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Hypoxia on hippocampal slices from mice deficient in dystrophin (mdx) and isoforms (mdx3cv)
J M Godfraind1, S B Tekkök, K Krnjević
1Département de Physiologie et Pharmacologie, Système Nerveux, Faculté de Médecine, UCL-Bruxelles, Brussels, Belgium.
Abstract:
Slices from control C57, mdx, and mdx3cv mice were made hypoxic until both field excitatory postsynaptic potential (fEPSP) and presynaptic afferent volley (AV) disappeared (H1). After reoxygenation and recovery of fEPSP, a second and longer hypoxic test (H2) lasted 3 minutes beyond the time required to block AV. When slices were kept in 10 mmol/L glucose, HI abolished AV 37 and 19% earlier in slices from mdr and mdx3cv mutants than in control slices (where HI = 12 +/- 4.6 minutes, mean +/- SD). During H2 or when slices were kept in 4 mmol/L glucose, AV vanished even more quickly, but the times to block did not differ significantly between slices from controls and mutants. After reoxygenation, AV fully recovered in most slices. Rates of blockade of fEPSPs were comparable in all slices, and most fEPSPs recovered fully after HI. But even in the presence of 10 mmol/L glucose, the second hypoxia suppressed fEPSPs irreversibly in some slices: 2 of 10 from control, 3 of 7 from mdx, and 1 of 6 from mdx3cv mice. Most slices in 4 mmol/L glucose showed no recovery at all: six of seven from control, three of five from mdx, and four of five from mdx3cv mice. Thus, slices from mdx mice were more susceptible than other slices to irreversible hypoxic failure when slices were kept in 10 mmol/L glucose, but they were less susceptible than other slices when kept in 4 mmol/L glucose. In conclusion, the lack of full-length dystrophin (427 kDa) predisposes to quicker loss of nerve conduction in slices from mdx and mdx3cv mutants and improved posthypoxic recovery of fEPSPs in 4 mmol/L glucose in slices from mdx but not mdx3cv mutants, perhaps because the 70-kDa and other C-terminal isoforms are still present in mdx mice.
Insights
Duchenne muscular dystrophy (DMD) mouse models show altered responses to hypoxia. Lack of dystrophin impacts nerve conduction and recovery, with varying susceptibility based on glucose levels.
Area of Science:
- Neuroscience
- Physiology
- Biochemistry
Background:
- Duchenne muscular dystrophy (DMD) is characterized by the absence of full-length dystrophin.
- Hypoxia significantly impacts neuronal function, including synaptic transmission and nerve conduction.
- Glucose availability is critical for neuronal survival and function during hypoxic conditions.
Purpose of the Study:
- To investigate the effects of hypoxia on neuronal function in mouse models lacking full-length dystrophin (mdx and mdx3cv mice) compared to controls.
- To assess the role of glucose concentration in neuronal susceptibility and recovery from hypoxic injury in these models.
Main Methods:
- Electrophysiological recordings of field excitatory postsynaptic potential (fEPSP) and afferent volley (AV) in brain slices from control, mdx, and mdx3cv mice.
- Induction of two hypoxic periods (H1 and H2) with varying durations and glucose concentrations (10 mmol/L and 4 mmol/L).
- Assessment of AV and fEPSP blockade and recovery after reoxygenation.
Main Results:
- Slices from mdx and mdx3cv mice showed faster loss of AV during initial hypoxia (H1) in 10 mmol/L glucose compared to controls.
- Under severe hypoxia (H2) or low glucose (4 mmol/L), AV blockade times did not differ significantly between groups.
- Irreversible fEPSP suppression occurred more frequently in mdx slices under 10 mmol/L glucose, but mdx slices showed better recovery in 4 mmol/L glucose compared to controls and mdx3cv.
Conclusions:
- The absence of full-length dystrophin predisposes to quicker nerve conduction loss during hypoxia.
- MDX mice exhibit improved post-hypoxic recovery of fEPSPs in low glucose, potentially due to retained C-terminal dystrophin isoforms.
- Glucose availability significantly modulates neuronal vulnerability and recovery from hypoxic insults in dystrophin-deficient models.