Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome

Hereditary spastic paraplegias (HSPs) are genetically-determined, neurodegenerative disorders characterized by progressive weakness and spasticity of the lower limbs. Spastic paraplegia type 11 (SPG11) is a complicated form of HSP, which is caused by mutations in the SPG11 gene encoding spatacsin, a protein possibly involved in lysosomal reformation. Based on our previous studies demonstrating that secondary neuroinflammation can be a robust amplifier of various genetically-mediated diseases of both the central and peripheral nervous system, we here test the possibility that neuroinflammation may modify the disease outcome also in a mouse model for SPG11. Spg11-knockout (Spg11^-/-) mice develop early walking pattern and behavioral abnormalities, at least partially reflecting motor, and behavioral changes typical for patients. Furthermore, we detected a progressive increase in axonal damage and axonal spheroid formation in the white and grey matter compartments of the central nervous system of Spg11^-/- mice. This was accompanied by a concomitant substantial increase of secondary inflammation by cytotoxic CD8⁺ and CD4⁺ T-lymphocytes. We here provide evidence that disease-related changes can be ameliorated/delayed by the genetic deletion of the adaptive immune system. Accordingly, we provide evidence that repurposing clinically approved immunomodulators (fingolimod/FTY720 or teriflunomide), that are in use for treatment of multiple sclerosis (MS), also improve disease symptoms in mice, when administered in an early (before neural damage) or late (after/during neural damage) treatment regime. This work provides strong evidence that immunomodulation can be a therapeutic option for the still untreatable SPG11, including its typical neuropsychological features. This poses the question if inflammation is not only a disease amplifier in SPG11 but can act as a unifying factor also for other genetically mediated disorders of the CNS. If true, this may pave the way to therapeutic options in a wide range of still untreatable, primarily genetic, neurological disorders by repurposing approved immunomodulators

Glaucoma is one of the leading causes of irreversible blindness worldwide and vision loss in the disease results from the deterioration of retinal ganglion cells (RGC) and their axons. Metabolic dysfunction of RGC plays a significant role in the onset and progression of the disease in both human patients and rodent models, highlighting the need to better define the mechanisms regulating cellular energy metabolism in glaucoma. This study sought to determine if Sarm1, a gene involved in axonal degeneration and NAD+ metabolism, contributes to glaucomatous RGC loss in a mouse model with chronic elevated intraocular pressure (IOP). Our data demonstrate that after 16 weeks of elevated IOP, Sarm1 knockout (KO) mice retain significantly more RGC than control animals. Sarm1 KO mice also performed significantly better when compared to control mice during optomotor testing, indicating that visual function is preserved in this group. Our findings also indicate that Sarm1 KO mice display mild ocular developmental abnormalities, including reduced optic nerve axon diameter and lower visual acuity than controls. Finally, we present data to indicate that SARM1 expression in the optic nerve is most prominently associated with oligodendrocytes. Taken together, these data suggest that attenuating Sarm1 activity through gene therapy, pharmacologic inhibition, or NAD+ supplementation, may be a novel therapeutic approach for patients with glaucoma.

The purpose of this study was to examine the effect of a blast exposure generated from a shock tube on retinal ganglion cell (RGC) function and structure. Mice were exposed to one of three blast conditions using a shock tube; a single blast wave of 20 PSI, a single blast wave of 30 PSI, or three blast waves of 30 PSI given on three consecutive days with a one-day inter-blast interval. The structure and function of the retina were analyzed using the pattern electroretinogram (PERG), the optomotor reflex (OMR), and optical coherence tomography (OCT). The in vivo parameters were examined at baseline, and then again 1-week, 4-weeks, and 16-weeks following blast exposure. The number of surviving RGCs was quantified at the end of the study. Analysis of mice receiving a 20 PSI injury showed decreased PERG and OMR responses 16-weeks post blast, without evidence of changed retinal thickness or RGC death. Mice subjected to a 30 PSI injury showed decreased PERG responses 4 weeks and 16 weeks after injury, without changes in the retinal thickness or RGC density. Mice subjected to 30 PSI X 3 blast exposures had PERG deficits 1-week and 4-weeks post exposure. There was also significant change in retinal thickness 1-week and 16-weeks post blast exposure. Mice receiving 30 PSI X 3 blast injuries had regional loss of RGCs in the central retina, but not in the mid-peripheral or peripheral retina. Overall, this study has shown that increasing the number of blast exposures and the intensity leads to earlier functional loss of RGCs. We have also shown regional RGC loss only when using the highest blast intensity and number of blast injuries.

