[Are Visual Field Defects Reversible? - Visual Rehabilitation with Brains]. / Sind Gesichtsfelddefekte doch reversibel? ­ Visuelle Rehabilitation mit Gehirn.

Visual field defects are considered irreversible because the retina and optic nerve do not regenerate. Nevertheless, there is some potential for recovery of the visual fields. This can be accomplished by the brain, which analyses and interprets visual information and is able to amplify residual signals through neuroplasticity. Neuroplasticity refers to the ability of the brain to change its own functional architecture by modulating synaptic efficacy. This is actually the neurobiological basis of normal learning. Plasticity is maintained throughout life and can be induced by repetitively stimulating (training) brain circuits. The question now arises as to how plasticity can be utilised to activate residual vision for the treatment of visual field loss. Just as in neurorehabilitation, visual field defects can be modulated by post-lesion plasticity to improve vision in glaucoma, diabetic retinopathy or optic neuropathy. Because almost all patients have some residual vision, the goal is to strengthen residual capacities by enhancing synaptic efficacy. New treatment paradigms have been tested in clinical studies, including vision restoration training and non-invasive alternating current stimulation. While vision training is a behavioural task to selectively stimulate "relative defects" with daily vision exercises for the duration of 6 months, treatment with alternating current stimulation (30 min. daily for 10 days) activates and synchronises the entire retina and brain. Though full restoration of vision is not possible, such treatments improve vision, both subjectively and objectively. This includes visual field enlargements, improved acuity and reaction time, improved orientation and vision related quality of life. About 70 % of the patients respond to the therapies and there are no serious adverse events. Physiological studies of the effect of alternating current stimulation using EEG and fMRI reveal massive local and global changes in the brain. These include local activation of the visual cortex and global reorganisation of neuronal brain networks. Because modulation of neuroplasticity can strengthen residual vision, the brain deserves a better reputation in ophthalmology for its role in visual rehabilitation. For patients, there is now more light at the end of the tunnel, because vision loss in some areas of the visual field defect is indeed reversible.

[The 2-Scale Model of the National Eye Institute Visual Function Questionnaire (NEI-VFQ) to Assess Vision-Related Quality of Life]. / Das 2-Skalen-Modell des National Eye Institute Visual Function Questionnaire (NEI-VFQ) zur Erfassung der sehbezogenen Lebensqualität.

Aim This study addresses the examination of the factorial validity of the National Eye Institute Visual Function Questionnaire 39 (NEI-VFQ 39) and the neuro-ophthalmological supplement in a German sample. Method Eighty-one patients with visual field defects affecting at least one eye answered the NEI-VFQ 39 and the supplement. Theoretical factor structures reported in the manuals were examined in confirmatory factor analysis. Because of a misfit, items retained after item analysis were subjected to exploratory factor analysis. Results The originally postulated factor structures could not be replicated. Many items revealed floor effects. The 21 remaining items could be assigned to two factors - "visual functioning" and "socio-emotional impairment". Conclusion The weakness of the theoretical factors can be avoided by using the 2-scale model.

Computer-based training for the treatment of partial blindness.

Partial blindness after brain injury has been considered non-treatable. To evaluate whether patients with visual-field defects can profit from computer-based visual restitution training (VRT), two independent clinical trials were conducted using patients with optic nerve (n = 19) or post-chiasmatic brain injury (n = 19). In post-chiasma patients, VRT led to a significant improvement (29.4%) over baseline in the ability to detect visual stimuli; in optic nerve patients, the effects were even more pronounced (73.6% improvement). Visual-field enlargements were confirmed by the observation of a visual-field expansion of 4.9 degrees-5.8 degrees of visual angle and improved acuity in optic nerve patients. Ninety five percent of the VRT-treated patients showed improvements, 72.2% confirmed visual improvements subjectively. Patients receiving a placebo training did not show comparable improvements. In conclusion, VRT with a computer program improves vision in patients with visual-field defects and offers a new, cost-effective therapy for partial blindness.

