Long-Range Interhemispheric Projection Neurons Show Biased Response Properties and Fine-Scale Local Subnetworks in Mouse Visual Cortex.

Integration of information processed separately in distributed brain regions is essential for brain functions. This integration is enabled by long-range projection neurons, and further, concerted interactions between long-range projections and local microcircuits are crucial. It is not well known, however, how this interaction is implemented in cortical circuits. Here, to decipher this logic, using callosal projection neurons (CPNs) in layer 2/3 of the mouse visual cortex as a model of long-range projections, we found that CPNs exhibited distinct response properties and fine-scale local connectivity patterns. In vivo 2-photon calcium imaging revealed that CPNs showed a higher ipsilateral (to their somata) eye preference, and that CPN pairs showed stronger signal/noise correlation than random pairs. Slice recordings showed CPNs were preferentially connected to CPNs, demonstrating the existence of projection target-dependent fine-scale subnetworks. Collectively, our results suggest that long-range projection target predicts response properties and local connectivity of cortical projection neurons.

Control of Spontaneous Ca2+ Transients Is Critical for Neuronal Maturation in the Developing Neocortex.

Neural activity plays roles in the later stages of development of cortical excitatory neurons, including dendritic and axonal arborization, remodeling, and synaptogenesis. However, its role in earlier stages, such as migration and dendritogenesis, is less clear. Here we investigated roles of neural activity in the maturation of cortical neurons, using calcium imaging and expression of prokaryotic voltage-gated sodium channel, NaChBac. Calcium imaging experiments showed that postmigratory neurons in layer II/III exhibited more frequent spontaneous calcium transients than migrating neurons. To test whether such an increase of neural activity may promote neuronal maturation, we elevated the activity of migrating neurons by NaChBac expression. Elevation of neural activity impeded migration, and induced premature branching of the leading process before neurons arrived at layer II/III. Many NaChBac-expressing neurons in deep cortical layers were not attached to radial glial fibers, suggesting that these neurons had stopped migration. Morphological and immunohistochemical analyses suggested that branched leading processes of NaChBac-expressing neurons differentiated into dendrites. Our results suggest that developmental control of spontaneous calcium transients is critical for maturation of cortical excitatory neurons in vivo: keeping cellular excitability low is important for migration, and increasing spontaneous neural activity may stop migration and promote dendrite formation.

Cytopathologic findings of cell block materials from the vitreous: Diagnostic distinction between intraocular lymphoma and non-lymphomatous diseases.

Intraocular lymphoma is a rare neoplasm that occurs only in the eyes and/or central nervous system. Diagnosis of intraocular lymphoma is difficult because its clinical manifestations mimic chronic uveitis. Pathological examination of the vitreous is one of the main diagnostic tools for intraocular lymphoma, but this is challenging due to the sparse cellularity and specimen degeneration. Here, we reviewed 33 cell block preparations from vitreous perfusion fluid in order to examine the significance of cytopathological findings for differential diagnosis using vitreous samples. The cases comprised 12 intraocular lymphomas and 21 non-lymphomatous diseases. Cytologically, vitreous samples from non-lymphoma cases showed lower cellularity than the lymphoma cases. Whereas vitreous material from cases with infectious endophthalmitis showed prominent neutrophilic infiltration, material from sarcoidosis cases showed infiltration of small lymphoid cells, especially CD4-positive T cells. On the other hand, lymphoma cases showed higher cellularity, with large, irregular and atypical lymphoid cells, frequent necrotic cells in the background, and less pronounced neutrophil infiltration. Immunocytochemically, 11 of the 12 lymphoma cases were of the B-cell phenotype and the remaining case was of the T/NK-cell phenotype. In conclusion, careful cytopathological examination or immunocytochemistry of vitreous material facilitates appropriate diagnosis of intraocular lymphoma.

Evaluating the efficacy of epinastine ophthalmic solution using a conjunctivitis allergen challenge model in patients with birch pollen allergic conjunctivitis.