Purpose: Intrinsically photosensitive retinal ganglion cells (ipRGCs) play a crucial role in non–image-forming visual functions. Given their significant loss observed in various ocular degenerative diseases at early stages, this study aimed to assess changes in both the morphology and associated behavioral functions of ipRGCs in mice between 6 (mature) and 12 (late adult) months old. The findings contribute to understanding the preservation of ipRGCs in late adults and their potential as a biomarker for early ocular degenerative diseases. Methods: Female and male C57BL/6J mice were used to assess the behavioral consequences of aging to mature and old adults, including pupillary light reflex, light aversion, visual acuity, and contrast sensitivity. Immunohistochemistry on retinal wholemounts from these mice was then conducted to evaluate ipRGC dendritic morphology in the ganglion cell layer (GCL) and inner nuclear layer (INL). Results: Morphological analysis showed that ipRGC dendritic field complexity was remarkably stable through 12 months old of age. Similarly, the pupillary light reflex, visual acuity, and contrast sensitivity were stable in mature and old adults. Although alterations were observed in ipRGC-independent light aversion distinct from the pupillary light reflex, aged wild-type mice continuously showed enhanced light aversion with dilation. No effect of sex was observed in any tests. Conclusions: The preservation of both ipRGC morphology and function highlights the potential of ipRGC-mediated function as a valuable biomarker for ocular diseases characterized by early ipRGC loss. The consistent stability of ipRGCs in mature and old adult mice suggests that detected changes in ipRGC-mediated functions could serve as early indicators or diagnostic tools for early-onset conditions such as Alzheimer's disease, Parkinson's disease, and diabetes, where ipRGC loss has been documented.

Glaucoma, a chronic neurodegenerative disease, is a leading cause of age-related blindness worldwide and characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons. Previously, we developed a novel epigenetic rejuvenation therapy, based on the expression of the three transcription factors Oct4, Sox2, and Klf4 (OSK), which safely rejuvenates RGCs without altering cell identity in glaucomatous and old mice after 1 month of treatment. In the current year-long study, mice with continuous or cyclic OSK expression induced after glaucoma-induced vision damage had occurred were tracked for efficacy, duration, and safety. Surprisingly, only 2 months of OSK fully restored impaired vision, with a restoration of vision for 11 months with prolonged expression. In RGCs, transcription from the doxycycline (DOX)-inducible Tet-On AAV system, returned to baseline 4 weeks after DOX withdrawal. Significant vision improvements remained for 1 month post switching off OSK, after which the vision benefit gradually diminished but remained better than baseline. Notably, no adverse effects on retinal structure or body weight were observed in glaucomatous mice with OSK continuously expressed for 21 months providing compelling evidence of efficacy and safety. This work highlights the tremendous therapeutic potential of rejuvenating gene therapies using OSK, not only for glaucoma but also for other ocular and systemic injuries and age-related diseases.

This study describes phenotypic differences between constitutive and conditional mutant mouse models of Sifrim-Hitz-Weiss syndrome, a neurodevelopmental disorder caused by mutations in the CHD4 gene. Behavioral and organ-ic deficits depended on the location and timing of the loss-of-function mutation of CHD4, resulting in unexpected phenotypic divergence. As many of the behavioral tests were vision-based, Larrigan et al used the OptoDrum to es-tablish that there were no obvious visual deficits in these mice.