[The neuroophthalmic supplement to the NEI-VFQ: test statistics and validation with a cohort of patients with pre- and postchiasmatic damage]. / Das neuroophthalmologische Supplement des NEI-VFQ: Teststatistische Überprüfung und Validierung an einer Stichprobe prä- und postchiasmatisch geschädigter Patienten.

BACKGROUND: The National Eye Institute Visual Function Questionnaire (NEI-VFQ) is not sufficient to assess vision-related quality of life in patients with vision impairments caused by neuroophthalmic deficits. The neuroophthalmic supplement to the NEI-VFQ is currently only available in an English version. The supplement was translated into German and three items concerning visual field loss were added. MATERIAL AND METHODS: NEI-VFQ and supplement data were collected from 62 pre- and postchiasmatic patients with visual field defects and from 245 healthy reference persons. NEI-VFQ and supplement were psychometrically tested and validated. Relations between visual field variables and vision-related quality of life were assessed. RESULTS: The patient group showed diminished quality of life in 10 NEI-VFQ subscales and in eight supplement items when compared to age-matched healthy controls. Correlations between supplement and visual field diagnostic variables demonstrate moderate relations between visual field loss and deterioration of vision-related quality of life. A Cronbach's α of 0.81 for the supplement can be increased to 0.92 in combination with the NEI-VFQ, the sole application of the NEI-VFQ generates an alpha of 0.93 in this sample. A factor analysis reveals four factors that cover the 13 items capturing the following issues: 'severity/problems due to the visual field defect", "unusual eyelid appearances", "blurry vision/double vision" and "diverse vision of both eyes"; 72 % of the variance can be explained by these four factors. CONCLUSION: The German translation of the neuroophthalmic supplement to the NEI-VFQ captures additional vision-specific problems beyond the sole NEI-VFQ that are often reported by patients with vision impairments after brain damage. Although the relevance of some items can be questioned, nevertheless the supplement qualifies for an enhanced outline of subjective vision impairments that are not included in the previous NEI-VFQ.

Evaluating Current Density Modeling of Non-Invasive Eye and Brain Electrical Stimulation Using Phosphene Thresholds.

Because current flow cannot be measured directly in the intact retina or brain, current density distribution models were developed to estimate it during magnetic or electrical stimulation. A paradigm is now needed to evaluate if current flow modeling can be related to physiologically meaningful signs of true current distribution in the human brain. We used phosphene threshold measurements (PTs) as surrogate markers of current-flow to determine if PTs, evoked by transcranial alternating current stimulation (tACS), can be matched with current density estimates generated by head model-based computer simulations. Healthy, male subjects (n=15) were subjected to three-staged PT measurements comparing six unilateral and one bilateral stimulation electrode montages according to the 10/20 system: Fp2-Suborbital right (So), Fp2-right shoulder (rS), Fp2-Cz, Fp2- O2, So-rS, Cz-F8 and F7-F8. The stimulation frequency was set at 16 Hz. Subjects were asked to report the appearance and localization of phosphenes in their visual field for every montage. Current density models were built using multi-modal imaging data of a standard brain, meshed with isotropic conductivities of different tissues of the head using the SimBio and SCIRun software packages. We observed that lower PTs were associated with higher simulated current levels in the unilateral montages of the model head, and shorter electrode distances to the eye had lower PTs. The lowest mean PT and the lowest variability were found in the F7-F8 montage ( [Formula: see text]). Our results confirm the hypothesis that phosphenes are primarily of retinal origin, and they provide the first in vivo evidence that computer models of current flow using head models are a valid tool to estimate real current flow in the human eye and brain.

[Impairments of vision- and health-related quality of life in stroke patients with homonymous visual field defects depend on severity of visual function loss]. / Beeinträchtigung der seh- und gesundheitsbezogenen Lebensqualität bei Schlaganfallpatienten mit homonymen Gesichtsfelddefekten in Abhängigkeit von der Schwere des visuellen Funktionsverlustes.

