White Matter Vulnerability to Ischemic Injury Increases with Age Because of Enhanced Excitotoxicity

Baltan, Selva; Besancon, Elaine; Mbow, Brianna; Ye, Zu Cheng; Hamner, Margaret A.; Ransom, Bruce R.

doi:10.1523/jneurosci.5137-07.2008

Cited by 117 publications

(191 citation statements)

References 59 publications

Supporting

Mentioning

182

Contrasting

Unclassified

Order By: Relevance

“…In addition, Ca 21 levels also increase in myelin itself during ischemia (an effect that is abolished by broad-spectrum NMDA receptor antagonists), causing ultrastructural damage to the myelin sheath (Micu et al, 2006). WM becomes intrinsically more vulnerable to ischemia with age and the mechanisms of glutamate-mediated damage change (Baltan et al, 2008). Thus, ischemic WM injury in older mice is predominately mediated by glutamate release through reverse glutamate transport (probably from astrocytes) and the ensuing activation of AMPA/kainate-type glutamate receptors (Baltan et al, 2008).…”

mentioning

confidence: 99%

Neurotransmitter signaling in white matter

Butt

Fern

Matute

2014

Glia

113

View full text Add to dashboard Cite

White matter (WM) tracts are bundles of myelinated axons that provide for rapid communication throughout the CNS and integration in grey matter (GM). The main cells in myelinated tracts are oligodendrocytes and astrocytes, with small populations of microglia and oligodendrocyte precursor cells. The prominence of neurotransmitter signaling in WM, which largely exclude neuronal cell bodies, indicates it must have physiological functions other than neuron-to-neuron communication. A surprising aspect is the diversity of neurotransmitter signaling in WM, with evidence for glutamatergic, purinergic (ATP and adenosine), GABAergic, glycinergic, adrenergic, cholinergic, dopaminergic and serotonergic signaling, acting via a wide range of ionotropic and metabotropic receptors. Both axons and glia are potential sources of neurotransmitters and may express the respective receptors. The physiological functions of neurotransmitter signaling in WM are subject to debate, but glutamate and ATP-mediated signaling have been shown to evoke Ca 21 signals in glia and modulate axonal conduction. Experimental findings support a model of neurotransmitters being released from axons during action potential propagation acting on glial receptors to regulate the homeostatic functions of astrocytes and myelination by oligodendrocytes. Astrocytes also release neurotransmitters, which act on axonal receptors to strengthen action potential propagation, maintaining signaling along potentially long axon tracts. The co-existence of multiple neurotransmitters in WM tracts suggests they may have diverse functions that are important for information processing. Furthermore, the neurotransmitter signaling phenomena described in WM most likely apply to myelinated axons of the cerebral cortex and GM areas, where they are doubtless important for higher cognitive function. GLIA 2014;62:1762-1779 Key words: glia, axon, astrocyte, oligodendrocyte, glutamate, ATP Introduction W hite matter (WM) is defined as a tract of myelinated axons-WM appears opaque or dense due to the fatty myelin in anatomical sections and in brain scans. Notwithstanding this, myelination is not restricted to WM and is also critical to rapid communication and integration in grey matter (GM) areas, such as in axons in the cortical GM and hippocampus. Hence, many aspects of neurotransmitter signaling to be covered in this review have resonance in GM and higher cognitive function. Indeed, in the human brain WM is a prominent feature of the cerebral cortex, the seat of higher intelligence. Myelination of GM is also evident in rodents, but discrete WM tracts are not pronounced in the cerebral cortex. As a general concept, WM are simply concentrations of myelinated axons bundled together into tracts that interconnect areas of GM. The molecular physiology of myelinated axons will be very similar in WM and GM, and they will be subject to the same neurotransmitter signaling phenomena that is the subject of this review. The main cells associated with myelinated axons are the myelinating oligodendro...

show abstract

mentioning

confidence: 99%

Neurotransmitter signaling in white matter

Butt

Fern

Matute

2014

Glia

113

View full text Add to dashboard Cite

show abstract

“…The age-related change in HDAC 1 expression is similarly noteworthy, such that astrocyte nuclei and proximal processes become immunoreactive for HDAC 1 in addition to axons. Although it has the lowest intensity, HDAC 3 expression preserves a punctate pattern while extending to axons and glial nuclei, rather than astrocyte processes [16].…”

Section: Expression Of Zn-dependent Hdacs In Mouse Brainmentioning

confidence: 97%

“…WM becomes intrinsically more vulnerable to ischemia as a function of age [16]. Among several age-related changes, the class I HDAC expression pattern also changes in older animals.…”

Section: Expression Of Zn-dependent Hdacs In Mouse Brainmentioning

confidence: 99%

“…The optic nerve offers the capacity to quantitatively study the structure-function relationship of WM injury mechanisms. In addition, optic nerve is intrinsically sensitive to the process of aging [16,[25][26][27][28][29], and shows progressive molecular and functional changes as a function of age [16,28,29]. HDAC inhibitors preserve function in both young and aging axons [28,29].…”

