Protection of photosystem I during sudden light stress depends on ferredoxin:NADP(H) reductase abundance and interactions.

Plant tolerance to high light and oxidative stress is increased by overexpression of the photosynthetic enzyme Ferredoxin:NADP(H) reductase (FNR), but the specific mechanism of FNR-mediated protection remains enigmatic. It has also been reported that the localization of this enzyme within the chloroplast is related to its role in stress tolerance. Here, we dissected the impact of FNR content and location on photoinactivation of photosystem I (PSI) and photosystem II (PSII) during high light stress of Arabidopsis (Arabidopsis thaliana). The reaction center of PSII is efficiently turned over during light stress, while damage to PSI takes much longer to repair. Our results indicate a PSI sepcific effect, where efficient oxidation of the PSI primary donor (P700) upon transition from darkness to light, depends on FNR recruitment to the thylakoid membrane tether proteins: thylakoid rhodanase-like protein (TROL) and translocon at the inner envelope of chloroplasts 62 (Tic62). When these interactions were disrupted, PSI photoinactivation occurred. In contrast, there was a moderate delay in the onset of PSII damage. Based on measurements of ΔpH formation and cyclic electron flow, we propose that FNR location influences the speed at which photosynthetic control is induced, resulting in specific impact on PSI damage. Membrane tethering of FNR therefore plays a role in alleviating high light stress, by regulating electron distribution during short-term responses to light.

WRKY transcription factors and ethylene signaling modify root growth during the shade-avoidance response.

Shade-intolerant plants rapidly elongate their stems, branches, and leaf stalks to compete with neighboring vegetation, maximizing sunlight capture for photosynthesis. This rapid growth adaptation, known as the shade-avoidance response (SAR), comes at a cost: reduced biomass, crop yield, and root growth. Significant progress has been made on the mechanistic understanding of hypocotyl elongation during SAR; however, the molecular interpretation of root growth repression is not well understood. Here, we explore the mechanisms by which SAR induced by low red:far-red light restricts primary and lateral root (LR) growth. By analyzing the whole-genome transcriptome, we identified a core set of shade-induced genes in roots of Arabidopsis (Arabidopsis thaliana) and tomato (Solanum lycopersicum) seedlings grown in the shade. Abiotic and biotic stressors also induce many of these shade-induced genes and are predominantly regulated by WRKY transcription factors. Correspondingly, a majority of WRKY genes were among the shade-induced genes. Functional analysis using transgenics of these shade-induced WRKYs revealed that their role is essentially to restrict primary root and LR growth in the shade; captivatingly, they did not affect hypocotyl elongation. Similarly, we also found that ethylene hormone signaling is necessary for limiting root growth in the shade. We propose that during SAR, shade-induced WRKY26, 45, and 75, and ethylene reprogram gene expression in the root to restrict its growth and development.

Insights into Gene Regulation of Jasmonate-Induced Whole-Plant Senescence of Tobacco under Non-Starvation Conditions.

Jasmonate (JA)-induced plant senescence has been mainly studied with a dark/starvation-promoted system using detached leaves; yet, the induction of whole-plant senescence by JA remains largely unclear. This work reports the finding of a JA-induced whole-plant senescence of tobacco under light/non-starvation conditions and the investigation of underlying regulations. Methyl jasmonate (MeJA) treatment induces the whole-plant senescence of tobacco in a light-intensity-dependent manner, which is suppressed by silencing of NtCOI1 that encodes the receptor protein of JA-Ile (the bioactive derivative of JA). MeJA treatment could induce the senescence-specific cysteine protease gene SAG12 and another cysteine protease gene SAG-L1 to high expression levels in the detached leaf patches under dark conditions but failed to induce their expression in tobacco whole plants under light conditions. Furthermore, MeJA attenuates the RuBisCo activase (RCA) level in the detached leaves but has no effect on this protein in the whole plant under light conditions. A genome-wide transcriptional assay also supports the presence of a differential regulatory pattern of senescence-related genes during MeJA-induced whole-plant senescence under non-starvation conditions and results in the finding of a chlorophylase activity increase in this process. We also observed that the MeJA-induced senescence of tobacco whole plants is reversible, which is accompanied by a structural change of chloroplasts. This work provides novel insights into JA-induced plant senescence under non-starvation conditions and is helpful to dissect the JA-synchronized process of whole-plant senescence.