Vision depends on accurate signal conduction from the retina to the brain through the optic nerve, an important part of the central nervous system that consists of bundles of axons originating from retinal ganglion cells. The mammalian optic nerve, an important part of the central nervous system, cannot regenerate once it is injured, leading to permanent vision loss. To date, there is no clinical treatment that can regenerate the optic nerve and restore vision. Our previous study found that the mobile zinc (Zn²⁺) level increased rapidly after optic nerve injury in the retina, specifically in the vesicles of the inner plexiform layer. Furthermore, chelating Zn²⁺ significantly promoted axonal regeneration with a long-term effect. In this study, we conditionally knocked out zinc transporter 3 (ZnT3) in amacrine cells or retinal ganglion cells to construct two transgenic mouse lines (VGAT^CreZnT3^fl/fl and VGLUT2^CreZnT3^fl/fl, respectively). We obtained direct evidence that the rapidly increased mobile Zn²⁺ in response to injury was from amacrine cells. We also found that selective deletion of ZnT3 in amacrine cells promoted retinal ganglion cell survival and axonal regeneration after optic nerve crush injury, improved retinal ganglion cell function, and promoted vision recovery. Sequencing analysis of reginal ganglion cells revealed that inhibiting the release of presynaptic Zn²⁺ affected the transcription of key genes related to the survival of retinal ganglion cells in postsynaptic neurons, regulated the synaptic connection between amacrine cells and retinal ganglion cells, and affected the fate of retinal ganglion cells. These results suggest that amacrine cells release Zn²⁺ to trigger transcriptomic changes related to neuronal growth and survival in retinal ganglion cells, thereby influencing the synaptic plasticity of retinal networks. These results make the theory of zinc-dependent retinal ganglion cell death more accurate and complete and provide new insights into the complex interactions between retinal cell networks.

Regulation of gene expression is required for embryogenesis and maintenance of the highly specialized and diverse neuron populations of the retina. Chromatin remodelling proteins control gene expression by modifying chromatin structure and are essential for many biological processes including mammalian development. The ATP-dependent chromatin remodelling protein Snf2h is highly expressed in the central nervous system, and pathogenic variants that cause neurodevelopmental abnormalities in the human population have recently been identified. This work aims to characterize the effects of Snf2h loss in the retina. Snf2h retinal conditional knockout (cKO) mice were generated using Snf2h-floxed mice and Chx10-Cre retina-specific Cre driver lines to ablate the Snf2h protein from the retina at embryonic day 10.5. Visual function was assessed via optomotor response-based testing and full-field scotopic electroretinography, and histological changes were examined via immunohistochemistry. Disease progression was tracked at one, two, three, and six months of age. Snf2h cKO mice showed a significant decline in visual function and exhibited retinal neuron loss compared to wildtype control littermates at all time points assessed. This work shows that the chromatin remodelling protein Snf2h plays an essential role in the structure and function of the retina.

Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8⁺ T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.

Introduction: Optic neuritis (ON) is often an early sign of multiple sclerosis (MS), and recent studies show a link between HIF-1 pathway activation and inflammation. This study aimed to determine if inhibition of the HIF-1 pathway using the HIF-1a antagonist acriflavine (ACF) can reduce clinical progression and rescue the ocular phenotype in an experimental autoimmune encephalomyelitis (EAE) ON model. Methods: EAE-related ON was induced in 60 female C57BL/6J mice by immunization with MOG33-55, and 20 EAE mice received daily systemic injections of ACF at 5 mg/kg. Changes in the visual function and structure of ACF-treated EAE mice were compared to those of placebo-injected EAE mice and naïve control mice. Results: ACF treatment improved motor–sensory impairment along with preserving visual acuity and optic nerve function. Analysis of retinal ganglion cell complex also showed preserved thickness correlating with increased survival of retinal ganglion cells and their axons. Optic nerve cell infiltration and magnitude of demyelination were decreased in ACF-treated EAE mice. Subsequent in vitro studies revealed improvements not only attributed to the inhibition of HIF-1 but also to previously unappreciated interaction with the eIF2a/ATF4 axis in the unfolded protein response pathway. Discussion: This study suggests that ACF treatment is effective in an animal model of MS via its pleiotropic effects on the inhibition of HIF-1 and UPR signaling, and it may be a viable approach to promote rehabilitation in MS.