BACKGROUND AND PURPOSE: Little is known about whether and to what extent health- and vision-related quality of life in stroke patients with visual field defects is influenced by the severity of visual function loss and which quality of life is achieved compared to healthy control persons. PATIENTS/MATERIALS AND METHODS: Results of the National Eye Institute-Visual Functioning Questionnaire (NEI-VFQ) and the Medical Outcome Study Short-Form 36 Health Survey (SF-36) of 177 first stroke patients with visual field defects were compared with scores of age- and sex-matched healthy reference persons. The influence of visual field loss, perimetric data, reduced visual acuity and demographic variables on NEI-VFQ and SF-36 scores were estimated by analyses of variance. RESULTS: First stroke patients showed worse results in 11/12 NEI-VFQ and in 6/8 SF-36 subscales when compared to healthy controls. The factor "intact central visual field" influenced 9/12 NEI-VFQ subscales (F-range 3.16 - 14.11; all p < 0.05), but only one SF-36 scale (F = 3.15; p < 0.05). Patients with larger intact visual fields, shorter reaction times in the visual field test and better visual acuity reached higher NEI-VFQ and SF-36 scores. Male patients reported worse scores for SF-36 subscale General Health Perceptions than female patients (F = 8.61; p = 0.004), but no differences in vision-related quality of life due to the factor gender could be detected. CONCLUSIONS: Patients with visual field defects showed considerable reductions in vision- and health-related quality of life compared to healthy control persons. These were mainly influenced by variables of visual functioning such as size of intact visual field, reaction times or visual acuity. The size of the intact central visual field influenced vision-related quality of life rather than health-related quality of life.

Personality and stress influence vision restoration and recovery in glaucoma and optic neuropathy following alternating current stimulation: implications for personalized neuromodulation and rehabilitation.

PURPOSE: Identifying factors that affect recovery or restoration of neurological function is a key goal of rehabilitation in neurology and ophthalmology. One such factor can be prolonged mental stress, which may be not only the consequence of nervous system damage but also a major risk factor, or cause, of neural inactivation. Using the visual system as a model of neural injury, we wished to study how patients' stress and personality profiles correlate with vision recovery as induced by therapy with alternating current stimulation (ACS) in patients with optic nerve damage. METHODS: Personality and stress questionnaires were sent retrospectively to a clinical convenience sample of patients who suffer low vision due to optic nerve damage, which had previously been treated with ACS. The questionnaires included the NEO Five-Factor Inventory (NEO-FFI), the Trier Inventory of Chronic Stress (TICS), and the Flammer syndrome (FS) checklist, which probes signs of vascular dysregulation (VD). These scores were then correlated with the extent of ACS-induced vision restoration as recorded 1-3 years earlier by perimetric visual field tests. RESULTS: Two NEO-FFI personality factors (lower neuroticism, higher conscientiousness) and the presence of physiological Flammer signs were associated with greater recovery as were individual items of the factors openness and agreeableness. Single NEO-FFI item analysis revealed that recovery relates to greater extraversion (optimistic and happy), openness (less guided by authorities for decisions on moral issues), and agreeableness (argue less, like working with others, thoughtful, considerate) as well as the presence of FS signs (cold hands/feet, hypotension, slim body shapes, tinnitus). This suggests that patients with better recovery were more calm, peaceful and secure, hard-working, and reliable, and with high organizational skills. In contrast, patients with poor recovery had a tendency to be emotionally unstable, anxious, unhappy and prone to negative emotions, impulsive, careless, and unorganized. Chronic stress assessed with TICS did not correlate with recovery. CONCLUSION: Vision restoration induced by ACS is greater in patients with less stress-prone personality traits and those who show signs of VD. Prospective studies are now needed to determine if personality has (i) a causal influence, i.e., patients with less stress-prone personalities and greater VD signs recover better, and/or (ii) if personality changes are an effect of the treatment, i.e., successful recovery induces personality changes. Though the cause-effect relationship is still open, we nevertheless propose that psychosocial factors and VD contribute to the highly variable outcome of vision restoration treatments in low vision rehabilitation. This has implications for preventive and personalized vision restoration and is of general value for our understanding of outcome variability in neuromodulation and neurological rehabilitation.

