Recurrent spontaneous spreading depolarizations facilitate acute dendritic injury in the ischemic penumbra
Open accessAbstract
Spontaneous spreading depolarizations (SDs) occur in the penumbra surrounding ischemic core. These SDs, often referred to as peri-infarct depolarizations, cause vasoconstriction and recruitment of the penumbra into the ischemic core in the critical first hours after focal ischemic stroke; however, the real-time spatiotemporal dynamics of SD-induced injury to synaptic circuitry in the penumbra remain unknown. A modified cortical photothrombosis model was used to produce a square-shaped lesion surrounding a penumbra-like "area at risk" in middle cerebral artery territory of mouse somatosensory cortex. Lesioning resulted in recurrent spontaneous SDs. In vivo two-photon microscopy of green fluorescent protein-expressing neurons in this penumbra-like area at risk revealed that SDs were temporally correlated with rapid (<6 s) dendritic beading. Dendrites quickly (<3 min) recovered between SDs to near-control morphology until the occurrence of SD-induced terminal dendritic injury, signifying acute synaptic damage. SDs are characterized by a breakdown of ion homeostasis that can be recovered by ion pumps if the energy supply is adequate. Indeed, the likelihood of rapid dendritic recovery between SDs was correlated with the presence of nearby flowing blood vessels, but the presence of such vessels was not always sufficient for rapid dendritic recovery, suggesting that energy needs for recovery exceeded energy supply of compromised blood flow. We propose that metabolic stress resulting from recurring SDs facilitates acute injury at the level of dendrites and dendritic spines in metabolically compromised tissue, expediting penumbral recruitment into the ischemic core.
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In traumatic brain injury, mechanical forces applied to the cranium and brain cause irreversible primary neuronal and astroglial damage associated with terminal dendritic beading and spine loss, representing acute damage to synaptic circuitry.
“In traumatic brain injury mechanical forces applied to the cranium and brain cause irreversible primary neuronal and astroglial damage associated with terminal dendritic beading and spine loss representing acute damage to synaptic circuitry.”
From Evolution of neuronal and astroglial disruption in the peri-contusional cortex of mice revealed by in vivo two-photon imaging (2013) · cites this paper as Risher et al., 2010
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Experimental — accuracy not yet measuredIn the absence of reperfusion, as seen in the ischaemic core, dendrites remain terminally beaded and spines are lost.
“and in the absence of reperfusion, as seen in the ischaemic core, dendrites remain terminally beaded and spines are lost (Zhang and Murphy, 2007;Risher et al., 2010).”
From Evolution of neuronal and astroglial disruption in the peri-contusional cortex of mice revealed by in vivo two-photon imaging (2013) · cites this paper as Risher et al., 2010
The Results section (‘Successive rounds of dendritic beading and recovery coincide with passage of SDs’; page unavailable) reports terminal beading and complete spine loss. The Discussion links irreversible injury to insufficient blood flow, but the experiments imaged the ischemic penumbra, not dendrites in an unreperfused ischemic core. The core-specific condition in the claim is therefore not directly supported. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTerminal dendritic beading is indicative of an irreversible acute neuronal injury and is an early sign of cell death pathway activation.
“Concurrently, terminal dendritic beading is indicative of an irreversible acute neuronal injury (Hori and Carpenter, 1994;Risher et al., 2010), and it is an early sign of cell death pathway activation (Enright et al., 2007).”
From Evolution of neuronal and astroglial disruption in the peri-contusional cortex of mice revealed by in vivo two-photon imaging (2013) · cites this paper as Risher et al., 2010
Spreading depolarizations facilitate injury to fine synaptic circuitry within the ischaemic penumbra.
“Spreading depolarizations facilitate injury to fine synaptic circuitry within the ischaemic penumbra (Risher et al., 2010)”
From Evolution of neuronal and astroglial disruption in the peri-contusional cortex of mice revealed by in vivo two-photon imaging (2013) · cites this paper as Risher et al., 2010
Stroke-induced spreading depolarizations result in dendritic beading in metabolically compromised tissue that is reversible if neurons are not severely energetically compromised.