Background: Increased age is a risk factor for the development and progression of retinal diseases including age-related macular degeneration (AMD). Understanding the changes that occur in the eye due to aging is important in enhancing our understanding of AMD pathogenesis and the development of novel AMD therapies. Microglia, the resident brain and retinal immune cells are associated with both maintaining homeostasis and protection of neurons and loss of microglia homeostasis could be a significant player in age related neurodegeneration. One important characteristic of retinal aging is the migration of microglia from the inner to outer retina where they reside in the subretinal space (SRS) in contact with the retinal pigment epithelial (RPE) cells. The role of aged subretinal microglia is unknown. Here, we depleted microglia in aged C57/BL6 mice fed for 6 weeks with a chow containing PLX5622, a small molecule inhibitor of colony-stimulating factor-1 receptor (Csf1r) required for microglial survival. Results: The subretinal P2RY12 + microglia in aged mice displayed a highly amoeboid and activated morphology and were filled with autofluorescence droplets reminiscent of lipofuscin. TEM indicates that subretinal microglia actively phagocytize shed photoreceptor outer segments, one of the main functions of retinal pigmented epithelial cells. PLX5622 treatment depleted up to 90% of the retinal microglia and was associated with significant loss in visual function. Mice on the microglia depletion diet showed reduced contrast sensitivity and significantly lower electroretinogram for the c-wave, a measurement of RPE functionality, compared to age-matched controls. The loss of c-wave coincided with a loss of RPE cells and increased RPE swelling in the absence of microglia. Conclusions: We conclude that microglia preserve visual function in aged mice and support RPE cell function, by phagocytosing shed photoreceptor outer segments and lipids, therefore compensating for the known age-related decline of RPE phagocytosis.

Background and objectives: Mechanisms of visual impairment in aquaporin 4 antibody (AQP4-IgG) seropositive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disorder (MOGAD) are incompletely understood. The respective impact of optic nerve demyelination and primary and secondary retinal neurodegeneration are yet to be investigated in animal models. Methods: Active MOG_35-55 experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6Jrj mice, and monoclonal MOG-IgG (8-18C5, murine), recombinant AQP4-IgG (rAb-53, human), or isotype-matched control IgG (Iso-IgG, human) was administered 10 days postimmunization. Mobility impairment was scored daily. Visual acuity by optomotor reflex and ganglion cell complex thickness (GCC, 3 innermost retinal layers) by optical coherence tomography (OCT) were longitudinally assessed. Histopathology of optic nerve and retina was investigated during presymptomatic, acute, and chronic disease phases for immune cells, demyelination, complement deposition, natural killer (NK) cell, AQP4, and astrocyte involvement, retinal ganglion cells (RGCs), and Müller cell activation. Groups were compared by nonparametric tests with a p value <0.05 indicating statistical significance. Results: Visual acuity decreased from baseline to chronic phase in MOG-IgG (mean ± standard error of the mean: 0.54 ± 0.01 to 0.46 ± 0.02 cycles/degree, p < 0.05) and AQP4-IgG EAE (0.54 ± 0.01 to 0.43 ± 0.02, cycles/degree, p < 0.05). Immune cell infiltration of optic nerves started in presymptomatic AQP4-IgG, but not in MOG-IgG EAE (5.85 ± 2.26 vs 0.13 ± 0.10 macrophages/region of interest [ROI] and 1.88 ± 0.63 vs 0.15 ± 0.06 T cells/ROI, both p < 0.05). Few NK cells, no complement deposition, and stable glial fibrillary acid protein and AQP4 fluorescence intensity characterized all EAE optic nerves. Lower GCC thickness (Spearman correlation coefficient r = -0.44, p < 0.05) and RGC counts (r = -0.47, p < 0.05) correlated with higher mobility impairment. RGCs decreased from presymptomatic to chronic disease phase in MOG-IgG (1,705 ± 51 vs 1,412 ± 45, p < 0.05) and AQP4-IgG EAE (1,758 ± 14 vs 1,526 ± 48, p < 0.01). Müller cell activation was not observed in either model. Discussion: In a multimodal longitudinal characterization of visual outcome in animal models of MOGAD and NMOSD, differential retinal injury and optic nerve involvement were not conclusively clarified. Yet optic nerve inflammation was earlier in AQP4-IgG-associated pathophysiology. Retinal atrophy determined by GCC thickness (OCT) and RGC counts correlating with mobility impairment in the chronic phase of MOG-IgG and AQP4-IgG EAE may serve as a generalizable marker of neurodegeneration.