BACKGROUND: The efficacy of epinastine 0.05% ophthalmic solution for pollen allergic conjunctivitis has already been shown in a conjunctival allergen challenge (CAC) test using cedar pollen as a challenge. The present study investigated the efficacy of this solution against birch pollen conjunctivitis in a CAC test. METHODS: Ten adult subjects (eight males and two females) with asymptomatic birch pollen conjunctivitis were enrolled in this study. The average age of the subjects was 41.1 years. This study was conducted during a period without birch pollen dispersion. In each subject, the epinastine 0.05% ophthalmic solution was instilled in one eye, and an artificial tear fluid was instilled in the fellow eye in a double-blind manner. Five minutes or 4 h after the drug instillation, both eyes were challenged with an optimal concentration of birch pollen, and ocular itching and conjunctival hyperemia were then graded. Tears were collected before the drug instillation and 20 min after the pollen challenge, and the histamine level was measured. RESULTS: The ocular itching scores and palpebral conjunctival hyperemia scores of the epinastine-treated eyes were significantly lower than those of the contralateral control eyes when the eyes were pretreated with the drug 4 h before the CAC. There was a significant correlation between the tear histamine level and mean ocular itching score of three time points (3, 5 and 10 min) following the CAC in the control eyes but not the epinastine-treated eyes. CONCLUSIONS: Epinastine is effective in suppressing ocular itching and conjunctival hyperemia in birch pollen conjunctivitis.

Dysfunction of KCNK potassium channels impairs neuronal migration in the developing mouse cerebral cortex.

Development of the cerebral cortex depends partly on neural activity, but the identity of the ion channels that might contribute to the activity-dependent cortical development is unknown. KCNK channels are critical determinants of neuronal excitability in the mature cerebral cortex, and a member of the KCNK family, KCNK9, is responsible for a maternally transmitted mental retardation syndrome. Here, we have investigated the roles of KCNK family potassium channels in cortical development. Knockdown of KCNK2, 9, or 10 by RNAi using in utero electroporation impaired the migration of late-born cortical excitatory neurons destined to become Layer II/III neurons. The migration defect caused by KCNK9 knockdown was rescued by coexpression of RNAi-resistant functional KCNK9 mutant. Furthermore, expression of dominant-negative mutant KCNK9, responsible for the disease, and electrophysiological experiments demonstrated that ion channel function was involved in the migration defect. Calcium imaging revealed that KCNK9 knockdown or expression of dominant-negative mutant KCNK9 increased the fraction of neurons showing calcium transients and the frequency of spontaneous calcium transients. Mislocated neurons seen after KCNK9 knockdown stayed in the deep cortical layers, showing delayed morphological maturation. Taken together, our results suggest that dysfunction of KCNK9 causes a migration defect in the cortex via an activity-dependent mechanism.

Relationship between choroidal blood flow velocity and choroidal thickness during systemic corticosteroid therapy for Vogt-Koyanagi-Harada disease.

PURPOSE: To investigate the relationship between circulation hemodynamics and morphology in the choroid during systemic corticosteroid therapy for patients with Vogt-Koyanagi-Harada (VKH) disease. METHODS: This retrospective case series includes 18 eyes of nine patients with VKH disease (two men and seven women; average age, 40.8 years) who received systemic corticosteroid therapy. Laser speckle flowgraphy (LSFG) and enhanced-depth imaging optical coherence tomography (EDI-OCT) were performed before treatment and at 1 week and 1 and 3 months after treatment. The average values of the mean blur rate (MBR) at the macula and the central choroidal thickness (CCT) were compared at each stage. RESULTS: The changing rates of the average MBR significantly increased at all examinations after the start of treatment compared with the pre-treatment value with resolution of serous retinal detachment (SRD) (P = 0.0002 for all). The CCT decreased significantly at all examinations after the start of treatment compared with the pre-treatment value (P = 0.0002 for all). Changes in MBR and CCT during the 3-month follow-up period correlated significantly (R = -0.5913, P = 0.0097). The best-corrected visual acuity at pre-treatment correlated significantly with the changing rate of the MBR from 0 to 3 months (R = 0.5944, P = 0.0093) but not with CCT. CONCLUSIONS: Our data suggest that circulatory disturbances and increased thickness of the choroid relate to the pathogenesis of VKH disease with link mutually. LSFG is useful as an index for evaluating the choroiditis activity of VKH disease as well as EDI-OCT.

