Zebrafish central nervous system (CNS) possesses a strong neural regeneration ability to restore visual function completely after optic nerve injury (ONI). However, whether neurogenesis of retinal ganglion cell (RGC) contributes to functional recovery remains controversial. Our quantitative analysis of RGCs in different ONI models showed that almost all RGCs survived in optic nerve crush (ONC) model; while over 90% of RGCs survived in the first 2 weeks with 75% remaining after 7 weeks in optic nerve transection (ONT) model. Retrograde labeling from tectum revealed a surprising regeneration rate, with over 90% and over 50% of RGCs regrowing axons to tectum at the first week in ONC and ONT model respectively. In the latter one, the number of regenerative RGCs after 4 weeks had no significant difference from the control group. As for neurogenesis, newborn RGCs were rarely detected either by double retrograde labeling or BrdU marker. Since few RGCs died, microglia number showed a temporary increase at 3 days post injury (dpi) and a decrease at 14 dpi. Finally, myelin structure within retina kept integrity and optomotor response (OMR) test demonstrated visual functional restoration at 5 weeks post injury (wpi). In conclusion, our results have directly shown that RGC survival and axon regrowth are responsible for functional recovery after ONI in adult zebrafish.
BackgroundTransmembrane protein 108 (Tmem108) is a risk gene of psychiatric diseases including schizophrenia, bipolar disorder and major depression disorder. However, the pathophysiological mechanisms of Tmem108 are largely unknown.ResultsHere we investigated the pathophysiological function of Tmem108 in the hippocampal dentate gyrus by using Tmem108 mutant mice. Tmem108 highly expressed in the dentate gyrus and CA3 of the hippocampus. Dentate gyrus is a brain region where adult neurogenesis occurs, and aberrant adult neurogenesis in dentate gyrus has been implicated in major depression disorder. Indeed, Tmem108 mutant mice had lower immobility than wild type mice in tail suspension test and forced swimming test. BrdU and anti-Ki67 antibody staining indicated that adult neurogenesis of the hippocampal dentate gyrus region decreased in Tmem108 mutant mice. qPCR results showed that expression of Axin2, DISC1 and β-Catenin, three dentate gyrus adult neurogenesis related genes in Wnt/β-Catenin signaling pathway, decreased in Tmem108 mutant mice. Furthermore, Tmem108 enhanced free β-Catenin level in dual luciferase assay.ConclusionsThus, our data suggest that Tmem108 increases adult neurogenesis and plays a complexity role in psychiatric disorders.
Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disease characterized by progressive muscle weakness and wasting. Stimulation of AMP-activated protein kinase (AMPK) has been demonstrated to increase muscle function and protect muscle against damage in dystrophic mice. Metformin is a widely used anti-hyperglycemic drug and has been shown to be an indirect activator of AMPK. Based on these findings, we sought to determine the effects of metformin on neuromuscular deficits in mdx murine model of DMD. In this study, we found metformin treatment increased muscle strength accompanied by elevated twitch and tetanic force of tibialis anterior (TA) muscle in mdx mice. Immunofluorescence and electron microscopy analysis of metformin-treated mdx muscles revealed an improvement in muscle fiber membrane integrity. Electrophysiological studies showed the amplitude of miniature endplate potentials (mEPP) was increased in treated mice, indicating metformin also improved neuromuscular transmission of the mdx mice. Analysis of mRNA and protein levels from muscles of treated mice showed an upregulation of AMPK phosphorylation and dystrophin-glycoprotein complex protein expression. In conclusion, metformin can indeed improve muscle function and diminish neuromuscular deficits in mdx mice, suggesting its potential use as a therapeutic drug in DMD patients.
PURPOSE. There is no myelination in most mammalian retinas, and if it does happen, it is always accompanied by eye disease. Although lower vertebrates are born with myelin, the precise temporal dynamics of myelination in which oligodendrocytes (OLs) are involved, the origin of OLs, their behaviors in myelination, and their function in retinas have not yet been clearly elaborated. Therefore, we focus on these aspects to study the oligodendrocytes and myelin sheath in the zebrafish retina. METHODS.Retinal whole mount, immunohistochemistry, and optic nerve retrograde labeling were performed to monitor the myelination. Taking advantage of whole eye eversion and transplantation techniques, we studied the retinal origin of OLs. By optic nerve transplantation, we can observe single OLs in zebrafish retina. The optokinetic reflex (OKR) behavior test and the lysophosphatidylcholine (LPC)-induced retinal demyelination model were used to test the function of the myelin.RESULTS. First, we demonstrated that myelination starts at 28 dpf in zebrafish retinas. Second, we directly proved that all the OLs in zebrafish retinas migrated from the optic nerve rather than from a domestic source. Third, we found that compared with adult OLs, younger OLs tend to generate longer but a fewer number of internodes. Finally, we found that the myelin in zebrafish eyes is functionally relevant to the elegant OKR.CONCLUSIONS. Our data suggest that the extraocular source of OLs first appeared at 28 dpf in zebrafish retina and then gradually developed with age, which contribute to optokinetic responses.
Mutations in some cell adhesion molecules (CAMs) cause abnormal synapse formation and maturation, and serve as one of the potential mechanisms of autism spectrum disorders (ASDs). Recently, DSCAM (Down syndrome cell adhesion molecule) was found to be a high-risk gene for autism. However, it is still unclear how DSCAM contributes to ASD. Here, we show that DSCAM expression was downregulated following synapse maturation, and that DSCAM deficiency caused accelerated dendritic spine maturation during early postnatal development.Mechanistically, the extracellular domain (ECD) of DSCAM interacts with neuroligin1 (NLGN1) to block the NLGN1-neurexin1β (NRXN1β) interaction. DSCAM-ECD was able to rescue spine overmaturation in DSCAM knockdown neurons. Precocious spines in DSCAM-deficient mice showed increased glutamatergic transmission in the developing cortex and induced autism-like behaviors such as social novelty deficits and repetitive behaviors. Thus, DSCAM might be a repressor that prevents premature spine maturation and excessive glutamatergic transmission, and its deficiency could lead to autism-like behaviors. Our study provides new insight into the potential pathophysiological mechanisms of ASDs.
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