Objective: Traumatic optic neuropathy (TON) causes partial or complete blindness because death of irreplaceable retinal ganglion cells (RGCs). Neuroprotective functions of erythropoietin (EPO) in the nervous system have been considered by many studies investigating effectiveness of this cytokine in various retinal disease models. It has been found that changes in retinal neurons under conditions of glial cells are effective in vision loss, therefore, the present study hypothesized that EPO neuroprotective effect could be mediated through glial cells in TON model. Materials and methods: In this experiment study, 72 rats were assessed in the following groups: intact and optic nerve crush which received either the 4000 IU EPO or saline. Visual evoked potential and optomotor response and RGC number were assessed and regenerated axons evaluated by anterograde test. Cytokines gene expression changes were compared by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Density of astrocytes cells, assessed by fluorescence intensity, in addition, possible cytotoxic effect of EPO was measured on mouse astrocyte culture in vitro. Results: in vitro data showed that EPO was not toxic for mouse astrocytes. Intravenous injection of EPO improved vision, in terms of visual behavioral tests. RGCs protection was more than two times in EPO, compared to the vehicle group. More regenerated axons were determined by anterograde tracing in the EPO group compared to the vehicle. Moreover, GFAP immunostaining showed while the intensity of reactive astrocytes was increased in injured retina, systemic EPO decreased it. In the treatment group, expression of GFAP was down-regulated, while CNTF was upregulated as assessed by qRT-PCR in the 60^th day post-crush. Conclusion: Our study showed that systemic administration of EPO can protect degenerating RGCs. Indeed, exogenous EPO exerted neuroprotective and neurotrophic functions by reducing reactive astrocytic gliosis. Therefore, reduction of gliosis by EPO may be considered as therapeutic targets for TON.

The cell death in retinal degenerative diseases, such as age-related macular degeneration (AMD) or retinitis pigmentosa (RP), is often caused by the body’s own immune system, which attacks retinal cells. In this study, Zhu et al discuss the effects of a compound called dBET6 against retinal degeneration in response to light damage. dBET6 inhibits a molecular pathway of the innate immune system known as cGAS-STING. The research demonstrates that dBET6 treatment effectively prevents retinal degeneration and reduces inflammation in the retina caused by exposure to excessive light. The study suggests that dBET6 could potentially be used as a therapeutic agent to mitigate retinal degenerative conditions and offers insights into the underlying mechanisms involved in light-induced retinal damage.

Li and Jacobs show that Vitamin C, administered through drinking water protects retinal ganglion cells during glaucoma and after optic nerve crush. The elucidate the pathway of Vitamin C action which involves reactive astrocytes. The positive effect of Vitamin C can be seen not only in histological examinations, but is also manifested in preserved visual acuity, as measured with Striatech’s OptoDrum.

Retinal ischemia/reperfusion (I/R) injury can cause permanent vision loss, and effective treatments are currently lacking. Xue et al have discovered that early damage to the optic nerve’s myelin sheath is a key factor in this injury. By targeting a receptor called S1PR2 and using a specific inhibitor called JTE-013, they were able to protect retinal cells, prevent demyelination, and promote visual function recovery.

This research focuses on understanding how the rhodopsin protein found in a box jellyfish utilizes a unique Gαs intracellular pathway to achieve fast vision. The study uncovers a mechanism where the rhodopsin protein constitutively binds to a single downstream Gαs partner, enabling rapid activation and inactivation of G-protein signaling within milliseconds. By studying the rhodopsin protein, van Wyk and Kleinlogel engineered an optogenetic tool and used it in viral gene therapy to restore light responses in blind mice.

This study explores the role of CD8+ T cells in conditions where the myelin sheath is damaged. These T cells specifically target and attack mutated cells responsible for producing myelin, leading to nerve damage and degeneration. They found that early treatment with a specific medication can reduce the recruitment of harmful T cells and prevent further damage. However, targeting these T cells later on is less effective. Understanding these interactions may help develop new treatments for conditions involving myelin defects and inflammation.

Looming dark stimuli (an expanding shadow) evoke evolutionary conserved fear or flight responses. This study looked at the effects on this behavior of ablating starburst amacrine cells, a specific interneuron in the retina which is involved in direction-selective retinal responses. Bohl et al found that looming-induced fear responses were eliminated when a sufficient number of OFF starburst cell were ablated. As a further behavioral readout to confirm successful starburst ablation, Bohl et al used measurements of the optomotor reflex which is known to depend on the direction-selective circuitry in the retina. OMR seemed to depend mostly on ON starburst cells, so that the two behavioral changes (OMR and looming-induced fear response) did not coincide in all mice.