Macular thickness changes in a patient with Leber's hereditary optic neuropathy.

BACKGROUND: Leber's hereditary optic neuropathy (LHON) refers to an optic nerve dysfunction due to mutations in the mitochondrial DNA, resulting in visual loss by apoptosis of retinal ganglion cells (RGC). In 20% of LHON cases, their fundus examination looks entirely normal at early stage. There are some reports regarding the circumpapillary retinal nerve fiber layer (cpRNFL) and the ganglion cell analysis around the macula in LHON patients and carriers by using optical coherence tomography. CASE PRESENTATION: A 40-year-old female complained of acute visual loss in both eyes. Her best-corrected visual acuity was 0.3 in the right eye and 0.2 in the left eye at the initial visit. Goldmann perimetry revealed bilateral central scotomas. Fundus examination and fluorescein angiography findings were normal, but decreased retinal inner layer thickness was detected around the macular area on spectral domain optical coherence tomography (SD-OCT). One month later, her visual acuity deteriorated to counting fingers in both eyes, and the thinning area of retinal inner layer spread rapidly. Suspected progressive RGC loss led us to check the possibility of LHON, with which the patient was diagnosed due to a positive result for the mitochondrial DNA (mtDNA) 11778 mutation. The ganglion cell complex (GCC) and cpRNFL thicknesses were observed for 24 months by using SD-OCT. The GCC thickness plunged sharply within 3 months followed by gradual decline until 6 months, thereafter showing a plateau up to 24 months. On the cpRNFL map, the temporal quadrant also showed the earliest thinning as seen in the macular area of the GCC map. The thicknesses of the superior, nasal, and inferior quadrants decreased gradually, keeping their normal ranges up to 6 months. CONCLUSIONS: SD-OCT was a useful tool in the diagnosis and follow-up of LHON. The macular GCC thickness map may detect the earliest morphological changes in LHON, as well as the temporal area of cpRNFL, before funduscopic examination reveals optic nerve atrophy.

Bilateral Neuroretinitis in Cat Scratch Disease with Exudative, Obliterative Vasculitis in the Optic Disc.

A 29-year-old fisherman exhibited optic disc oedema and peripapillary retinal detachment in the right eye, whereas in the left eye, optic atrophy and intraretinal exudates were already observed on first examination. About 6 months earlier, he noticed blurred vision of the left eye but took no medication. Visual acuity was 0.4 OD and 0.01 OS. Perimetry showed a large lower-half field defect with sparing 10° central field in the right eye and a large central scotoma in the left eye. Fluorescein angiography showed existence of arteriole or capillary nonperfusion and hyperpermeability of surrounding capillaries. Since serological examinations showed positive Bartonella immunoglobulin G (IgG) and other causes of neuroretinitis (NR) were excluded, NR in the present case was caused by cat scratch disease (CSD). Optic atrophy appeared 2 weeks after onset. Optical coherence tomography 13 weeks after onset revealed severe loss of retinal nerve fibre layer (RNFL) superior and nasal to the optic disc in both eyes and temporal in the left eye. Visual acuity of the right eye improved to 1.2 by the treatment, whereas visual field defects were persistent. CSD-NR in the present case developed abrupt appearance of optic atrophy with severe RNFL loss in the right eye, which was elicited by exudative, obliterative vasculitis in the superficial layer of the optic disc.

Effects of Mirogabalin on Hyperalgesia and Chronic Ocular Pain in Tear-Deficient Dry-Eye Rats.