GM1 ganglioside treatment facilitates behavioral recovery from bilateral brain damage.

Adult rats with bilateral lesions of the caudate nucleus were treated with GM1 ganglioside. Although animals injected with a control solution were severely impaired in their ability to learn a complex spatial task, those treated with ganglioside were able to learn spatial reversals.

Visual hallucinations during spontaneous and training-induced visual field recovery.

Visual hallucinations after post-geniculate visual system lesions were shown to be associated with spontaneous recovery of visual functions. We investigated the occurrence of hallucinations during spontaneous recovery and additionally tested whether hallucinations were re-instated in a phase of vision restoration therapy (VRT). Nineteen patients with post-geniculate lesions and homonymous visual loss participated in a prospective study, and 121 patients with various lesions were included in a retrospective study using a questionnaire including verbal descriptions as well as drawings of hallucinations experienced by the patients. In both samples, visual-field size was determined before and after 6 months of VRT. Many patients in both groups experienced post-lesion hallucinations (mostly colors, objects, motion) which subsided after spontaneous recovery of visual functions (increase of visual field size, recovery of more complex visual function) was ended. Hallucinations re-emerged during training. However, the majority of patients reported simple, unformed visual hallucinations (uncolored phosphenes, spots, flashes), especially when visual field recovery was most intense. Hallucinations were mainly found in patients with large shifts of the visual field border. They occurred in blind areas, particularly in areas of residual vision where recovery was predominantly observed. Hallucinations may reflect functional recovery in partially lesioned brain areas. While the colored/formed hallucinations during spontaneous recovery may represent non-specific activation of higher visual areas, the simple, unformed training-related hallucinations may indicate recovery in the primary visual cortex during treatment. Hallucinations should not generally be discarded as pathological or unimportant symptoms, but they may be functional indicators of visual system plasticity.

Publishing in the field of brain plasticity, repair and rehabilitation: an emerging neuroscience niche journal.

The journal Restorative Neurology and Neuroscience (RNN) is now published in its 25th volume since its inception in 1989. RNN focuses on the emerging field of brain plasticity, repair and rehabilitation, including original and review papers both in basic research (animal experiments, in vitro studies) and in the clinical domain, including brain imaging studies. During the last decade RNN has experienced a steady progress in its reference value and scientific impact. The ISI-impact factor has risen from 1.117 (1997) to 2.862 (2006). This places the journal at the 81st rank among all 200 neuroscience journals, i.e. 60% of all neuroscience journals have a lower impact factor. When compared to other journals in the field of rehabilitation, RNN ranks number 1. Causes for this positive development are, among others: (1) the field of neuroplasticity, regeneration, recovery and rehabilitation is an emerging field in medicine and therefore the number of publications and their citation rate overall increases, (2) the special issues strategy, (3) a top level editorial board, and (4) the quality of papers submitted to RNN continuously improves as RNN is gaining increasing acceptance in the scientific community. Thus, in the space of neuroscience in general, and rehabilitation in particular, RNN has become a visible, high impact journal and a leading source of original scientific information pertaining to brain plasticity , rehabilitation and repair. RNN is likely to gain more momentum as the field matures further.

Does visual restitution training change absolute homonymous visual field defects? A fundus controlled study.

AIM: To examine whether visual restitution training (VRT) is able to change absolute homonymous field defect, assessed with fundus controlled microperimetry, in patients with hemianopia. METHODS: 17 patients with stable homonymous visual field defects before and after a 6 month VRT period were investigated with a specialised microperimetric method using a scanning laser ophthalmoscope (SLO). Fixation was controlled by SLO fundus monitoring. The size of the field defect was quantified by calculating the ratio of the number of absolute defects and the number of test points; the training effect E was defined as the difference between these two ratios before and after training. A shift of the entire vertical visual field border by 1 degrees would result in an E value of 0.14. RESULTS: The mean training effect of all right eyes was E = 0.025 (SD 0.052) and all left eyes E = 0.008 (SD 0.034). In one eye, a slight non-homonymous improvement along the horizontal meridian occurred. CONCLUSIONS: In one patient, a slight improvement along the horizontal meridian was found in one eye. In none of the patients was an explicit homonymous change of the absolute field defect border observed after training.

