Enhanced sensitivity of hippocampal pyramidal neurons from mdx mice to hypoxia-induced loss of synaptic transmission

Mark F. Mehler, Kurt Z. Haas, John A. Kessler, Patric K. Stanton

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

The gene at the Duchenne/Becker muscular dystrophy locus encodes dystrophin, a member of a protein superfamily that links the actin cytoskeleton to transmembrane plasmalemmal proteins. In mature skeletal myocytes, the absence of dystrophin is associated with decreased membrane stability, altered kinetics of several calcium channels, and increased intracellular calcium concentration. In the central nervous system, dystrophin is restricted to specific neuronal populations that show heightened susceptibility to excitotoxic damage and is localized in proximal dendrites and the neuronal somata. We report that CA1 pyramidal neurons in a hippocampal slice preparation from a dystrophin-deficient mouse genetic model of Duchenne muscular dystrophy (the mdx mouse) exhibit significant increased susceptibility to hypoxia-induced damage to synaptic transmission. This selective vulnerability was substantially ameliorated by pretreatment with diphenylhydantoin, an anticonvulsant that blocks both sodium-dependent action potentials and low-threshold transient calcium conductances. These findings suggest that dystrophin deficiency could predispose susceptible neuronal populations to cumulative hypoxic insults that may contribute to the development of cognitive deficits in Duchenne/Becker muscular dystrophy patients and that the effects of such periods of hypoxia may be pharmacologically remediable.

Original languageEnglish (US)
Pages (from-to)2461-2465
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume89
Issue number6
StatePublished - 1992

Fingerprint

Inbred mdx Mouse
Dystrophin
Pyramidal Cells
Synaptic Transmission
Duchenne Muscular Dystrophy
Calcium
Genetic Models
Skeletal Muscle Fibers
Phenytoin
Carisoprodol
Calcium Channels
Dendrites
Actin Cytoskeleton
Anticonvulsants
Population
Action Potentials
Central Nervous System
Sodium
Hypoxia
Membranes

Keywords

  • Cognitive deficits
  • Cytoskeleton muscular dystrophy
  • Diphenylhydantoin
  • Dystrophin

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Enhanced sensitivity of hippocampal pyramidal neurons from mdx mice to hypoxia-induced loss of synaptic transmission. / Mehler, Mark F.; Haas, Kurt Z.; Kessler, John A.; Stanton, Patric K.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 89, No. 6, 1992, p. 2461-2465.

Research output: Contribution to journalArticle

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