Purpose: Patients with dry eye disease (DED) sometimes complain of ocular pain. DED-related ocular pain has many similarities with neuropathic pain. Mirogabalin, a novel ligand for the α2δ subunit of voltage-gated calcium channels, is approved for treating neuropathic pain in Japan. This study aimed to investigate the effect of mirogabalin on hyperalgesia and chronic ocular pain in a rat DED model. Methods: DED was induced in female Sprague Dawley rats by unilaterally excising the external lacrimal gland (ELG) and Harderian gland (HG). After 4 weeks of ELG and HG removal, tear production (pH threads) and corneal epithelial damage (fluorescein staining) were evaluated. Corneal hyperalgesia and chronic pain were analyzed, respectively, by measuring capsaicin-induced eye-wiping behavior and c-Fos expression in the trigeminal nucleus. Mirogabalin (10 or 3 mg/kg) was evaluated for effects on DED-induced hyperalgesia and chronic ocular pain. Results: Tear production was significantly lower in DED-induced eyes than in control eyes. Corneal damage was significantly higher in DED eyes than in control eyes. Hyperalgesia and chronic ocular pain were detected 4 weeks after ELG and HG removal. Five days of mirogabalin administration significantly suppressed capsaicin-induced eye-wiping behavior, which indicated the suppression of ocular hyperalgesia. Administration of 10 mg/kg mirogabalin significantly reduced c-Fos expression in the trigeminal nucleus, which indicated the amelioration of chronic ocular pain. Conclusions: Mirogabalin suppressed DED-induced hyperalgesia and chronic ocular pain in a rat DED model. Our findings suggested that mirogabalin might effectively alleviate chronic ocular pain in patients with DED.

Spatio-temporal control of neural activity in vivo using fluorescence microendoscopy.

Controlling neural activity with high spatio-temporal resolution is desired for studying how neural circuit dynamics control animal behavior. Conventional methods for manipulating neural activity, such as electrical microstimulation or pharmacological blockade, have poor spatial and/or temporal resolution. Algal protein channelrhodopsin-2 (ChR2) enables millisecond-precision control of neural activity. However, a photostimulation method for high spatial resolution mapping in vivo is yet to be established. Here, we report a novel optical/electrical probe, consisting of optical fiber bundles and metal electrodes. Optical fiber bundles were used as a brain-insertable endoscope for image transfer and stimulating light delivery. Light-induced activity from ChR2-expressing neurons was detected with electrodes bundled to the endoscope, enabling verification of light-evoked action potentials. Photostimulation through optical fiber bundles of transgenic mice expressing ChR2 in layer 5 cortical neurons resulted in single-whisker movement, indicating spatially restricted activation of neurons in vivo. The probe system described here and a combination of various photoactive molecules will facilitate studies on the causal link between specific neural activity patterns and behavior.

Activity-dependent callosal axon projections in neonatal mouse cerebral cortex.

Callosal axon projections are among the major long-range axonal projections in the mammalian brain. They are formed during the prenatal and early postnatal periods in the mouse, and their development relies on both activity-independent and -dependent mechanisms. In this paper, we review recent findings about the roles of neuronal activity in callosal axon projections. In addition to the well-documented role of sensory-driven neuronal activity, recent studies using in utero electroporation demonstrated an essential role of spontaneous neuronal activity generated in neonatal cortical circuits. Both presynaptic and postsynaptic neuronal activities are critically involved in the axon development. Studies have begun to reveal intracellular signaling pathway which works downstream of neuronal activity. We also review several distinct patterns of neuronal activity observed in the developing cerebral cortex, which might play roles in activity-dependent circuit construction. Such neuronal activity during the neonatal period can be disrupted by genetic factors, such as mutations in ion channels. It has been speculated that abnormal activity caused by such factors may affect activity-dependent circuit construction, leading to some developmental disorders. We discuss a possibility that genetic mutation in ion channels may impair callosal axon projections through an activity-dependent mechanism.

Developmental stage-specific spontaneous activity contributes to callosal axon projections.