Optogenetic restoration of visual function is a promising therapeutic avenue to restore vision after retinal degeneration. Targeted and efficient expression of optogenes, however, still proves challenging. In this study, Maddalena and Kleinlogel explored CRISPR-mediated expression of the optogene Opto-mGluR6 in retinal bipolar cells. They found, using Striatech’s OptoDrum, that treatment of otherwise blind rd1 mice improved their visual acuity significantly.

Varadarajan et al have discovered that stimulating specific brain cells can promote the regeneration of damaged optic nerve fibers, potentially restoring lost vision. By increasing neural activity in the brain’s visual target neurons, they found that retinal ganglion cell (RGC) axons can regrow and reconnect with their proper synaptic targets. This finding highlights the importance of postsynaptic brain targets in repairing visual circuits and offers hope for developing strategies to restore vision in individuals with vision loss.

Wolfram syndrome is a rare genetic disorder with mutations in the gene WFS1. The corresponding protein wolframin, a transmembrane protein located in the endoplasmic reticulum, is involved in multiple metabolic processes. Pa-tients suffer from several complications, including diabetes from infancy and progressive complete vision loss. Here, Rossi et al concentrated on the retinal phenotype in a Wolfram syndrome mouse model, to describe the progression of the disease and the underlying mechanisms.

This article is an in-depth investigation of molecular alterations underlying chiasmatic misrouting in the albino binocular circuit. During development, in a specialized retinal niche—the ciliary margin—fewer cells express the cellcycle regulator CyclinD2. Consequently, the cell cycle is elongated, resulting in fewer ipsilaterally projecting RGCs and perturbed binocular vision.

Neurovascular injury, such as retinal vein occlusion, triggers expression of endothelial caspase-9 (EC Casp9). EC Casp9 induces pathological changes, including retinal edema, capillary ischemia, and neurodegeneration. One of the behavioral consequences is decline of contrast sensitivity, as shown with our OptoDrum. This paper gives new mechanistic insights into EC Casp9 action.

Kralik et al show successful optogenetic vision restoration in blind mice by expressing an engineered melanopsin-mGluR6 chimeric protein in ON bipolar cells. The treated mice show visual behavior that approaches the quality of wild type mice, shown with optomotor measurements. The responses of retinal ganglion cells are highly diverse, indicating that parallel processing is restored in treated retinas.

Maity-Kumar et al provide extensive characterization of a new mouse model for the Allan-Herndon-Dudley syn-drome (AHDS).

Chronic autoimmune diseases, such as multiple sclerosis (MS), lead to demyelination of neurons. Recovery after demyelinating events is limited by cholesterol recycling. Godwin et al show that gentasic acid (GA) treatment amelio-rates the damages in a murine model of optic nerve demyelination, MOG-induced experimental autoimmune encephalomyelitis (EAE). Improved cholesterol homeostasis may therefore contribute to rehabilitation of MS patients.

Blast injuries are common in modern warfare. They lead to immediate damage to the nervous system, but often develop into chronic disease with progressive deterioration, including in the visual system. It is proposed that neuroinflammatory processes underly this chronic phase. 4 weeks after injury, Harper et al transferred splenocytes of mice exposed to blast-mediated traumatic brain injury (bTBI) into naïve animals. Those naïve animals developed visual symptoms and experienced ganglion cell dysfunction similar to the blast-injured mice, suggesting that the immune system is indeed involved in the chronic phase of bTBI.

Ripasudil (trade name Glanatec) is a rho kinase inhibitor drug used for the treatment of glaucoma and ocular hypertension. Yang et al tested 6 new derivatives of ripasudil in chronic ocular hypertension glaucoma mice, and found that one of them, RNO-6, showed superior efficacy compared to ripasudil.

Lin et al present a new experimental animal model for glaucoma. By injecting a newly formulated hydrogel, they induce consistent intraocular pressure increase.

Mitochondrial complex I disorders are a heterogeneous group of rare inherited diseases caused by mutations affecting proteins in the mitochondrial electron transport chain. Neurological and ophthalmic pathologies are common to many forms of complex I deficiency, due to the high energy demands of central nervous system tissues. Avrutsky et al characterized one such mouse model, carrying a mutation in Ndufs4 (NADH:ubiquinone oxidoreductase Fe-S pro-tein 4), which shows fast retinal degeneration within only a few weeks. They show that a range of non-invasive techniques (OCT for structural changes, ERG for electrophysiological properties, and OMR with our OptoDrum for behavioral assessment) can capture relevant measures of disease progression.