Section: Hdac Inhibition Reduces Ischemic Injurymentioning

confidence: 99%

“…5) [28]. Interestingly, a 2-fold increase in GLT1 expression and protein levels is correlated with early and robust release of glutamate in aging WM [16], while a similar outcome after HDAC inhibition results in delayed and less glutamate release in optic nerve [28].…”

Section: Hints From the Optic Nervementioning

confidence: 99%

See 2 more Smart Citations

Novel Protective Effects of Histone Deacetylase Inhibition on Stroke and White Matter Ischemic Injury

2013

View full text Add to dashboard Cite

Understanding how epigenetics influences the process and progress of a stroke could yield new targets and therapeutics for use in the clinic. Experimental evidence suggests that inhibitors of zinc-dependent histone deacetylases can protect neurons, axons, and associated glia from the devastating effects of oxygen and glucose deprivation. While the specific enzymes involved have yet to be clearly identified, there are hints from somewhat selective chemical inhibitors and also from the use of specific small hairpin RNAs to transiently knockdown protein expression. Neuroprotective mechanisms implicated thus far include the upregulation of extracellular glutamate clearance, inhibition of p53-mediated cell death, and maintenance of mitochondrial integrity. The histone deacetylases have distinct cellular and subcellular localizations, and discrete substrates. As a number of chemical inhibitors are already in clinical use for the treatment of cancer, repurposing for the stroke clinic should be expedited.

show abstract

Glutamate receptors on myelinated spinal cord axons: II. AMPA and GluR5 receptors

Ouardouz

Coderre

Zamponi

et al. 2009

Annals of Neurology

102

View full text Add to dashboard Cite

Objective-Glutamate receptors, which play a major role in the physiology and pathology of CNS gray matter, are also involved in the pathophysiology of white matter. However the cellular and molecular mechanisms responsible for excitotoxic damage to white matter elements are not fully understood. We explored the roles of AMPA and GluR5 kainate receptors in axonal Ca 2+ deregulation.Methods-Dorsal column axons were loaded with a Ca 2+ indicator and imaged in vitro using confocal microscopy.Results-Both AMPA and a GluR5 kainate receptor agonists increased intra-axonal Ca 2+ in myelinated rat dorsal column fibers. These responses were inhibited by selective antagonists of these glutamate receptors. The GluR5-mediated Ca 2+ rise was mediated by both canonical (i.e. ionotropic) and non-canonical (metabotropic) signalling, dependent on a pertussis toxin-sensitive G protein and a phospholipase C-dependent pathway, promoting Ca 2+ release from IP3-dependent stores. Additionally, the GluR5 response was significantly reduced by intra-axonal NO scavengers. In contrast, GluR4 AMPA receptors operated via Ca 2+ induced Ca 2+ release, dependent on ryanodine receptors, and unaffected by NO scavengers. Neither pathway depended on L-type Ca 2+ channels, in contrast to GlurR6 kainate receptor action 1. Immunohistochemistry confirmed the presence of GluR4 and GluR5 clustered at the surface of myelinated axons; GluR5 co-immunoprecipitated with nNOS and often co-localized with nNOS clusters on the internodal axon.Interpretation-Central myelinated axons express functional AMPA and GluR5 kainate receptors, and can directly respond to glutamate receptor agonists. These glutamate receptordependent signalling pathways promote an increase in intra-axonal Ca 2+ levels potentially contributing to axonal degeneration.The precise mechanisms of glutamate-mediated toxicity in white matter are not completely established. This transmitter likely causes damage to glia given that both astrocytes and oligodendrocytes express a variety of glutamate receptors 2 -8, with oligodendrocytes being indicator Oregon Green BAPTA-1 (250 μM) (both from Molecular Probes) using a suction electrode applied to the cut end. The final dye concentration in the axons was estimated at ≈ 2 μM. Tissue was transferred to a custom-built chamber on a Nikon C1 confocal microscope and imaged every 60 sec at 37°C with a 60× 1.0 NA water immersion lens warmed to 37°C. Green signal was ratioed against the Ca 2+ -insensitive red channel, and then percent change during exposure to various agents compared to control was calculated. PTX was first activated by adding ATP (1mM) and glutathione (2mM) and incubated at 37°C overnight. Final PTX concentration in the loading pipette was 5 μM. ImmunohistochemistryFor light microscopy, deeply anesthetized rats were perfused with saline then 4% paraformaldehyde in 0.1 M phosphate buffer. Dorsal columns were excised, post-fixed, and immersed in 20% sucrose overnight. 40 μm sections were cut with a freezing microtome and washed with Tris b...

show abstract

White Matter Vulnerability to Ischemic Injury Increases with Age Because of Enhanced Excitotoxicity

Cited by 117 publications

References 59 publications

Neurotransmitter signaling in white matter

Neurotransmitter signaling in white matter

Novel Protective Effects of Histone Deacetylase Inhibition on Stroke and White Matter Ischemic Injury

Glutamate receptors on myelinated spinal cord axons: II. AMPA and GluR5 receptors

Contact Info

Product

Resources

About