“Stroke-induced spreading depolarizations result in dendritic beading in metabolically compromised tissue that is reversible if neurons are not severely energetically compromised (Murphy et al., 2008;Risher et al., 2010).”
From Evolution of neuronal and astroglial disruption in the peri-contusional cortex of mice revealed by in vivo two-photon imaging (2013) · cites this paper as Risher et al., 2010
Without spreading depolarizations, the development of dendritic beading in the metabolically compromised ischaemic penumbra is gradual and depends on the availability of local blood flow.
“It has been demonstrated that without spreading depolarizations the development of dendritic beading in the metabolically compromised ischaemic penumbra is gradual and depends on the availability of local blood flow (Zhang and Murphy, 2007;Risher et al., 2010).”
From Evolution of neuronal and astroglial disruption in the peri-contusional cortex of mice revealed by in vivo two-photon imaging (2013) · cites this paper as Risher et al., 2010
Recurrent spreading depolarizations increase metabolic stress in the ischaemic penumbra, greatly accelerating damage to synaptic circuitry even in the presence of nearby flowing blood vessels.
“Yet, recurrent spreading depolarizations increase metabolic stress in the ischaemic penumbra greatly accelerating damage to synaptic circuitry even in the presence of nearby flowing blood vessels (Risher et al., 2010).”
From Evolution of neuronal and astroglial disruption in the peri-contusional cortex of mice revealed by in vivo two-photon imaging (2013) · cites this paper as Risher et al., 2010
Recent studies using in vivo 2PLSM imaging showed that without recurrent spreading depolarizations injury to dendritic structure is gated by the degree of ischaemia after local blood flow loss in a photothrombotic model of focal stroke.
“Indeed, recent studies using in vivo 2PLSM imaging showed that without recurrent spreading depolarizations injury to dendritic structure is gated by the degree of ischaemia after local blood flow loss in a photothrombotic model of focal stroke (Zhang et al., 2005;Risher et al., 2010).”
From Evolution of neuronal and astroglial disruption in the peri-contusional cortex of mice revealed by in vivo two-photon imaging (2013) · cites this paper as Risher et al., 2010
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References 59 · Cited by 153
Research works printed but not linked: 1
- Holtmaat AJ Wilbrecht L Karpova A Portera-Cailliau C Burbach B Trachtenberg T Svoboda K 2005 Long-term, high-resolution imaging of neurons in the neocortex in vivo Imaging in Neuroscience and Development: A Laboratory Manual Yuste R Konnerth A Cold Spring Harbor Cold spring Harbor Laboratory Press
- Authors
- Risher, W. C., Ard, D., Yuan, J., & Kirov, S. A.
- Affiliations
- Augusta University (US)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-07-21
- Volume
- 30
- Issue
- 29
- Pages
- 9859-9868
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2918261
- OpenAlex
- W2073402789
- Semantic Scholar
- 66155257633e5b80714fa8d7919b61b0f11a0556
- Cited by
- 153
- References
- 59
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 4 · 2023: 7 · 2022: 14 · 2021: 9 · 2020: 13 · 2019: 5 · 2018: 7 · 2017: 11 · 2016: 15 · 2015: 8 · 2014: 15 · 2013: 10 · 2012: 9
- FWCI
- 6.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS057113, F31NS064753, NS057113, NS064753)
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- peri-infarct depolarization, ischemic penumbra, focal ischemic stroke, ion homeostasis, energy metabolism, somatosensory cortex, two-photon microscopy
- MeSH terms
- Animals, Brain Ischemia, Cerebrovascular Circulation, Dendrites, Electroencephalography, Image Enhancement, Mice, Transgenic, Recurrence, Somatosensory Cortex, Cortical Spreading Depression, Ultrasonography, Dendritic Spines, Mice
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