Maintaining the Chloroplast Redox Balance through the PGR5-Dependent Pathway and the Trx System Is Required for Light-Dependent Activation of Photosynthetic Reactions.

Light-dependent activation of chloroplast enzymes is required for the rapid induction of photosynthesis after a shift from dark to light. The thioredoxin (Trx) system plays a central role in this process. In chloroplasts, the Trx system consists of two pathways: the ferredoxin (Fd)/Trx pathway and the nicotinamide adenine dinucleotide phosphate (NADPH)-Trx reductase C (NTRC) pathway. In Arabidopsis (Arabidopsis thaliana) mutants defective in either pathway, the photoreduction of thiol enzymes was impaired, resulting in decreased carbon fixation. The close relationship between the Fd/Trx pathway and proton gradient regulation 5 (PGR5)-dependent photosystem I cyclic electron transport (PSI CET) in the induction of photosynthesis was recently elucidated. However, how the PGR5-dependent pathway is involved in the NTRC pathway is unclear, although NTRC has been suggested to physically interact with PGR5. In this study, we analyzed Arabidopsis mutants lacking either the PGR5 or the chloroplast NADH dehydrogenase-like complex (NDH)-dependent PSI CET pathway in the ntrc mutant background. The ntrc pgr5 double mutant suppressed both the growth defects and the high non-photochemical quenching phenotype of the ntrc mutant when grown under long-day conditions. By contrast, the inactivation of NDH activity with the chlororespiratory reduction 2-2 mutant failed to suppress either phenotype. We discovered that the phenotypic rescue of ntrc by pgr5 is caused by the partial restoration of Trx-dependent reduction of thiol enzymes. These results suggest that electron partitioning to the PGR5-dependent pathway and the Trx system needs to be properly regulated for the activation of the Calvin-Benson-Bassham cycle enzymes during the induction of photosynthesis.

Interplay between differentially expressed enzymes contributes to light color acclimation in marine Synechococcus.

Marine Synechococcus, a globally important group of cyanobacteria, thrives in various light niches in part due to its varied photosynthetic light-harvesting pigments. Many Synechococcus strains use a process known as chromatic acclimation to optimize the ratio of two chromophores, green-light-absorbing phycoerythrobilin (PEB) and blue-light-absorbing phycourobilin (PUB), within their light-harvesting complexes. A full mechanistic understanding of how Synechococcus cells tune their PEB to PUB ratio during chromatic acclimation has not yet been obtained. Here, we show that interplay between two enzymes named MpeY and MpeZ controls differential PEB and PUB covalent attachment to the same cysteine residue. MpeY attaches PEB to the light-harvesting protein MpeA in green light, while MpeZ attaches PUB to MpeA in blue light. We demonstrate that the ratio of mpeY to mpeZ mRNA determines if PEB or PUB is attached. Additionally, strains encoding only MpeY or MpeZ do not acclimate. Examination of strains of Synechococcus isolated from across the globe indicates that the interplay between MpeY and MpeZ uncovered here is a critical feature of chromatic acclimation for marine Synechococcus worldwide.

Zebrafish dscaml1 Deficiency Impairs Retinal Patterning and Oculomotor Function.

