Dark rearing maintains tyrosine hydroxylase expression in retinal amacrine cells following optic nerve transection

The present study examined changes in retinal tyrosine hydroxylase （TH） expression in rats having undergone optic nerve transection and housed under a normal day/night cycle or in the dark. The aim was to investigate the effects of amacrine cells on axonal regeneration in retinal ganglion cells and on the synapses that transmit visual signals. The results revealed that retinal TH expression gradually decreased following optic nerve transection in rats housed under a normal day/night cycle reaching a minimum at 5 days. In contrast, retinal TH expression decreased to a minimum at 1 day following optic nerve transection in dark reared rats, gradually increasing afterward and reaching a normal level at 5 7 days. The number of TH-positive synaptic particles correlated with the TH levels indicating that dark rearing can help maintain TH expression during the synaptic degeneration stage （5 7 days after optic nerve injury） in retinal amacrine cells.

Starburst amacrine cells,involved in visual motion perception,lose their synaptic input from dopaminergic amacrine cells and degenerate in Parkinson’s disease patients

Background The main clinical symptoms characteristic of Parkinson’s disease(PD)are bradykinesia,tremor,and other motor deficits.However,non-motor symptoms,such as visual disturbances,can be identified at early stages of the disease.One of these symptoms is the impairment of visual motion perception.Hence,we sought to determine if the starburst amacrine cells,which are the main cellular type involved in motion direction selectivity,are degenerated in PD and if the dopaminergic system is related to this degeneration.Methods Human eyes from control(n=10)and PD(n=9)donors were available for this study.Using immunohistochemistry and confocal microscopy,we quantified starburst amacrine cell density(choline acetyltransferase[ChAT]-positive cells)and the relationship between these cells and dopaminergic amacrine cells(tyrosine hydroxylase-positive cells and vesicular monoamine transporter-2-positive presynapses)in cross-sections and wholemount retinas.Results First,we found two different ChAT amacrine populations in the human retina that presented different ChAT immunoreactivity intensity and different expression of calcium-binding proteins.Both populations are affected in PD and their density is reduced compared to controls.Also,we report,for the first time,synaptic contacts between dopaminergic amacrine cells and ChAT-positive cells in the human retina.We found that,in PD retinas,there is a reduction of the dopaminergic synaptic contacts into ChAT cells.Conclusions Taken together,this work indicates degeneration of starburst amacrine cells in PD related to dopaminergic degeneration and that dopaminergic amacrine cells could modulate the function of starburst amacrine cells.Since motion perception circuitries are affected in PD,their assessment using visual tests could provide new insights into the diagnosis of PD.

Overexpressing NeuroD1 reprograms Müller cells into various types of retinal neurons

The onset of retinal degenerative disease is often associated with neuronal loss. Therefore, how to regenerate new neurons to restore vision is an important issue. NeuroD1 is a neural transcription factor with the ability to reprogram brain astrocytes into neurons in vivo. Here, we demonstrate that in adult mice, NeuroD1 can reprogram Müller cells, the principal glial cell type in the retina, to become retinal neurons. Most strikingly, ectopic expression of NeuroD1 using two different viral vectors converted Müller cells into different cell types. Specifically, AAV7 m8 GFAP681::GFP-ND1 converted Müller cells into inner retinal neurons, including amacrine cells and ganglion cells. In contrast, AAV9 GFAP104::ND1-GFP converted Müller cells into outer retinal neurons such as photoreceptors and horizontal cells, with higher conversion efficiency. Furthermore, we demonstrate that Müller cell conversion induced by AAV9 GFAP104::ND1-GFP displayed clear dose-and time-dependence. These results indicate that Müller cells in adult mice are highly plastic and can be reprogrammed into various subtypes of retinal neurons.

Connexins in neurons and glia: targets for intervention in disease and injury

Both neurons and glia throughout the central nervous system are organized into networks by gap junctions. Among glia, gap junctions facilitate metabolic homeostasis and intercellular communication. Among neurons, gap junctions form electrical synapses that function primarily for communication. However, in neurodegenerative states due to disease or injury gap junctions may be detrimental to survival. Electrical synapses may facilitate hyperactivity and bystander killing among neurons, while gap junction hemichannels in glia may facilitate inflammatory signaling and scar formation. Advances in understanding mechanisms of plasticity of electrical synapses and development of molecular therapeutics to target glial gap junctions and hemichannels offer new hope to pharmacologically limit neuronal degeneration and enhance recovery.

Extrinsic regulation of optic nerve regeneration

Retinal ganglion cells(RGCs)extend through the optic nerve,connecting with neurons in visually related nuclei.Similar to most mature neurons in the central nervous system,once damaged,RGCs are unable to regenerate their axons and swiftly progress to cell death.In addition to cell-intrinsic mechanisms,extrinsic factors within the extracellular environment,notably glial and inflammatory cells,exert a pivotal role in modulating RGC neurodegeneration and regeneration.Moreover,burgeoning evidence suggests that retinal interneurons,specifically amacrine cells,exert a substantial influence on RGC survival and axon regeneration.In this review,we consolidate the present understanding of extrinsic factors implicated in RGC survival and axon regeneration,and deliberate on potential therapeutic strategies aimed at fostering optic nerve regeneration and restoring vision.

Foxn4:A multi-faceted transcriptional regulator of cell fates in vertebrate development

Vertebrate development culminates in the generation of proper proportions of a large variety of different cell types and subtypes essential for tissue,organ and system functions in the right place at the right time.Foxn4,a member of the forkhead box/winged-helix transcription factor superfamily,is expressed in mitotic progenitors and/or postmitotic precursors in both neural(e.g.,retina and spinal cord)and non-neural tissues(e.g.,atrioventricular canal and proximal airway).During development of the central nervous system,Foxn4 is required to specify the amacrine and horizontal cell fates from multipotent retinal progenitors while suppressing the alternative photoreceptor cell fates through activating Dll4-Notch signaling.Moreover,it activates Dll4-Notch signaling to drive commitment of p2 progenitors to the V2b and V2c interneuron fates during spinal cord neurogenesis.In development of non-neural tissues,Foxn4 plays an essential role in the specification of the atrioventricular canal and is indirectly required for patterning the distal airway during lung development.In this review,we highlight current understanding of the structure,expression and developmental functions of Foxn4 with an emphasis on its cell-autonomous and non-cell-autonomous roles in different tissues and animal model systems.