Elevated intraocular pressure decreases response sensitivity of inner retinal neurons in experimental glaucoma mice

Glaucoma is the second leading cause of blindness in the United States and the world, characterized by progressive degeneration of the optic nerve and retinal ganglion cells (RGCs). Glaucoma patients exhibit an early diffuse loss of retinal sensitivity followed by focal loss of RGCs in sectored patterns. Recent evidence has suggested that this early sensitivity loss may be associated with dysfunctions in the inner retina, but detailed cellular and synaptic mechanisms underlying such sensitivity changes are largely unknown. In this study, we use whole-cell voltage-clamp techniques to analyze light responses of individual bipolar cells (BCs), AII amacrine cells (AIIACs), and ON and sustained OFF alpha-ganglion cells (ONαGCs and sOFFαGCs) in dark-adapted mouse retinas with elevated intraocular pressure (IOP). We present evidence showing that elevated IOP suppresses the rod ON BC inputs to AIIACs, resulting in less sensitive AIIACs, which alter AIIAC inputs to ONαGCs via the AIIAC→cone ON BC→ONαGC pathway, resulting in lower ONαGC sensitivity. The altered AIIAC response also reduces sOFFαGC sensitivity via the AIIAC→sOFFαGC chemical synapses. These sensitivity decreases in αGCs and AIIACs were found in mice with elevated IOP for 3–7 wk, a stage when little RGC or optic nerve degeneration was observed. Our finding that elevated IOP alters neuronal function in the inner retina before irreversible structural damage occurs provides useful information for developing new diagnostic tools and treatments for glaucoma in human patients.

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Neuroprotective effect of Erigeron Breviscapus (vant) Hand-mazz extract on retinal ganglion cells in rabbits with chronic elevated intraocular pressure

Asian Biomedicine ◽

10.5372/1905-7415.0502.025 ◽

2011 ◽

Vol 5 (2) ◽

pp. 195-203 ◽

Cited By ~ 1

Author(s):

Yi-sheng Zhong ◽

Min-hong Xiang ◽

Wen Ye ◽

Ping Huang ◽

Yu Cheng ◽

...

Keyword(s):

Intraocular Pressure ◽

Optic Nerve ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Neuroprotective Effect ◽

Treated Group ◽

Ultrastructural Changes ◽

Retinal Ganglion ◽

Elevated Intraocular Pressure ◽

Erigeron Breviscapus

Abstract Background: Retinal ganglion cells (RGCs) are protected in rats with acute elevated intraocular pressure (IOP) by Erigeron breviscapus (vant.) hand-mazz (EBHM). However, it is unclear whether EBHM has neuroprotective effect on RGCs in animal with chronic elevated IOP. Objective: Investigate the protective effect of EBHM extract on RGCs in rabbits with chronic elevated IOP. Methods: Unilateral chronic elevated IOP was produced in rabbits by repeated injection of 2% methylcellulose into the anterior chamber. Secondary degeneration was measured with and without EBHM extract treatment for 60 days. At 60 days, the cells density of the RGCs layer, the thickness of retinal nerve fiber layer (RNFL), and the optic nerve axons were observed and analyzed using an image analysis system. The ultrastructural changes of RGCs and optic nerve axons were observed using transmission electron microscopy. Results: Compared with their contralateral control eyes with normal IOP, in the retinas of 3-4 mm from the optic disc, the cells density of the RGCs layer in the eyes with chronic elevated IOP was 23.2±6.5 cells (n = 6) and 36.0±8.9 cells (n = 10) per three 400x fields at 60 days in untreated and EBHM-treated group, respectively. The RNFL thickness in eyes with chronic elevated IOP was 3.4±0.4 μm (n = 6) and 5.0±1.0 μm (n = 10) at 60 days in untreated and EBHM-treated group, respectively. The axons number per 15057.8 μm2 in eyes with chronic elevated IOP was 370.4±41.0 (n = 6) and 439.0±50.8 (n = 10) at 60 days in untreated and EBHM-treated group, respectively. The number of the organelles in RGCs plasm appeared decreased and mitochondrion vacuolated in the elevated IOP eyes of EBHM-treated group, while some dispersive mitochondrion and rough surfaced endoplasmic reticulum and ribosome still existed in the RGCs plasm. The myelin sheath plates condensed and degenerated, and the microfilaments and microtubules decreased or disappeared in the elevated IOP eyes, but the axons degeneration in the chronic elevated IOP with EBHM treatment was less than that in the chronic elevated IOP without treatment. Conclusion: EBHM extract provided a neuroprotective effect on retinal ganglion cells in rabbits with chronic elevated IOP.