Down syndrome cell adhesion molecules (dscam and dscaml1) are essential regulators of neural circuit assembly, but their roles in vertebrate neural circuit function are still mostly unexplored. We investigated the functional consequences of dscaml1 deficiency in the larval zebrafish (sexually undifferentiated) oculomotor system, where behavior, circuit function, and neuronal activity can be precisely quantified. Genetic perturbation of dscaml1 resulted in deficits in retinal patterning and light adaptation, consistent with its known roles in mammals. Oculomotor analyses revealed specific deficits related to the dscaml1 mutation, including severe fatigue during gaze stabilization, reduced saccade amplitude and velocity in the light, greater disconjugacy, and impaired fixation. Two-photon calcium imaging of abducens neurons in control and dscaml1 mutant animals confirmed deficits in saccade-command signals (indicative of an impairment in the saccadic premotor pathway), whereas abducens activation by the pretectum-vestibular pathway was not affected. Together, we show that loss of dscaml1 resulted in impairments in specific oculomotor circuits, providing a new animal model to investigate the development of oculomotor premotor pathways and their associated human ocular disorders.SIGNIFICANCE STATEMENTDscaml1 is a neural developmental gene with unknown behavioral significance. Using the zebrafish model, this study shows that dscaml1 mutants have a host of oculomotor (eye movement) deficits. Notably, the oculomotor phenotypes in dscaml1 mutants are reminiscent of human ocular motor apraxia, a neurodevelopmental disorder characterized by reduced saccade amplitude and gaze stabilization deficits. Population-level recording of neuronal activity further revealed potential subcircuit-specific requirements for dscaml1 during oculomotor behavior. These findings underscore the importance of dscaml1 in the development of visuomotor function and characterize a new model to investigate potential circuit deficits underlying human oculomotor disorders.

Modulation of CHT7 Complexes during Light/Dark- and Nitrogen-Mediated Life Cycle Transitions of Chlamydomonas.

The Chlamydomonas reinhardtii Compromised Hydrolysis of Triacylglycerols7 (CHT7) protein has been previously implicated in the regulation of DNA metabolism and cell-cycle-related gene expression during nitrogen (N) deprivation, and its predicted protein interaction domains are necessary for function. Here, we examined impacts of the cht7 mutation during the cell division cycle under nutrient deficiency in light-dark synchronized cultures. We explored the potential mechanisms affecting CHT7 complex activities during the cell cycle and N starvation, with a focus on the possible interaction between CHT7 and the C. reinhardtii retinoblastoma tumor suppressor (RB) protein homolog MAT3. Notably, the absence of CHT7 did not negatively impact the synchrony of cell division and cell cycle progression during diel growth. Although the majority of CHT7 and MAT3/RB proteins were observed in separate complexes by blue native-PAGE, the two proteins coimmunoprecipitated both during synchronized growth and following N deprivation, suggesting the presence of low abundance subcomplexes containing CHT7 and MAT3/RB. Furthermore, we observed several phosphorylated isoforms of CHT7 under these conditions. To test the potential role of phosphorylation on the structure and function of CHT7, we performed site-directed mutagenesis of previously identified phosphorylated amino acids within CHT7. These phosphorylated residues were dispensable for CHT7 function, but phosphorylated variants of CHT7 persisted, indicating that yet-unidentified residues within CHT7 are also likely phosphorylated. Based on the interaction of CHT7 and MAT3/RB, we postulate the presence of a low-abundance or transient regulatory complex in C. reinhardtii that may be similar to DREAM-like complexes in other organisms.

Deletion of the cytochrome bc complex from Heliobacterium modesticaldum results in viable but non-phototrophic cells.

The heliobacteria, a family of anoxygenic phototrophs, possess the simplest known photosynthetic apparatus. Although they are photoheterotrophs in the light, the heliobacteria can also grow chemotrophically via pyruvate metabolism in the dark. In the heliobacteria, the cytochrome bc complex is responsible for oxidizing menaquinol and reducing cytochrome c553 in the electron flow cycle used for phototrophy. However, there is no known electron acceptor for the mobile cytochrome c553 other than the photochemical reaction center. We have, therefore, hypothesized that the cytochrome bc complex is necessary for phototrophy, but unnecessary for chemotrophic growth in the dark. We used a two-step method for CRISPR-based genome editing in Heliobacterium modesticaldum to delete the genes encoding the four major subunits of the cytochrome bc complex. Genotypic analysis verified the deletion of the petCBDA gene cluster encoding the catalytic components of the complex. Spectroscopic studies revealed that re-reduction of cytochrome c553 after flash-induced photo-oxidation was over 100 times slower in the ∆petCBDA mutant compared to the wild-type. Steady-state levels of oxidized P800 (the primary donor of the photochemical reaction center) were much higher in the ∆petCBDA mutant at every light level, consistent with a limitation in electron flow to the reaction center. The ∆petCBDA mutant was unable to grow phototrophically on acetate plus CO2 but could grow chemotrophically on pyruvate as a carbon source similar to the wild-type strain in the dark. The mutants could be complemented by reintroduction of the petCBDA gene cluster on a plasmid expressed from the clostridial eno promoter.