The developing neocortex exhibits spontaneous network activity with various synchrony levels, which has been implicated in the formation of cortical circuits. We previously reported that the development of callosal axon projections, one of the major long-range axonal projections in the brain, is activity dependent. However, what sort of activity and when activity is indispensable are not known. Here, using a genetic method to manipulate network activity in a stage-specific manner, we demonstrated that network activity contributes to callosal axon projections in the mouse visual cortex during a 'critical period': restoring neuronal activity during that period resumed the projections, whereas restoration after the period failed. Furthermore, in vivo Ca2+ imaging revealed that the projections could be established even without fully restoring highly synchronous activity. Overall, our findings suggest that spontaneous network activity is selectively required during a critical developmental time window for the formation of long-range axonal projections in the cortex.

Cerebrospinal fluid hypovolemia syndrome mimicking ocular myasthenia gravis: A case report.

Purpose: Cerebrospinal fluid hypovolemia syndrome (CHS) is a rare clinical entity that can be caused by spontaneous cerebrospinal fluid (CSF) leakage. The aim of this study is to report a rare case of CHS after a traffic accident in a patient who presented with diplopia and ptosis with fluctuation and was initially diagnosed with ocular myasthenia gravis. Observeations: A 29-year-old man exhibited fluctuating left ptosis and diplopia after a traffic accident. Although he was suspected of having myasthenia gravis and was treated using oral pyridostigmine bromide, his symptoms did not improve. He also had orthostatic headaches and malaise after the accident. His symptoms were suspected to be associated with traumatic cerebrospinal fluid hypovolemia. After 1000-mL fluid replacement, his diplopia and ptosis improved, and orbital T2-weghted MRI detected a high-signal zone around the optic nerve. We diagnosed him with oculomotor nerve paresis associated with cerebrospinal fluid hypovolemia. The symptoms, including ptosis, diplopia, orthostatic headaches, and malaise, disappeared after epidural blood patch therapy. Conclusions and Importance: When treating patients with fluctuating ocular symptoms, such as diplopia and ptosis, who have a history of trauma and orthostatic headaches, the possibility of CHS should be considered in the differential diagnosis.

Involvement of Calcium-Dependent Pathway and ß Subunit-Interaction in Neuronal Migration and Callosal Projection Deficits Caused by the Cav1.2 I1166T Mutation in Developing Mouse Neocortex.

Introduction: Gain-of-function mutations in the L-type Ca2+ channel Cav1.2 cause Timothy syndrome (TS), a multisystem disorder associated with neurologic symptoms, including autism spectrum disorder (ASD), seizures, and intellectual disability. Cav1.2 plays key roles in neural development, and its mutation can affect brain development and connectivity through Ca2+-dependent and -independent mechanisms. Recently, a gain-of-function mutation, I1166T, in Cav1.2 was identified in patients with TS-like disorder. Its channel properties have been analyzed in vitro but in vivo effects of this mutation on brain development remain unexplored. Methods: In utero electroporation was performed on ICR mice at embryonic day 15 to express GFP, wild-type, and mutant Cav1.2 channels into cortical layer 2/3 excitatory neurons in the primary somatosensory area. The brain was fixed at postnatal days 14-16, sliced, and scanned using confocal microscopy. Neuronal migration of electroporated neurons was examined in the cortex of the electroporated hemisphere, and callosal projection was examined in the white matter and contralateral hemisphere. Results: Expression of the I1166T mutant in layer 2/3 neurons caused migration deficits in approximately 20% of electroporated neurons and almost completely diminished axonal arborization in the contralateral hemisphere. Axonal projection in the white matter was not affected. We introduced second mutations onto Cav1.2 I1166T; L745P mutation blocks Ca2+ influx through Cav1.2 channels and inhibits the Ca2+-dependent pathway, and the W440A mutation blocks the interaction of the Cav1.2 α1 subunit to the ß subunit. Both second mutations recovered migration and projection. Conclusion: This study demonstrated that the Cav1.2 I1166T mutation could affect two critical steps during cerebrocortical development, migration and axonal projection, in the mouse brain. This is mediated through Ca2+-dependent pathway downstream of Cav1.2 and ß subunit-interaction.