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Erythropoietin with Retrobulbar Administration Protects Retinal Ganglion Cells from Acute Elevated Intraocular Pressure in Rats

Journal of Ocular Pharmacology and Therapeutics ◽

10.1089/jop.2008.0021 ◽

2008 ◽

Vol 24 (5) ◽

pp. 453-460 ◽

Cited By ~ 22

Author(s):

Yi-sheng Zhong ◽

Xiao-hong Liu ◽

Yu Cheng ◽

Ying-jun Min

Keyword(s):

Intraocular Pressure ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Elevated Intraocular Pressure

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THE FINE STRUCTURAL LOCALIZATION OF ACETYLCHOLINESTERASE ACTIVITY IN THE RETINA AND OPTIC NERVE OF RABBITS

Journal of Histochemistry & Cytochemistry ◽

10.1177/19.2.85 ◽

1971 ◽

Vol 19 (2) ◽

pp. 85-96 ◽

Cited By ~ 41

Author(s):

E. REALE ◽

L. LUCIANO ◽

M. SPITZNAS

Keyword(s):

Endoplasmic Reticulum ◽

Optic Nerve ◽

Ganglion Cells ◽

Plexiform Layer ◽

Amacrine Cells ◽

Acetylcholinesterase Activity ◽

Horizontal Cells ◽

Histochemical Reaction ◽

Fiber Layer ◽

Structural Localization

In the rabbit retina acetylcholinesterase activity is localized in the perinuclear cisterna, in the cisternae of the rough surfaced endoplasmic reticulum and in the Golgi apparatus of ganglion cells and amacrine cells. The histochemical reaction is positive also in the rough surfaced endoplasmic reticulum of some horizontal cells. The highest activity is seen in the internal plexiform layer; because of artifacts caused by the diffusion of the enzyme, a clear demonstration of relation of the positivity to one or the other regular components of this layer, however, is not possible. Myelinated fibers which exhibit acetylcholinesterase activity and are most probably efferent are found in the internal plexiform layer. In the retinal nerve fiber layer and in the optic nerve only a few fibers show a positive reaction.

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Inherited glaucoma in DBA/2J mice: Pertinent disease features for studying the neurodegeneration

Visual Neuroscience ◽

10.1017/s0952523805225130 ◽

2005 ◽

Vol 22 (5) ◽

pp. 637-648 ◽

Cited By ~ 208

Author(s):

RICHARD T. LIBBY ◽

MICHAEL G. ANDERSON ◽

IOK-HOU PANG ◽

ZACHARY H. ROBINSON ◽

OLGA V. SAVINOVA ◽

...

Keyword(s):

Optic Nerve ◽

Ganglion Cells ◽

The Elderly ◽

Nerve Degeneration ◽

Retinal Ganglion ◽

Cell Degeneration ◽

Future Studies ◽

Age Related ◽

Iop Elevation ◽

Mechanistic Basis

The glaucomas are neurodegenerative diseases involving death of retinal ganglion cells and optic nerve head excavation. A major risk factor for this neurodegeneration is a harmfully elevated intraocular pressure (IOP). Human glaucomas are typically complex, progressive diseases that are prevalent in the elderly. Family history and genetic factors are clearly important in human glaucoma. Mouse studies have proven helpful for investigating the genetic and mechanistic basis of complex diseases. We previously reported inherited, age-related progressive glaucoma in DBA/2J mice. Here, we report our updated findings from studying the disease in a large number of DBA/2J mice. The period when mice have elevated IOP extends from 6 months to 16 months, with 8–9 months representing an important transition to high IOP for many mice. Optic nerve degeneration follows IOP elevation, with the majority of optic nerves being severely damaged by 12 months of age. This information should help with the design of experiments, and we present the data in a manner that will be useful for future studies of retinal ganglion cell degeneration and optic neuropathy.