Analysis of experience-regulated transcriptome and imprintome during critical periods of mouse visual system development reveals spatiotemporal dynamics.

Visual system development is light-experience dependent, which strongly implicates epigenetic mechanisms in light-regulated maturation. Among many epigenetic processes, genomic imprinting is an epigenetic mechanism through which monoallelic gene expression occurs in a parent-of-origin-specific manner. It is unknown if genomic imprinting contributes to visual system development. We profiled the transcriptome and imprintome during critical periods of mouse visual system development under normal- and dark-rearing conditions using B6/CAST F1 hybrid mice. We identified experience-regulated, isoform-specific and brain-region-specific imprinted genes. We also found imprinted microRNAs were predominantly clustered into the Dlk1-Dio3 imprinted locus with light experience affecting some imprinted miRNA expression. Our findings provide the first comprehensive analysis of light-experience regulation of the transcriptome and imprintome during critical periods of visual system development. Our results may contribute to therapeutic strategies for visual impairments and circadian rhythm disorders resulting from a dysfunctional imprintome.

APP Regulates Microglial Phenotype in a Mouse Model of Alzheimer's Disease.

UNLABELLED: Prior work suggests that amyloid precursor protein (APP) can function as a proinflammatory receptor on immune cells, such as monocytes and microglia. Therefore, we hypothesized that APP serves this function in microglia during Alzheimer's disease. Although fibrillar amyloid ß (Aß)-stimulated cytokine secretion from both wild-type and APP knock-out (mAPP(-/-)) microglial cultures, oligomeric Aß was unable to stimulate increased secretion from mAPP(-/-) cells. This was consistent with an ability of oligomeric Aß to bind APP. Similarly, intracerebroventricular infusions of oligomeric Aß produced less microgliosis in mAPP(-/-) mice compared with wild-type mice. The mAPP(-/-) mice crossed to an APP/PS1 transgenic mouse line demonstrated reduced microgliosis and cytokine levels and improved memory compared with wild-type mice despite robust fibrillar Aß plaque deposition. These data define a novel function for microglial APP in regulating their ability to acquire a proinflammatory phenotype during disease. SIGNIFICANCE STATEMENT: A hallmark of Alzheimer's disease (AD) brains is the accumulation of amyloid ß (Aß) peptide within plaques robustly invested with reactive microglia. This supports the notion that Aß stimulation of microglial activation is one source of brain inflammatory changes during disease. Aß is a cleavage product of the ubiquitously expressed amyloid precursor protein (APP) and is able to self-associate into a wide variety of differently sized and structurally distinct multimers. In this study, we demonstrate both in vitro and in vivo that nonfibrillar, oligomeric forms of Aß are able to interact with the parent APP protein to stimulate microglial activation. This provides a mechanism by which metabolism of APP results in possible autocrine or paracrine Aß production to drive the microgliosis associated with AD brains.

Loss of Either Rac1 or Rac3 GTPase Differentially Affects the Behavior of Mutant Mice and the Development of Functional GABAergic Networks.

Rac GTPases regulate the development of cortical/hippocampal GABAergic interneurons by affecting the early development and migration of GABAergic precursors. We have addressed the function of Rac1 and Rac3 proteins during the late maturation of hippocampal interneurons. We observed specific phenotypic differences between conditional Rac1 and full Rac3 knockout mice. Rac1 deletion caused greater generalized hyperactivity and cognitive impairment compared with Rac3 deletion. This phenotype matched with a more evident functional impairment of the inhibitory circuits in Rac1 mutants, showing higher excitability and reduced spontaneous inhibitory currents in the CA hippocampal pyramidal neurons. Morphological analysis confirmed a differential modification of the inhibitory circuits: deletion of either Rac caused a similar reduction of parvalbumin-positive inhibitory terminals in the pyramidal layer. Intriguingly, cannabinoid receptor-1-positive terminals were strongly increased only in the CA1 of Rac1-depleted mice. This increase may underlie the stronger electrophysiological defects in this mutant. Accordingly, incubation with an antagonist for cannabinoid receptors partially rescued the reduction of spontaneous inhibitory currents in the pyramidal cells of Rac1 mutants. Our results show that Rac1 and Rac3 have independent roles in the formation of GABAergic circuits, as highlighted by the differential effects of their deletion on the late maturation of specific populations of interneurons.

Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice.

Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here, we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood-cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviors in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behavior. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.

Inhibition of Acid Sphingomyelinase by Antidepressants Counteracts Stress-Induced Activation of P38-Kinase in Major Depression.

BACKGROUND/AIMS: Major depressive disorder is a common disease with serious morbidity, including increased risk of death from suicide. Major depressive disorder is treated with antidepressants. However, the molecular targets of antidepressants remained ill-defined and require further elucidation. METHODS: Mice were treated with corticosterone to induce stress, amitriptyline and the p38-kinase (p38K) inhibitor SB239063 or a combination of these drugs. Phosphorylation of p38K in hippocampal neurons was determined by immunostaining with a phospho-specific antibody, neuronal proliferation using BrdU-labelling and behaviour employing a set of behavioural tests. RESULTS: Corticosterone induced phosphorylation/activation of p38K in the hippocampus in vivo. Antidepressants reversed the effect of corticosterone on p38K activation in wildtype mice, but had no effect in acid sphingomyelinase-deficient animals. Corticosterone also reduced neurogenesis and triggered depression-like behavioural changes, effects that were prevented by pharmacological inhibition of p38K. CONCLUSION: Stress induces p38K phosphorylation/activation in the hippocampus and thereby reduces neurogenesis and induces depression-like symptoms, events that are prevented by antidepressants via inhibition of the acid sphingomyelinase/ceramide system.

Paradoxical visuomotor adaptation to reversed visual input is predicted by BDNF Val66Met polymorphism.

Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the brain, influencing neural development, plasticity, and repair (Chen et al., 2004; Thoenen, 1995). The BDNF gene contains a single-nucleotide polymorphism (SNP) called Val(66)Met. The Met allele interferes with intracellular BDNF-trafficking, decreases activity-dependent BDNF secretion, and consequently is often associated with a shift from plasticity to stability in neural circuits (Egan et al., 2003). We investigated the behavioral consequences of the presence of the Met allele by comparing how 40 heterozygous subjects with the Val/Met genotype and 35 homozygous subjects with the Val/Val genotype performed on visuomotor tasks (reaching and navigation) under two conditions: normal vision and completely left-right reversed vision. As expected, subjects did not differ in their short-term ability to learn the tasks with normal vision (p = 0.58). Intuitively, it would be expected that homozygous Val/Val subjects with a propensity for greater BDNF-induced activity-dependent plasticity would learn new tasks more quickly than heterozygous Val/Met subjects with decreased BDNF secretion (Gilbert, Li, & Piech, 2009). However, we found the opposite here. When short-term mechanisms of visuomotor adaptation were engaged to compensate for the misalignment of visual and somatomotor information created by the left-right reversal of vision, heterozygous Val/Met subjects learned significantly more quickly than their homozygous Val/Val counterparts (p = 0.027). Our results demonstrate the paradoxical finding that the presence of the Met allele, which is thought to promote cortical stability, here improves immediate visuomotor adaptation to left-right-reversed visual input.

The relationship between slow photoresponse recovery rate and temporal resolution of vision.

The rate at which photoreceptors recover from excitation is thought to be critical for setting the temporal resolution of vision. Indeed, mutations in RGS9 (regulator of G-protein signaling 9) and R9AP (RGS9 anchor protein) proteins mediating rapid photoresponse recovery impair patients' ability to see moving objects. In this study, we analyzed temporal properties of retinal sensitivity and spatiotemporal aspects of visual behavior in R9AP knock-out mice. Surprisingly, we have found that this knock-out does not affect dim-light vision mediated by rods acting as single-photon counters. Under these conditions, vision was also unaffected in mice overexpressing R9AP in rods, which causes accelerated photoresponse recovery. However, in brighter light, slow photoresponse recovery in rods and cones impaired visual responses to high temporal frequency stimuli, as reported for the daylight vision of human patients. Therefore, the speed of photoresponse recovery can affect temporal resolution and motion detection when photoreceptors integrate signals from multiple photons but not when they act as single-photon counters.