Repetitive Transcorneal Alternating Current Stimulation Reduces Brain Idling State After Long-term Vision Loss.

BACKGROUND: Deafferentation of visual system structures following brain or optic nerve injury leaves cortical areas deprived of visual input. Deprived cortical areas have a reduced sensory information processing and are characterized with localized enhanced or synchronized rhythms believed to represent an "idling state". OBJECTIVE/HYPOTHESIS: We hypothesized that cortical idling can be modified with transcorneal alternating current stimulation (tACS) known to modulate cortical oscillations and thus change the functional state of the deafferented areas. METHODS: tACS was applied in rat model of severe optic nerve crush using a protocol similar to our clinical studies (200 µA, 2-8 Hz) for 5 treatment days right after the lesion and at the chronic stage (3 months later). EEG and VEP were recorded over the visual cortices. In vivo confocal neuroimaging of the retina and histology of the optic nerves were performed. RESULTS: Morphological investigations showed massive retinal ganglion cells death and degeneration of the optic nerves after crush. Visual loss was associated with increased EEG spectral power and lower coherence, indicating an "idling state". Stimulation induced a significant decrease of EEG power towards normal values. These effects were especially pronounced in the chronic stage. CONCLUSION: Our results suggest that alternating current injected via the eye is able to modulate visually deprived brain areas and thus reduce cortical idling.

R-esp1, a rat homologue of drosophila groucho, is differentially expressed after optic nerve crush and mediates NGF-induced survival of PC12 cells.

The differential display reverse transcription polymerase chain reaction method was used to detect alterations in gene expression in the superior colliculus after optic nerve crush in adult rats. One of the most prominent changes observed was the selective induction of R-esp1, a homologue of the Drosophila enhancer of split locus (Groucho). Therefore, we studied the influence of R-esp1 on nerve growth factor (NGF)-induced cell survival of PC12 cells. Overexpression of R-esp1 promotes cell survival even in the absence of NGF and, conversely, it is reduced by antisense-mediated inhibition of R-esp1 expression. In conclusion, we propose a novel model in which R-esp1 protein mediates the NGF-signaling pathway.

Systemic L-kynurenine administration partially protects against NMDA, but not kainate-induced degeneration of retinal ganglion cells, and reduces visual discrimination deficits in adults rats.

PURPOSE: Kynurenic acid (KYNA), an endogenous tryptophan metabolite, is an N-methyl-D-aspartate (NMDA) antagonist active at the glycine-binding site of the NMDA-receptor complex. The authors investigated whether systemic administration of a biochemical precursor of KYNA, L-kynurenine (L-Kyn), could block NMDA- or kainic acid (KA)-induced cell death in adult rat retinal ganglion cells (RGCs) and protect NMDA-treated animals from lesion-induced visual deficits. METHODS: Rats were injected with 20-nmol NMDA or 5-nmol KA intraocularly. To quantify the number of surviving RGCs, the retrograde tracer horseradish-peroxidase was injected into the superior colliculus contralateral to the lesioned eye. Surviving RGCs were counted on wholemounted retinae in a centroperipheral gradient, as well as in the four quadrants, using a computer-assisted image analysis system. RESULTS: The NMDA-injections resulted in an approximately 82% RGC loss in the adult rat retina compared with control retinae and a cell loss of approximately 50% in KA-treated retinae. Pretreatment with L-Kyn significantly reduced NMDA-induced RGC degeneration to values of approximately 60%, but KA toxicity was not significantly affected by L-Kyn pretreatment. Intraocular injections of NMDA resulted in an impairment of visual discrimination behavior, which partially recovered within a period of approximately 3 weeks. However, when treated systemically with L-Kyn, brightness discrimination was significantly improved as compared with NMDA-treated rats. CONCLUSIONS: These findings show that systemic administration of L-Kyn in adult rats can block NMDA-induced retinal ganglion cell death in vivo and preserves brightness discrimination performance.