Optical coherence tomography as a possible tool to monitor and predict disease progression in mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes.

Optical coherence tomography (OCT) is an imaging technique used to obtain three-dimensional information on the retina. In this article, we evaluated the structural neuro-retinal abnormalities, especially the thickness in the ganglion cell complex (GCC), in patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). The GCC thickness in MELAS patients was significantly thinner than that in normal controls even when they had no history of transient homonymous hemianopia. There was a negative correlation between GCC thickness and disease duration. In conclusion, OCT may be an effective tool to monitor and predict disease progression in MELAS patients.

Control of cortical axon elongation by a GABA-driven Ca2+/calmodulin-dependent protein kinase cascade.

Ca(2+) signaling plays important roles during both axonal and dendritic growth. Yet whether and how Ca(2+) rises may trigger and contribute to the development of long-range cortical connections remains mostly unknown. Here, we demonstrate that two separate limbs of the Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK)-CaMKI cascades, CaMKK-CaMKIalpha and CaMKK-CaMKIgamma, critically coordinate axonal and dendritic morphogenesis of cortical neurons, respectively. The axon-specific morphological phenotype required a diffuse cytoplasmic localization and a strikingly alpha-isoform-specific kinase activity of CaMKI. Unexpectedly, treatment with muscimol, a GABA(A) receptor agonist, selectively stimulated elongation of axons but not of dendrites, and the CaMKK-CaMKIalpha cascade critically mediated this axonogenic effect. Consistent with these findings, during early brain development, in vivo knockdown of CaMKIalpha significantly impaired the terminal axonal extension and thereby perturbed the refinement of the interhemispheric callosal projections into the contralateral cortices. Our findings thus indicate a novel role for the GABA-driven CaMKK-CaMKIalpha cascade as a mechanism critical for accurate cortical axon pathfinding, an essential process that may contribute to fine-tuning the formation of interhemispheric connectivity during the perinatal development of the CNS.

Pre-synaptic and post-synaptic neuronal activity supports the axon development of callosal projection neurons during different post-natal periods in the mouse cerebral cortex.

Callosal projection neurons, one of the major types of projection neurons in the mammalian cerebral cortex, require neuronal activity for their axonal projections [H. Mizuno et al. (2007) J. Neurosci., 27, 6760-6770; C. L. Wang et al. (2007) J. Neurosci., 27, 11334-11342]. Here we established a method to label a few callosal axons with enhanced green fluorescent protein in the mouse cerebral cortex and examined the effect of pre-synaptic/post-synaptic neuron silencing on the morphology of individual callosal axons. Pre-synaptic/post-synaptic neurons were electrically silenced by Kir2.1 potassium channel overexpression. Single axon tracing showed that, after reaching the cortical innervation area, green fluorescent protein-labeled callosal axons underwent successive developmental stages: axon growth, branching, layer-specific targeting and arbor formation between post-natal day (P)5 and P9, and the subsequent elaboration of axon arbors between P9 and P15. Reducing pre-synaptic neuronal activity disturbed axon growth and branching before P9, as well as arbor elaboration afterwards. In contrast, silencing post-synaptic neurons disturbed axon arbor elaboration between P9 and P15. Thus, pre-synaptic neuron silencing affected significantly earlier stages of callosal projection neuron axon development than post-synaptic neuron silencing. Silencing both pre-synaptic and post-synaptic neurons impaired callosal axon projections, suggesting that certain levels of firing activity in pre-synaptic and post-synaptic neurons are required for callosal axon development. Our findings provide in-vivo evidence that pre-synaptic and post-synaptic neuronal activities play critical, and presumably differential, roles in axon growth, branching, arbor formation and elaboration during cortical axon development.

Cerebrospinal fluid hypovolemia syndrome after a traffic accident with abnormal eye movements: A case report.