In a large study, spanning identification of patient cohorts, characterization of those patients’ phenotypes, genetic analysis, generation and characterization of animal models, Kozycki et al show that ROSAH syndrome (cause by mutations in the ALPK1 gene) is an autoinflammatory disease with a large range of consequences. They show that treatment with anti-inflammatory drugs is successful. The newly generated animal model only partially replicated the human phenotypes. For example, the mice did not have visual deficits and showed no signs of retinal degeneration.

Cha et al characterize the rd10 mouse model at the level of behavior (optomotor reflex with our OptoDrum), as well as ex-vivo spike recordings of ganglion cells to light stimulation and electrical stimulation. Thy find that the retina responds differently to electrical stimulation depending on the stage of degeneration.

Exosomes are small vesicles enclosed by a single outer membrane secreted from cells, ranging from 30 to 200 nm in diameter, containing messenger RNAs, non-coding RNAs, proteins, and biological factors, and they may play a cru-cial role in intercellular communication. Exosomes have been identified as potential therapeutic methods and drug delivery tools. Exosomes derived from mesenchymal stem cells (MSCs) have been investigated in disorders such as stroke, corneal diseases, and liver diseases, but not yet in an acute glaucoma model, such as the ischemia-reperfusion model in the eye. Yu et al show that exosomes from MSCs have strong neuroprotective effects which is even better when the MSCs had been stimulated with TNF-α, and they identify the underlying signaling pathway. Their findings my pave the way for a new cell-free therapeutic approach for glaucoma.

Hollingsworth et al describe and characterize a new polygenic mouse model of inherited retinal dystrophies, the BXD32 mouse strain. They present evidence that a proinflammatory environment in the retina supports and accelerates the degeneration of the retina and the loss of visual function.

The experimental autoimmune encephalomyelitis (EAE) mouse model is commonly used to study visual impairments associated with autoimmune demyelinating diseases. EAE is classically induced by immunization with the peptide MOG35-55. This mouse model lacks certain characteristics of analog diseases in humans, in particular the participation of B-cells in the immune response. Joly et al characterize the effects of immunization with a different peptide, bMOG, and find that these mice show hallmarks of common human diseases, such as multiple sclerosis and neuromyelitis optica. This new mouse model therefore offers new avenues to test protective or restorative ophthalmic treatments.

In two mouse models of Glaucoma, Zeng et al show that Pioglitazone, given orally, can reduce or even reverse vision loss. Pioglitazone reduces inflammatory responses. The positive effects could be observed even with continued elevation of intraocular pressure, suggesting that the neuroinflammation experienced during Glaucoma may be more harmful than the elevated pressure.

Demyelinating autoimmune diseases usually impact the optic nerve and thus visual abilities. Optomotor reflex measurements can therefore be used to non-invasively monitor disease progression and treatment efficacy. Remlinger et al studied MOGAD, a rare autoimmune demyelinating CNS disorder, in a murine model of experimental autoimmune encephalomyelitis (EAE). They assessed the effects of treating those mice with monoclonal antibodies against the neonatal Fc receptor and found that this treatment reduced the severity of the disease. Measurements of visual acuity with Striatech’s OptoDrum correlated well with other disease markers.

Aging is often associated with damages and degeneration to the peripheral and central nervous system. Groh et al show that CD8+ T lymphocytes are causally involved in driving axon degeneration in the CNS in aging mice, a process that is further aggravated in aged mice by systemic inflammation. Functionally, these changes are also manifested in the visual system and Groh et al monitored them with our OptoDrum. Targeting such T cells may be a promising treatment against age-related decline of brain function.

Experimental autoimmune encephalomyelitis (EAE) is the most widely used animal model for multiple sclerosis (MS), an autoimmune disease where the immune system attacks myelin, which coats neurons in the CNS. Histamine has been thought to play a role in MS, effecting disease progression either positively or negatively, depending on the location of histamine action. In this study, Morin et al created a conditional mouse KO model of Hdc, the enzyme that synthesizes histamine, and induced EAE in these mice. Surprisingly, while some phenotypes in these mice were consistent with the lack of histamine, it had no impact on the development and severity of EAE. One behavioral readout of the disease progression in EAE is the decline of visual acuity, which can be measured with our OptoDrum. Consistent with the other observation, visual acuity declined in EAE Hdc-KO animals in the same way as in EAE Hdc-WT animals.

