SPATIAL DISCRIMINATION-LEARNING AND CA1 HIPPOCAMPAL SYNAPTIC PLASTICITY IN MDX AND MDX(3CV) MICE LACKING DYSTROPHIN GENE-PRODUCTS

Duchenne muscular dystrophy is frequently associated with a non-progre ssive cognitive deficit attributed to the absence of 427,000 mel. wt b rain dystrophin, or to altered expression of other C-terminal products of this protein, Dp71 and/or Dp140. To further explore the role of th ese membrane cytoskeleton-associated proteins in brain function, we st udied spatial learning and ex vivo synaptic plasticity in the mdx mous e, which lacks 427,000 mel, wt dystrophin, and in the mdx(3cv) mutant, which shows a dramatically reduced expression of all the dystrophin g ene products known so far. We show that reference and working memories are largely unimpaired in the two mutant mice performing a spatial di scrimination task in a radial maze. However, mdx(3cv) mice showed enha nced emotional reactivity and developed different strategies in learni ng the task, as compared to control mice. We also showed that both mut ants display apparently normal levels of long-term potentiation and pa ired-purse facilitation in the CAI field of the hippocampus. On the ot her hand, an increased post-tetanic potentiation was shown by mdx, but not mdx(3cv) mice, which might be linked to calcium-regulatory defect s. Otherwise, immunoblot analyses suggested an increased expression of a 400,000 moi, wt protein in brain extracts from both mdx and mdx(3cv ) mice, but not in those from control mice. This protein might corresp ond to the dystrophin-homologue utrophin. The present results suggest that altered expression of dystrophin or C-terminal dystrophin protein s in brain did not markedly affect hippocampus-dependent spatial learn ing and CA1 hippocampal long-term potentiation in mdx and mdx(3cv) mic e. The role of these membrane cytoskeleton-associated proteins in norm al brain function and pathology remains to be elucidated. Furthermore, the possibility that redundant mechanisms could partially compensate for dystrophins' deficiency in the mdx and mdx(3cv) models should be f urther considered. (C) 1998 IBRO. Published by Elsevier Science Ltd.