Chronic low-dose glutamate is toxic to retinal ganglion cells. Toxicity blocked by memantine.

PURPOSE: It is well known that acute exposure to high concentrations of glutamate is toxic to central mammalian neurons. However, the effect of a chronic, minor elevation over endogenous glutamate levels has not been explored. The authors have suggested that such chronic exposure may play a role in glaucomatous neuronal loss. In the current study, they sought to explore whether a chronic, low-dose elevation in vitreal glutamate was toxic to retinal ganglion cells and whether this toxicity could be prevented with memantine, a glutamate antagonist. METHODS: Rats were injected serially and intravitreally with glutamate to induce chronic elevations in glutamate concentration. A second group of rats was treated with intraperitoneal memantine and glutamate. Control groups received vehicle injection with or without concurrent memantine therapy. After 3 months, the animals were killed, and ganglion cell survival was evaluated. RESULTS: Intravitreal injections raised the intravitreal glutamate levels from an endogenous range of 5 to 12 microM glutamate to 26 to 34 microM. This chronic glutamate elevation killed 42% of the retinal ganglion cells after 3 months. Memantine treatment alone had no effect on ganglion cell survival. However, when memantine was given concurrently with low-dose glutamate, memantine was partially protective against glutamate toxicity. CONCLUSIONS: These data suggest that minor elevations in glutamate concentration can be toxic to ganglion cells if this elevation is maintained for 3 months. Furthermore, memantine is efficacious at protecting ganglion cells from chronic low-dose glutamate toxicity.

Neuroleptics ameliorate phencyclidine-induced impairments of short-term memory.

1. Phencyclidine (PCP), a non-competitive NMDA-receptor antagonist, is able to induce schizophrenia-like symptoms in animals and in humans. It is known that schizophrenic patients have deficits in memory processes. 2. Therefore, it was investigated whether subchronic pulsatile or continuous application of 5.0 mg kg(-1) PCP over 5 days induce short-term memory deficits in holeboard learning and the action of two different neuroleptics on this behavioural test. 3. First, an impairment in the holeboard task was described when the animals were tested 24 h after the last application but not after 15 min or 1 h after the last injection. Secondly, the influence of haloperidol and risperidone on the PCP-induced short-term memory changes was tested. 4. The combined application of PCP and risperidone led to a complete antagonism of the short-term deficits, but the combined treatment with haloperidol was accompanied by a partial abolishment of the PCP-induced deficits. 5. PCP led to an upregulation of the glutamate binding sites in striatum and nucleus accumbens whereas the D(2) binding sites were reduced in striatum. The D(1) binding sites seem to be unchanged. The receptor protein expression of glutamate receptors mGluR1, GluR2, GluR5/7 and NMDAR1 were not modified in response to PCP treatment. 6. The determination of a subpopulation of GABAergic interneurons shows a decrease of the cells within the CA3 of the hippocampal formation. 7. These findings indicate that PCP induced impairments in short term memory can be detected by holeboard learning and may provide an interesting tool for the search of new neuroleptics.

Localization of a 42-kDa inositol 1,3,4,5-tetrakisphosphate receptor protein in retina and change in expression after optic nerve injury.

