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Cited by 63Neuroscience and Neuropharmacology ResearchIon channel regulation and functionEpilepsy research and treatment

Strain-dependent differences in calcium signaling predict excitotoxicity in murine hippocampal neurons

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Shuttleworth, C. William R., Connor, John A.·2001·The Journal of Neuroscience
DOI 10.1523/jneurosci.21-12-04225.2001PMC PMC6762744
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Abstract

Commonly used inbred murine strains differ substantially in their vulnerability to excitotoxic insults. We investigated whether differences in dendritic Ca 2+signaling could underlie the differential vulnerability of C57BL/6 (resistant to kainate excitotoxicity) and C57BL/10 strains (vulnerable). A striking difference was found in fine dendrite Ca 2+responses after kainate exposure. Ca 2+signals in distal dendrites were large in C57BL/10 neurons, and, if a threshold concentration of ∼1.5 μ m was reached, a region of sustained high Ca 2+was established in the distal dendritic tree. This region then served as an initiation site for a degenerative cascade, producing high Ca 2+levels that slowly spread to involve the entire neuron and led to cell death. Dendritic Ca 2+signals in C57BL/6 neurons were much smaller and did not trigger these propagating secondary responses. Strain differences in dendritic Ca 2+signaling were also evident after tetanic stimulation of Schaffer collaterals. Ca 2+responses were much larger and peaked earlier in distal dendrites of C57BL/10 compared with those in C57BL/6. Neurons from both strains had similar membrane properties and responded to kainate with intense action potential firing. Degenerative Ca 2+responses were seen in both strains if soma Ca 2+could be sustained above 1.5 μ m. The early phases of secondary Ca 2+responses were attributable to Ca 2+influx and were abolished rapidly by buffered zero Ca 2+saline. Taken together, these data indicate that the substantial difference in Ca 2+signals in fine distal dendrites and in the initiation of spreading secondary responses may underlie the selective vulnerability of these neurons to excitotoxic insults.

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  • Sustained high calcium levels that develop in distal dendrites upon excitotoxic insult are capable of slowly spreading to the soma, ultimately resulting in acute neuronal death.

    “Indeed, sustained high calcium levels that were shown to develop in distal dendrites upon excitotoxic insult are capable of slowly spreading to the soma, ultimately resulting in acute neuronal death (Shuttleworth and Connor, 2001;Vander Jagt et al., 2008).”

    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 Shuttleworth and Connor, 2001

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Authors
Shuttleworth, C. W. R., & Connor, J. A.
Affiliations
University of New Mexico (US)
ORCID
Shuttleworth, C. William R.
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2001-06-15
Volume
21
Issue
12
Pages
4225-4236
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.21-12-04225.2001
PMC
PMC6762744
OpenAlex
W1547058570
Cited by
63
References
41
Citations by year
2025: 1 · 2022: 3 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 2 · 2013: 2 · 2012: 3
FWCI
1.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (NS35644, R01NS035644)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
Keywords
excitotoxicity, calcium signaling, dendritic calcium, strain differences, C57BL/6 mice, C57BL/10 mice, kainic acid, hippocampal neurons, calcium influx, Schaffer collaterals, tetanic stimulation, neurodegeneration, cell death
MeSH terms
Action Potentials, Animals, Calcium, Chelating Agents, Dendrites, Drug Resistance, Egtazic Acid, Electric Stimulation, Female, Fluorescent Dyes, Hippocampus, Kainic Acid, Male, Mice, Inbred C57BL, Neurons, Sensory Thresholds, Species Specificity, Fura-2, Cell Death, Calcium Signaling, Mice, In Vitro Techniques

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