of retinal metabolism is tightly controlled by multiple signaling pathways, such as the unfolded protein response(UPR), and the close interactions between retinal neurons and other retinal cell types including vascular cells and Müller glia. The UPR is a highly conserved adaptive cellular response and can be triggered by many physiological stressors and pathophysiological conditions. Activation of the UPR leads to changes in glycolytic rate, ATP production, de novo serine synthesis, and the hexosamine biosynthetic pathway, which are considered critical components of Müller glia metabolism and provide metabolic support to surrounding neurons. When these pathways are disrupted, neurodegeneration occurs rapidly. In this review, we summarize recent advance in studies of the UPR in Müller glia and highlight the potential role of the UPR in retinal degeneration through regulation of Müller glia metabolism.     

Functional recovery and muscle atrophy in pre-clinical models of peripheral nerve transection and gap-grafting in mice:effects of 4-aminopyridine

We recently demonstrated a repurposing beneficial effect of 4-aminopyridine(4-AP),a potassium channel blocker,on functional recove ry and muscle atrophy after sciatic nerve crush injury in rodents.However,this effect of 4-AP is unknown in nerve transection,gap,and grafting models.To evaluate and compare the functional recovery,nerve morphology,and muscle atrophy,we used a novel stepwise nerve transection with gluing(STG),as well as 7-mm irreparable nerve gap(G-7/0) and 7-mm isografting in 5-mm g...     

View on microRNAs as a potential tool to fight blindness: focus on Müller glia and gliosis

The neural retina is a part of the central nervous system.As it lacks regenerative capacity,in an event of injury or disease,neuronal loss leads to visual impairment and often to blindness.Moreover,Müller glia(MG),the predominant glia in the retina,undergo a variety of molecular and cellular changes and discontinue to carry out their important regular functions in the tissue(e.g.,maintaining tissue homeostasis and nurturing neurons).     

The role of gap junctions in cell death and neuromodulation in the retina

Vision altering diseases,such as glaucoma,diabetic retinopathy,age-related macular degeneration,myopia,retinal vascular disease,traumatic brain injuries and others cripple many lives and are projected to continue to cause anguish in the foreseeable future.Gap junctions serve as an emerging target for neuromodulation and possible regeneration as they directly connect healthy and/or diseased cells,thereby playing a crucial role in pathophysiology.Since they are permeable for macromolecules,able to cross the cellular barriers,they show duality in illness as a cause and as a therapeutic target.In this review,we take recent advancements in gap junction neuromodulation(pharmacological blockade,gene therapy,electrical and light stimulation)into account,to show the gap junction’s role in neuronal cell death and the possible routes of rescuing neuronal and glial cells in the retina succeeding illness or injury.     

Stressed axons craving for glial sugar: links to regeneration?

<正>Extract The contrary but interrelated processes of axon degeneration and regeneration are the yin and yang of many neurodegenerative conditions. Here we discuss recent evidence for metabolic cross-talk between glia and injured axons regulating these processes. We especially focus on potential bioenergetic mechanisms as to how axon-flanking glia may promote regeneration.     

Retinal regeneration requires dynamic Notch signaling

Retinal damage in the adult zebrafish induces Müller glia reprogramming to produce neuronal progenitor cells that proliferate and differentiate into retinal neurons.Notch signaling,which is a fundamental mechanism known to drive cell-cell communication,is required to maintain Müller glia in a quiescent state in the undamaged retina,and repression of Notch signaling is necessary for Müller glia to reenter the cell cycle.The dynamic regulation of Notch signaling following retinal damage also directs proliferation and neurogenesis of the Müller glia-derived progenitor cells in a robust regeneration response.In contrast,mammalian Müller glia respond to retinal damage by entering a prolonged gliotic state that leads to additional neuronal death and permanent vision loss.Understanding the dynamic regulation of Notch signaling in the zebrafish retina may aid efforts to stimulate Müller glia reprogramming for regeneration of the diseased human retina.Recent findings identified DeltaB and Notch3 as the ligand-receptor pair that serves as the principal regulators of zebrafish Müller glia quiescence.In addition,multi-omics datasets and functional studies indicate that additional Notch receptors,ligands,and target genes regulate cell proliferation and neurogenesis during the regeneration time course.Still,our understanding of Notch signaling during retinal regeneration is limited.To fully appreciate the complex regulation of Notch signaling that is required for successful retinal regeneration,investigation of additional aspects of the pathway,such as post-translational modification of the receptors,ligand endocytosis,and interactions with other fundamental pathways is needed.Here we review various modes of Notch signaling regulation in the context of the vertebrate retina to put recent research in perspective and to identify open areas of inquiry.     