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Optic Nerve Head Astrocytes Display Axon-Dependent and -Independent Reactivity in Response to Acutely Elevated Intraocular Pressure

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.18-25447 ◽

2019 ◽

Vol 60 (1) ◽

pp. 312 ◽

Cited By ~ 3

Author(s):

Shandiz Tehrani ◽

Lauren Davis ◽

William O. Cepurna ◽

R. Katherine Delf ◽

Diana C. Lozano ◽

...

Keyword(s):

Intraocular Pressure ◽

Optic Nerve ◽

Optic Nerve Head ◽

Elevated Intraocular Pressure

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Measuring the Biaxial Stress-Strain Characteristics of Human Sclera

ASME 2007 Summer Bioengineering Conference ◽

10.1115/sbc2007-176531 ◽

2007 ◽

Cited By ~ 3

Author(s):

C. G. Olesen ◽

I. Tertinegg ◽

A. Eilaghi ◽

G. W. Brodland ◽

C. Horst ◽

...

Keyword(s):

Risk Factor ◽

Intraocular Pressure ◽

Optic Nerve ◽

Ganglion Cell ◽

Mechanical Strain ◽

Biaxial Stress ◽

Retinal Ganglion ◽

Irreversible Loss ◽

Elevated Intraocular Pressure ◽

Primary Risk Factor

Glaucoma is a common ocular disease that causes irreversible loss of vision. Elevated intraocular pressure (IOP) is the primary risk factor for developing glaucoma. It is believed that increased IOP causes mechanical strain on the glial cells that support the retinal ganglion cell axons and thereby causes ganglion cell apoptosis [1,2]. This damage occurs in the optic nerve head (ONH) region of the eye, and is important for understanding ONH biomechanics.

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Regional distribution of nitrergic neurons in the inner retina of the chicken

Visual Neuroscience ◽

10.1017/s0952523811000083 ◽

2011 ◽

Vol 28 (3) ◽

pp. 205-220 ◽

Cited By ~ 10

Author(s):

MARTIN WILSON ◽

NICK NACSA ◽

NATHAN S. HART ◽

CYNTHIA WELLER ◽

DAVID I. VANEY

Keyword(s):

Ganglion Cell ◽

Ganglion Cells ◽

Regional Distribution ◽

Plexiform Layer ◽

Visual Image ◽

Amacrine Cells ◽

Cell Types ◽

Inner Plexiform Layer ◽

Inner Retina ◽

Neuronal Types

AbstractUsing both NADPH diaphorase and anti-nNOS antibodies, we have identified—from retinal flatmounts—neuronal types in the inner retina of the chicken that are likely to be nitrergic. The two methods gave similar results and yielded a total of 15 types of neurons, comprising 9 amacrine cells, 5 ganglion cells, and 1 centrifugal midbrain neuron. Six of these 15 cell types are ubiquitously distributed, comprising 3 amacrine cells, 2 displaced ganglion cells, and a presumed orthotopic ganglion cell. The remaining nine cell types are regionally restricted within the retina. As previously reported, efferent fibers of midbrain neurons and their postsynaptic partners, the unusual axon-bearing target amacrine cells, are entirely confined to the ventral retina. Also confined to the ventral retina, though with somewhat different distributions, are the “bullwhip” amacrine cells thought to be involved in eye growth, an orthotopic ganglion cell, and two types of large axon-bearing amacrine cells whose dendrites and axons lie in stratum 1 of the inner plexiform layer (IPL). Intracellular fills of these two cell types showed that only a minority of otherwise morphologically indistinguishable neurons are nitrergic. Two amacrine cells that branch throughout the IPL are confined to an equatorial band, and one small-field orthotopic ganglion cell that branches in the proximal IPL is entirely dorsal. These findings suggest that the retina uses different processing on different regions of the visual image, though the benefit of this is presently obscure.

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