CLN disease, a subtype of Batten disease, is characterized by progressive neurodegeneration with onset in early childhood. This also affects vision. Some immunomodulatory drugs are clinically established to significantly attenuate the condition. Groh et al show in a mouse model of CLN1 that such treatment can help both when given before symptom onset, and to a lesser degree also during disease progression, by interfering with neuroinflammatory activity of immune cells.

The role of circular RNAs is not well understood, including Cdr1as, which is abundant in vertebrate retina. Chen et al show that CDR1as-KO mice had only minor deficits. Those included reduced contrast sensitivity, as measured with our OptoDrum. Overall, however, Cdr1as abundance is not required for retinal development and maintenance.

Tau, a protein known to be involved in Alzheimer’s disease, has elusive functionality in the healthy CNS. Using behavioral measurements with our OptoDrum as a readout, Rodriguez et al could show that Tau is involved in adaptive plasticity in the adult brain, in response to changes in sensory experience.

Neuroinflammation can have devastating degenerative consequences in the central nervous system when the immune system attacks the body’s own cells. This paper shows that neuroinflammation can be attenuated by treatment with proper pharmacological substances. This has beneficial consequences from the cellular to the behavioral level. For example, Berve et al show with our OptoDrum that vision degenerates strongly in Ppt1-/- mice due to optic nerve atrophy. Pharmacological inhibition of innate immune cells ameliorates those effects.

Human congenital myopathies are most commonly caused by mutations in the RYR1 gene, encoding for a muscular calcium channel. In a corresponding mouse model, this study investigates the molecular basis of the eye muscle phenotype which is part of the congenital myopathy. In the mutants, the altered calcium homeostasis and reduced calcium released by muscle fibres in the extraocular muscles lead to reduced activity of the eye muscles during development. This causes mis-expression of Myelin heavy chain (MyHC) isoforms, lack of the isoform MyHC-EO, myofibrillar disorganization, displacement and decreased number of mitochondria.

The authors present a crucial missing piece on the way to healing blindness: they describe a new promoter that can efficiently drive gene expression in human ON bipolar cells. Previous promotors worked well in mouse retina, but not in human retina. The new findings can pave the way to optogenetic gene therapy in blind human patients to restore functional vision. In this paper, Hulliger et al use our OptoDrum and show functional vision restoration in the rd1 mouse, a mouse model for Retinitis pigmentosa, at normal everyday light levels.

Nogo-A is a potent myelin-associated inhibitor of neuronal growth and nervous system plasticity. It may be involved in many ocular diseases by preventing healing and recovery after physiological insults. This study shows that antibodies directed against Nogo-A promoted recovery after retinal injury. Baya Mdzomba et al monitor the visual acuity of the treated mice with our OptoDrum which provided a non-invasive readout of the injury and recovery, and enabled the researchers to get daily measurements of disease progression.

The chromatin in the nucleus of rod photoreceptors has an inverted structure in nocturnal animals. Metabolically, this is expensive to maintain, so it has been proposed that the inverted architecture provides an advantage during night vision. Subramanian et al could show with our OptoDrum that the inverted nuclear architecture provides improved contrast sensitivity in dark environments.

Application of our OptoDrum measurements to a small bottom-dwelling fish shows that these fish feature excellent contrast sensitivity.

The Jimpy mutant mouse has no myelination in the central nervous system, including of axons in the optic nerve. Despite severe consequences such as seizures and motor deficits, and early death at around P20, the lack of myelination has no major consequences on the early development of retinal morphology or function, and they show normal optomotor visual behavior.

Carido et al present the sodium iodate mouse model of age-related macular degeneration. Systemic injection of sodium iodate leads to death of retinal pigment epithelium, with subsequent photoreceptor cell death. OptoDrum measurements show that the vision loss can be tracked at the behavioral level.

In this paper, Benkner et al introduced the algorithm underlying the optomotor measurements in what later would become the OptoDrum. Proof-of-concept data is presented with wild-type and rd10 retinal degeneration mice.