Enteric glia mediate neuronal outgrowth through release of neurotrophic factors

Previous studies have shown that transplanted enteric glia enhance axonal regeneration, reduce tissue damage, and promote functional recovery following spinal cord injury. However, the mechanisms by which enteric glia mediate these beneficial effects are unknown. Neurotrophic factors can promote neuronal differentiation, survival and neurite extension. We hypothesized that enteric glia may exert their protective effects against spinal cord injury partially through the secretion of neurotrophic factors. In the present study, we demonstrated that primary enteric glia cells release nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor over time with their concentrations reaching approximately 250, 100 and 50 pg/mL of culture medium respectively after 48 hours. The biological relevance of this secretion was assessed by incubating dissociated dorsal root ganglion neuronal cultures in enteric glia-conditioned medium with and/or without neutralizing antibodies to each of these proteins and evaluating the differences in neurite growth. We discovered that conditioned medium enhances neurite outgrowth in dorsal root ganglion neurons. Even though there was no detectable amount of neurotrophin-3 secretion using ELISA analysis, the neurite outgrowth effect can be attenuated by the antibody-mediated neutralization of each of the aforementioned neurotrophic factors. Therefore, enteric glia secrete nerve growth factor, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor and neurotrophin-3 into their surrounding environment in concentrations that can cause a biological effect.     

Neural and Müller glial adaptation of the retina to photoreceptor degeneration

The majority of inherited retinal degenerative diseases and dry age-related macular degeneration are characterized by decay of the outer retina and photoreceptors, which leads to progressive loss of vision. The inner retina, including second-and third-order retinal neurons, also shows aberrant structural changes at all stages of degeneration. Müller glia, the major glial cells maintain retinal homeostasis, activating and rearranging immediately in response to photoreceptor stress. These phenomen...     

Live-cell imaging: new avenues to investigate retinal regeneration

Sensing and responding to our environment requires functional neurons that act in concert. Neuronal cell loss resulting from degenerative diseases cannot be replaced in humans, causing a functional impairment to integrate and/or respond to sensory cues. In contrast, zebrafish(Danio rerio) possess an endogenous capacity to regenerate lost neurons. Here, we will focus on the processes that lead to neuronal regeneration in the zebrafish retina. Dying retinal neurons release a damage signal, tumor necrosis factor α, which induces the resident radial glia, the Müller glia, to reprogram and re-enter the cell cycle. The Müller glia divide asymmetrically to produce a Müller glia that exits the cell cycle and a neuronal progenitor cell. The arising neuronal progenitor cells undergo several rounds of cell divisions before they migrate to the site of damage to differentiate into the neuronal cell types that were lost. Molecular and immunohistochemical studies have predominantly provided insight into the mechanisms that regulate retinal regeneration. However, many processes during retinal regeneration are dynamic and require live-cell imaging to fully discern the underlying mechanisms. Recently, a multiphoton imaging approach of adult zebrafish retinal cultures was developed. We will discuss the use of live-cell imaging, the currently available tools and those that need to be developed to advance our knowledge on major open questions in the field of retinal regeneration.     