Pten deletion in adult hippocampal neural stem/progenitor cells causes cellular abnormalities and alters neurogenesis.

Adult neurogenesis persists throughout life in restricted brain regions in mammals and is affected by various physiological and pathological conditions. The tumor suppressor gene Pten is involved in adult neurogenesis and is mutated in a subset of autism patients with macrocephaly; however, the link between the role of PTEN in adult neurogenesis and the etiology of autism has not been studied before. Moreover, the role of hippocampus, one of the brain regions where adult neurogenesis occurs, in development of autism is not clear. Here, we show that ablating Pten in adult neural stem cells in the subgranular zone of hippocampal dentate gyrus results in higher proliferation rate and accelerated differentiation of the stem/progenitor cells, leading to depletion of the neural stem cell pool and increased differentiation toward the astrocytic lineage at later stages. Pten-deleted stem/progenitor cells develop into hypertrophied neurons with abnormal polarity. Additionally, Pten mutant mice have macrocephaly and exhibit impairment in social interactions and seizure activity. Our data reveal a novel function for PTEN in adult hippocampal neurogenesis and indicate a role in the pathogenesis of abnormal social behaviors.

Differential involvement of the gamma-synuclein in cognitive abilities on the model of knockout mice.

BACKGROUND: Gamma-synuclein is a member of the synuclein family of cytoplasmic, predominantly neuron-specific proteins. Despite numerous evidences for the importance of gamma-synuclein in the control of monoamine homeostasis, cytoskeleton reorganization and chaperone activity, its role in the regulation of cognitive behavior still remain unknown. Our previous study revealed that gamma-synuclein knockout mice are characterized by high habituation scores. Since a number of processes including spatial memory of the environment may affect habituation, in the present study we have carried out behavioral evaluation of spatial and working memory in gamma-synuclein knockout mice. RESULTS: Inactivation of gamma-synuclein gene led to the improvement of working memory in mice as revealed by passive and active avoidance tests. At the same time behavioral tests, designed to assess spatial learning and memory (Morris water maze and Object location tests), showed no differences between gamma-synuclein knockouts and wild type mice. CONCLUSIONS: These findings indicate that young mice with targeted inactivation of gamma-synuclein gene have improved working memory, but not spatial learning and memory. Our results suggest that gamma-synuclein is directly involved in the regulation of cognitive functions.

Retinal morphological and functional changes in an animal model of retinitis pigmentosa.

The P23H-1 transgenic rat carries a mutated mouse opsin gene, in addition to endogenous opsin genes, and undergoes progressive photoreceptor loss that is generally characteristic of human autosomal dominant retinitis pigmentosa (RP). Here, we examined morphological changes correlated with visual function that is comparable to clinical application in the pigmented P23H-1 rat retina as photoreceptor degeneration progressed. We found that rod function was compromised as early as postnatal day 28 and was a good indicator for tracking retinal degeneration. Cone function was normal and did not change until the thickness of the photoreceptor layer was reduced by 75%. Similar to the threshold versus intensity curves used to evaluate vision of RP patients, light-adaptation curves showed that cone thresholds depended on the number of remaining functioning cones, but not on its length of outer segments (OS). By 1 year of age, both rod and cone functions were significantly compromised. Correlating with early abnormal rod function, rods and related secondary neurons also underwent progressive degeneration, including shortening of inner and OS of photoreceptors, loss of rod bipolar and horizontal cell dendrites, thickening of the outer Müller cell processes, and reduced density of pre- and postsynaptic markers. Similar early morphological modifications were also observed in cones and their related secondary neurons. However, cone function was maintained at nearly normal level for a long period. The dramatic loss of rods at late stage of degeneration may contribute to the dysfunction of cones. Attention has to be focused on preserving cone function and identifying factors that damage cones when therapeutic regimes are applied to treat retinal degeneration. As such, these findings provide a foundation for future studies involving treatments to counter photoreceptor loss.