PURPOSE: To describe a rare case of cerebrospinal fluid hypovolemia syndrome after a traffic accident with abnormal eye movements. OBSERVATIONS: A 19-year-old man was referred to our clinic after being hit by a car five months ago while riding a bicycle. After the accident, he sometimes noticed oscillopsia, and had postural headaches and reading difficulties. His eye movement recording revealed square wave jerks during fixation and decreased pursuit gain during horizontal smooth pursuit. MR myelography detected cerebrospinal fluid leakage and the patient was diagnosed with cerebrospinal fluid hypovolemia. After undergoing epidural blood patch therapy, the leakage disappeared, and his postural headaches improved immediately. Square wave jerks and decreased pursuit gain improved, and his oscillopsia and reading difficulty also improved after therapy. CONCLUSIONS AND IMPORTANCE: A patient with cerebrospinal fluid hypovolemia presented with square wave jerks and decreased pursuit gain. Epidural blood patch therapy was effective for the symptoms. When treating patients with oscillopsia and postural headaches, we should consider the possibility of cerebrospinal fluid hypovolemia syndrome in the differential diagnosis.

Receptor-Associated Prorenin System in the Trabecular Meshwork of Patients with Primary Open-Angle Glaucoma and Neovascular Glaucoma.

The receptor-associated prorenin system (RAPS) is associated with several pathologic conditions, including diabetic retinopathy, age-related macular degeneration, and uveitis. Here, we show the involvement of RAPS in the trabecular meshwork (TM) from patients with primary open-angle glaucoma (POAG) and neovascular glaucoma (NVG) due to proliferative diabetic retinopathy. Anterior chamber (AC) levels of prorenin significantly increased in both POAG and NVG, as did those of angiotensin II in NVG alone, compared to cataract. In surgically excised TM tissues, (pro)renin receptor ((P)RR) and angiotensin II type 1 receptor (AT1R) co-localized with prorenin and angiotensinogen, respectively. In screening for various genes related to glaucoma, prorenin stimulation to human TM cells exclusively upregulated cell junction constituents connexin 43 and zona occludens 1, while downregulating an extracellular matrix-degrading enzyme tissue plasminogen activator, all of which were reversed by (P)RR blockade. In contrast, angiotensin II application upregulated a pro-angiogenic factor placental growth factor alone, which was abolished by AT1R blockade. Consistently, (P)RR and AT1R co-localized with these corresponding proteins in patient TM tissues. Oxidative stress, a known etiology for glaucoma, induced the expression of prorenin and angiotensinogen in human TM cells. These data suggest the contribution of RAPS to the molecular pathogenesis of POAG and NVG through TM tissue remodeling and AC angle angiogenesis.

Diabetic Cataract in Spontaneously Diabetic Torii Fatty Rats.

Spontaneously Diabetic Torii (SDT) fatty rat is a novel animal model of type 2 diabetes with obesity. SDT fatty rats develop hyperglycemia, dyslipidemia, and other diabetic complications including ocular disorders; however, diabetic cataract formation in SDT fatty rats has not been fully investigated. The aim of the current study was to investigate the characteristics of cataract in the SDT fatty rats. The mean body weight of SDT fatty rats is larger than that of age-matched Sprague-Dawley (SD) rats and control animals until 8 weeks of age, and thereafter the growing speed decreased until the end of observation at 16 weeks of age. Blood glucose levels in SDT fatty rats were significantly higher than those in SD rats throughout the observational period. Slit-lamp examination revealed that no rats showed cataract formation at 5 weeks of age; however, SDT fatty rats gradually developed cortical cataract and posterior subcapsular cataract, both of which are the common types of cataract in patients with type 2 diabetes. The levels of glucose, sorbitol, and fructose were higher in the lens tissues of SDT fatty rats in comparison with that of SD rats. Furthermore, the level of 4-hydroxynonenal (4-HNE) was higher in the lens of SDT fatty rats than in that of SD rats. By contrast, total glutathione (GSH) concentration was lower in the lens of SDT fatty rats than in that of SD rats. The present study demonstrated that the cataractogenesis in SDT fatty rats resembled human diabetic cataract formation, indicating that SDT fatty rats serve as a potential animal model in researches on human cataract associated with type 2 diabetes and obesity.