Building the toolbox for in vivo glia-to-neuron reprogramming

<正>Unlike regenerative-competent species that possess a remarkable intrinsic capacity to replenish lost neurons and restore neurocircuits spontaneously, the central nervous system in adult mammals lacks the ability to compensate for the neuronal loss caused by neurodegenerative diseases or traumatic injuries resulting in permanent loss of functionality. Inspired by earlier discoveries that radial glia or astrocytes isolated from the postnatal cortex can generate neurons,     

Effect of glial cells on remyelination after spinal cord injury

Remyelination plays a key role in functional recovery of axons after spinal cord injury. Glial cells are the most abundant cells in the central nervous system. When spinal cord injury occurs, many glial cells at the lesion site are immediately activated, and different cells differentially affect inflammatory reactions after injury. In this review, we aim to discuss the core role of oligodendrocyte precursor cells and crosstalk with the rest of glia and their subcategories in the remyelination process. Activated astrocytes influence prolif-eration, differentiation, and maturation of oligodendrocyte precursor cells, while activated microglia alter remyelination by regulating the inflammatory reaction after spinal cord injury. Understanding the interac-tion between oligodendrocyte precursor cells and the rest of glia is necessary when designing a therapeutic plan of remyelination after spinal cord injury.     

Preserving GABAergic interneurons in acute brain slices of mice using the N-methyl-<Emphasis Type="Italic">D</Emphasis>-glucamine-based artificial cerebrospinal fluid method

Defects in the function and development of GABAergic interneurons have been linked to psychiatric disorders, so preservation of these interneurons in brain slices is important for successful electrophysiological recording in various ex vivo methods. However, it is difficult to maintain the activity and morphology of neurons in slices from mice of >30 days old. Here we evaluated the N-methyl-D-glucamine(NMDG)-based artificial cerebrospinal fl uid(a CSF) method for the preservation of interneurons in slices from mice of up to ~6 months old and discussed the steps that may affect their quality during slicing. We found that the NMDG-a CSF method rescued more cells than sucrose-a CSF and successfully preserved different types of interneurons including parvalbumin- and somatostatin-positive interneurons. In addition, both the chemical and electrical synaptic signaling of interneurons were maintained. These results demonstrate that the NMDG-a CSF method is suitable for the preservation of interneurons, especially in studies of gap junctions.     

Glial cells in neuronal development: recent advances and insights from Drosophila melanogaster

Gila outnumber neurons and are the most abundant cell type in the nervous system. Whereas neurons are the major carriers, transducers, and processors of information, glial cells, once considered mainly to play a passive supporting role, are now recognized for their active contributions to almost every aspect of nervous system development. Recently, insights from the invertebrate organism Drosophila melanogaster have advanced our knowledge of glial cell biology. In particular, findings on neuron-glia interactions via intrinsic and extrinsic mechanisms have shed light on the importance of gtia during different stages of neuronal development. Here, we summarize recent advances in understanding the functions of Drosophila glia, which resemble their mammalian counterparts in morphology and function, neural stem-cell conversion, synapse formation, and developmental axon pruning. These discoveries reinforce the idea that glia are substantial players in the developing nervous system and further advance the understanding of mechanisms leading to neurodegeneration.     

Can lithium enhance the extent of axon regeneration and neurological recovery following peripheral nerve trauma?

The clinical"gold standard"technique for attempting to restore function to nerves with a gap is to bridge the gap with sensory autografts.However,autografts induce good to excellent recovery only across short nerve gaps,in young patients,and when repairs are performed a short time post nerve trauma.Even under the best of conditions,<50%of patients recover good recovery.Although many alternative techniques have been tested,none is as effective as autografts.Therefore,alternative techniques are required that increase the percentage of patients who recover function and the extent of their recovery.This paper examines the actions of lithium,and how it appears to trigger all the cellular and molecular events required to promote axon regeneration,and how both in animal models and clinically,lithium administration enhances both the extent of axon regeneration and neurological recovery.The paper proposes more extensive clinical testing of lithium for its ability and reliability to increase the extent of axon regeneration and functional recovery.     

