Visual abnormalities associated with enhanced optic nerve myelination

Yu, Minzhong; Narayanan, S. Priya; Wang, Feng; Morse, Emily N.; Macklin, Wendy B.; Peachey, Neal S.

doi:10.1016/j.brainres.2010.12.043

Cited by 16 publications

(17 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…9B) with markedly increased amplitudes at 7 months (Fig. 9D) consistent with previous studies of murine flash VEP development (Yu et al, 2011; Yu et al, 2012). The remaining op/op mice showed some measurable, generally low amplitude VEP at P30 and increased VEP amplitude at 7 months.…”

Section: Resultssupporting

confidence: 90%

See 1 more Smart Citation

Spontaneous Optic Nerve Compression in the Osteopetrotic (op/op) Mouse: A Novel Model of Myelination Failure

Kondo

Ramaker²,

Radcliff³

et al. 2013

J. Neurosci.

View full text Add to dashboard Cite

We report a focal disturbance in myelination of the optic nerve in the osteopetrotic (op/op) mouse, which results from a spontaneous compression of the nerve due to stenosis of the optic canal. The growth of the op/op optic nerve was significantly affected, being maximally suppressed at postnatal day (P)-30 (33% of age matched control). Myelination of the nerve in the optic canal was significantly delayed at P15 and myelin was almost completely absent at P30. The size of nerves and myelination were conserved both in the intracranial and intraorbital segments at P30, suggesting that the axons in the compressed site are spared in all animals at P30. Interestingly, we observed recovery both in the nerve size and the density of myelinated axons at 7 months in almost half of the optic nerves examined though some nerves lost axons and became atrophic. In vivo and ex vivo electrophysiological examinations of P30 op/op mice showed that nerve conduction was significantly delayed but not blocked with partial recovery in some mice by 7 months. Transcardial perfusion of FITC-labeled albumin suggested that local ischemia was at least in part the cause of this myelination failure. These results suggest that the primary abnormality is dysmyelination of the optic nerve in early development. This non-invasive model system will be a valuable tool to study the effects of nerve compression on the function and survival of oligodendrocyte progenitor cells (OPCs)/oligodendrocytes and axons and to explore the mechanism of redistribution of OPCs with compensatory myelination.

show abstract

Section: Resultssupporting

confidence: 90%

“…Amplifiers gain for ERG was 1 K with a bandpass of DC-500Hz. The VEP was recorded with the active subdermal electrode inserted along the midline of the visual cortex (Ren et al, 2000; Yu et al, 2011). The reference and ground was as for the ERG.…”

Section: Methodsmentioning

confidence: 99%

Spontaneous Optic Nerve Compression in the Osteopetrotic (op/op) Mouse: A Novel Model of Myelination Failure

Kondo

Ramaker²,

Radcliff³

et al. 2013

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Figure 6A shows representative VEP waveforms obtained using 3 stimulus intensities from a WT mouse and a cbs +/− littermate at 30 weeks of age. The mouse VEP is dominated by a large negative wave (N1), the implicit time of which decreases with increasing flash intensity (Yu et al ., 2011). Intensity-response functions for N1 implicit time are shown in Figure 6B–D for mice tested at 5 weeks (B), 10 weeks (C) or 30 weeks (D) of age.…”

Section: Resultsmentioning

confidence: 99%

“…The ISI ranged from 1.1 to 6 s, increasing with stimulus intensity from −2.4 to 2.1 log cd s/m 2 ; 60 to 20 successive responses were averaged to obtain a VEP waveform. The mouse VEP is dominated by a negative component which is referred to as N1 (Peachey et al ., 1997; Ridder and Nusinowitz, 2006; Yu et al ., 2011). The implicit time of the N1 component was measured at the negative peak.…”

Section: Methodsmentioning

confidence: 99%

Age-related changes in visual function in cystathionine-beta-synthase mutant mice, a model of hyperhomocysteinemia