The mRNA and protein expression of a 42-kDa inositol 1,3,4,5-tetrakisphosphate receptor (InsP4R) was investigated in cryostat and paraffin sections from rat, porcine and bovine retina. InsP4R mRNA was localized by in situ hybridization in the ganglion cell layer, the inner nuclear cell layer and the outermost part of the outer nuclear cell layer. For immunocytochemistry, we used an antibody raised against a 19-amino-acid peptide (peptide-3) derived from previous microsequencing of proteolytic fragments of the porcine InsP4R (Stricker et al., FEBS Lett., 370 (1995) 236). The distribution of immunoreactivity was similar in all species investigated. Two cell types, most likely wide-field amacrine and retinal ganglion cells, were intensely stained. Prominent immunoreactivity in the on/off sublaminae of the inner plexiform layer and in the optic nerve layer indicates a pre- and/or post-synaptic localization of the protein. Moreover, significant InsP4R protein expression in the inner segment of photoreceptors points to a putative role of the second messenger InsP4 in signaling processes related to phototransduction. However, also the endfeet of Müller glia cells in the optic nerve layer were intensely stained. Optic nerve crush caused only minor changes in retinal InsP4R mRNA levels whereas InsP4R immunoreactivity was attenuated for more than 4 weeks in the photoreceptor inner segments, wide-field amacrine cells, and in retinal ganglion cells. The immunopositive sublaminae of the inner plexiform layer appeared to have shrunken. However, the signal intensity gradually recovered after 10 weeks. Since in parallel sections stained with a monoclonal antibody directed against the vesicular protein synaptophysin no changes were found, the alterations in InsP4R immunoreactivity induced by nerve injury are not due to a general decline in the expression of pre-synaptic proteins. We, therefore, hypothesize that the InsP4R might be linked to altered intracellular Ca2+ signaling after neuronal injury.

Co-expression of c-Jun and ATF-2 characterizes the surviving retinal ganglion cells which maintain axonal connections after partial optic nerve injury.

The expression of c-fos, c-jun, jun-b, jun-d, srf and pc4 mRNA was examined after partial optic nerve crush in the adult rat retina by in situ hybridization. Optic nerve injury led exclusively to the upregulation of c-jun, with cellular label indicative for c-jun mRNA in the retinal ganglion cell layer after two days, three days and one week post-injury. This expression pattern was in accordance with the appearance of c-Jun immunoreactivity in retinal flat mounts. Injection of an antisense but not a missense oligonucleotide against c-jun after partial crush resulted in a reduced number of connected retinal ganglion cells (RGCs) as shown by retrograde labeling. Prelabeling of RGCs with fluorogold before optic nerve section and subsequent antisense targeting against c-jun, however, led to a slightly higher number of surviving but axotomized RGCs. C-Jun antibody staining of retinal whole mounts pre- or postlabeled after crush by intracollicular administration of fluorogold showed strong c-Jun immunoreactivity in connected RGCs and also in a population of disconnected RGCs. Double labeling with an antibody directed against the transcription factor ATF-2 revealed strong co-expression of c-Jun and ATF-2 in connected RGCs but not in axotomized cells. Taken together these data indicate that both RGCs in continuity and those in discontinuity with the superior colliculus respond both equally to the noxious stimulus with c-Jun expression. Moreover, the co-expression of c-Jun with high levels of ATF-2 appears to be essential for either the continuity or survival of RGCs which remain connected with their target. In disconnected RGCs, however, low levels of ATF-2 and the co-expression of c-Jun may be related to cell death.

MK-801 reduces retinal ganglion cell survival but improves visual performance after controlled optic nerve crush.

Excitotoxicity is implicated in secondary cell death after ischemic or traumatic brain injury. We therefore evaluated the role of excitotoxicity mediated by the NMDA glutamate receptor subtype on retinal ganglion cell (RGC) survival and visual performance after optic nerve injury in adult rats. To monitor visual deficits after mild optic nerve crush, rats were trained in a two-choice pattern discrimination task. Immediately after the crush and on postoperative day 1, MK-801 (1 nmol), a noncompetitive open channel blocker of the NMDA-receptor, was injected intraocularly. Within the first few days after crush, all rats showed a loss of their discrimination ability that was followed by a significant recovery within a 3-week testing period. Although animals treated with MK-801 had a significantly smaller initial deficit compared with PBS-injected controls, anatomic investigations using retrograde HRP tracing revealed a significant retrograde loss of RGC in lesioned rats that was significantly exacerbated by MK-801. These results confirm our earlier studies suggesting that neuronal damage does not uniformly match behavioral defects in CNS injury paradigms and that near-normal visual performance occurs in rats with only about 10% of RGC being connected to their target. The observation that after traumatic injury MK-801 is neuroprotective functionally while being neurotoxic anatomically is a structural-functional paradox that needs to be explored further.