Gap junction communication involved in brain protection following focal ischemia and reperfusion in rats

BACKGROUND： Studies have suggested that gap junctions not only modulate the fate of the neocortex, but are also involved in maintaining homeostasis in the mature brain. However, the neuroprotective effects of gap junction communication following brain ischemic injury remain poorly understood.
OBJECTIVE： To investigate the neuroprotective effects and possible mechanisms of gap junction communication following focal ischemia and reperfusion.
DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the School of Basic Medical Sciences of Lanzhou University between June 2007 and May 2008.
MATERIALS： Rabbit polyclonal anti-connexin 43 （Cx43） and gap junction blocking agent octanol were purchased from Sigma, USA; mouse monoclonal anti-rat glial fibrillary acidic protein （GFAP） was provided by Santa Cruz, USA; mouse monoclonal anti-rat CD11 b was produced by Abcam, England.
METHODS： A total of 52 adult, male, Sprague Dawley rats were randomly assigned to three groups： sham-operated （n = 12）, vehicle control （n = 20）, and octanol-treated （n = 20）. Brain ischemia and reperfusion were induced by transient middle cerebral artery occlusion （MCAO） in vehicle control and octanol-treated groups, while no MCAO was administered to the sham-operated group. In the octanol-treated group, 5 mmol/kg octanol was dissolved in dimethyl sulfoxide （0.005% v/v） and was intraperitoneally injected 30 minutes prior to ischemic onset. Sham-operated and vehicle groups received equivalent volumes of dimethyl sulfoxide.
MAIN OUTCOME MEASURES： Infarct volumes in ipsilateral striatum after MCAO were measured using cresyl violet dye; GFAP, CD11 b, and Cx43 expression in the ipsilateral striatum following MCAO were detected by immunohistochemistry; Western blot analysis was employed to determine Cx43 and GFAP expression.
RESULTS： At 1 and 3 days following MCAO and reperfusion, ipsilateral striatum infarct volumes in the octanol group were significantly greater than in the vehicle group （P 〈 0.05）. There was no infarction in the sham-operated group. Cx43 and GFAP expression in the ipsilateral striatum of the octanol group was remarkably decreased compared with the vehicle group （P 〈 0.05）, and expression in the sham-operated group was less than in the other two groups （P 〈 0.05）. In the octanol-treated group, CD11 b expression was significantly increased compared with the vehicle group （P 〈 0.05）, and there were less CD11 b-immunoreactive cells in the sham-operated group compared with the other two groups （P 〈 0.05）.
CONCLUSION： The pretreatment of blocking gap junction aggravated brain injury following MCAO. These results were possibly due to reduced astrocyte proliferation and activation, as well as reduced inflammatory response via activated microglia.     

Non-coding RNAs and stem cells:the dream team for neural regeneration in Parkinson’s disease?

Parkinson’s disease(PD)is a widely spread neurodegenerative movement disorder,affecting approximately 10 million people worldwide.It is primarily caused by the loss of dopaminergic neurons in the substantia nigra,which causes decreased secretion of dopamine leading to tremors,bradykinesia and rigid muscle movement.The development of PD is complex and needs to be better understood.Current treatment strategies primarily involve targeting disease symptoms,however,since there is a continuous loss of dopaminergic neurons in the brain,PD appears to be incurable.Moreover,treatment strategies often carry severe side effects related to dopamine production,where too little or too much can cause debilitating issues such as dyskinesia.The pool of neural stem/progenitor cells(NSCs)located in sub-ventricular zone and hippocampal dentate gyrus,proliferate and are responsible to give rise to neurons and glia in response to any cellular damage.Though this activation of NSCs is highly regulated,it is insufficient to overcome the loss of dopaminergic neurons in PD.In this line,non-coding RNAs(ncRNAs)are involved in the underlying mechanisms of PD and are known to have important functional roles in neural regeneration(Acharya et al.,2020).Thus,the study of ncRNAs in NSC activation and adult neurogenesis post PD development is an extremely attractive area of research with significant clinical application potential.