Sturgill-Short

Ganapathy

et al. 2012

Experimental Eye Research

Self Cite

View full text Add to dashboard Cite

Homocysteine is an amino acid required for the metabolism of methionine. Excess homocysteine is implicated in cardiovascular and neurological disease and new data suggest a role in various retinopathies. Mice lacking cystathionine-beta-synthase (cbs−/−) have an excess of retinal homocysteine and develop anatomical abnormalities in multiple retinal layers, including photoreceptors and ganglion cells; heterozygous (cbs+/−) mice demonstrate ganglion cell loss and mitochondrial abnormalities in the optic nerve. The purpose of the present study was to determine whether elevated homocysteine, due to absent or diminished cbs, alters visual function. We examined cbs−/− (3 weeks) and cbs−+/− mice (5, 10, 15, 30 weeks) and results were compared to those obtained from wildtype (WT) littermates. Light- and dark-adapted ERGs were recorded along with dc-ERG to assess retinal pigment epithelial (RPE) function. The visual evoked potential (VEP) was used to assess transmission to the visual cortex. The amplitudes of the major ERG components were reduced in cbs−/− mice at age 3 weeks and VEPs were delayed markedly. These findings are consistent with the early retinal disruption observed anatomically in these mice. In comparison, at 3 weeks of age, responses of cbs+/− mice did not differ significantly from those of WT mice. Functional abnormalities were not observed in cbs+/− mice until 15 weeks of age, at which time amplitude reductions were noted for the ERG a- and b-wave and the light peak component, but not for other components generated by the RPE. VEP implicit times were delayed in cbs+/− mice at 15 and 30 weeks. The later onset of functional defects in cbs+/− mice is consistent with a slow loss of ganglion cells reported previously in the heterozygous mutant. Light peak abnormalities indicate that RPE function is also compromised in older cbs+/− mice. The data suggest that severe elevations of homocysteine are associated with marked alterations of retinal function while modest homocysteine elevation is reflected in modest and delayed alterations of retinal function. The work lays the foundation to explore the role of homocysteine in retinal diseases such as glaucoma and optic neuropathy.

show abstract

“…When Akt is driven to be constitutively active, hypermyelination without increasing oligodendrocyte numbers is specifically observed in CNS but not in PNS (Flores et al, 2008; Yu et al, 2011). Conversely, over-expression of GSK3β reduces myelination (Azim and Butt, 2011), brain size, and cortical thickness without a decline in neuron number and thus results in increased neuronal density (Spittaels et al, 2002).…”

Section: Psychotropic Treatments Influence Glia and Myelinationmentioning

confidence: 99%

Neuroglialpharmacology: Myelination as a shared mechanism of action of psychotropic treatments

2012

View full text Add to dashboard Cite

Current psychiatric diagnostic schema segregate symptom clusters into discrete entities, however, large proportions of patients suffer from comorbid conditions that fit neither diagnostic nor therapeutic schema. Similarly, psychotropic treatments ranging from lithium and antipsychotics to serotonin reuptake inhibitors (SSRIs) and acetylcholinesterase inhibitors have been shown to be efficacious in a wide spectrum of psychiatric disorders ranging from autism, schizophrenia (SZ), depression, and bipolar disorder (BD) to Alzheimer’s disease (AD). This apparent lack of specificity suggests that psychiatric symptoms as well as treatments may share aspects of pathophysiology and mechanisms of action that defy current symptom-based diagnostic and neuron-based therapeutic schema. A myelin-centered model of human brain function can help integrate these incongruities and provide novel insights into disease etiologies and treatment mechanisms. Available data are integrated herein to suggest that widely used psychotropic treatments ranging from antipsychotics and antidepressants to lithium and electroconvulsive therapy share complex signaling pathways such as Akt and glycogen synthase kinase-3 (GSK3) that affect myelination, its plasticity, and repair. These signaling pathways respond to neurotransmitters, neurotrophins, hormones, and nutrition, underlie intricate neuroglial communications, and may substantially contribute to the mechanisms of action and wide spectra of efficacy of current therapeutics by promoting myelination. Imaging and genetic technologies make it possible to safely and noninvasively test these hypotheses directly in humans and can help guide clinical trial efforts designed to correct myelination abnormalities. Such efforts may provide insights into novel avenues for treatment and prevention of some of the most prevalent and devastating human diseases. Pervasive brain myelination underlies neural network synchrony and our distinctiveness as a species. Psychiatric diagnoses may share deficits in myelin development, plasticity, or repair. Treatments act on neuroglial signaling pathways such as Akt and GSK3 that improve myelination. Treatment efficacy may derive from myelination-driven improved neural network synchronization. “Neuroglialpharmacology” encapsulates a paradigm shift in medication development strategy.

show abstract

Visual abnormalities associated with enhanced optic nerve myelination

Cited by 16 publications

References 24 publications

Spontaneous Optic Nerve Compression in the Osteopetrotic (op/op) Mouse: A Novel Model of Myelination Failure

Spontaneous Optic Nerve Compression in the Osteopetrotic (op/op) Mouse: A Novel Model of Myelination Failure

Age-related changes in visual function in cystathionine-beta-synthase mutant mice, a model of hyperhomocysteinemia

Neuroglialpharmacology: Myelination as a shared mechanism of action of psychotropic treatments

Contact Info

Product

Resources

About