title: Role of mental retardation-associated dystrophin-gene product Dp71 in excitatory synapse organization, synaptic plasticity and behavioral functions.
abstract: BACKGROUND
  Duchenne muscular dystrophy (DMD) is caused by deficient expression of the cytoskeletal protein, dystrophin. One third of DMD patients also have mental retardation (MR), likely due to mutations preventing expression of dystrophin and other brain products of the DMD gene expressed from distinct internal promoters. Loss of Dp71, the major DMD-gene product in brain, is thought to contribute to the severity of MR; however, the specific function of Dp71 is poorly understood.
  
  
  RESULTS
  Complementary approaches were used to explore the role of Dp71 in neuronal function and identify mechanisms by which Dp71 loss may impair neuronal and cognitive functions. Besides the normal expression of Dp71 in a subpopulation of astrocytes, we found that a pool of Dp71 colocalizes with synaptic proteins in cultured neurons and is expressed in synaptic subcellular fractions in adult brains. We report that Dp71-associated protein complexes interact with specialized modular scaffolds of proteins that cluster glutamate receptors and organize signaling in postsynaptic densities. We then undertook the first functional examination of the brain and cognitive alterations in the Dp71-null mice. We found that these mice display abnormal synapse organization and maturation in vitro, altered synapse density in the adult brain, enhanced glutamatergic transmission and reduced synaptic plasticity in CA1 hippocampus. Dp71-null mice show selective behavioral disturbances characterized by reduced exploratory and novelty-seeking behavior, mild retention deficits in inhibitory avoidance, and impairments in spatial learning and memory.
  
  
  CONCLUSIONS
  Results suggest that Dp71 expression in neurons play a regulatory role in glutamatergic synapse organization and function, which provides a new mechanism by which inactivation of Dp71 in association with that of other DMD-gene products may lead to increased severity of MR.
authors: Institut Cochin, Université Paris-Descartes, CNRS, UMR 8104, Paris, France.
authors: Fatma
authors: F
authors: Daoud
authors: Aurora
authors: A
authors: Candelario-Martínez
authors: Jean-Marie
authors: JM
authors: Billard
authors: Avi
authors: A
authors: Avital
authors: Malik
authors: M
authors: Khelfaoui
authors: Yael
authors: Y
authors: Rozenvald
authors: Maryvonne
authors: M
authors: Guegan
authors: Dominique
authors: D
authors: Mornet
authors: Danielle
authors: D
authors: Jaillard
authors: Uri
authors: U
authors: Nudel
authors: Jamel
authors: J
authors: Chelly
authors: Dalila
authors: D
authors: Martínez-Rojas
authors: Serge
authors: S
authors: Laroche
authors: David
authors: D
authors: Yaffe
authors: Cyrille
authors: C
authors: Vaillend
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002478:Cells, Cultured; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism; D008607:Intellectual Disability / Q000503:physiopathology*; D007858:Learning; D008568:Memory; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology*; D011485:Protein Binding; D013569:Synapses / Q000502:physiology*
chemical_list: D016189:Dystrophin; C085339:apo-dystrophin 1; D018698:Glutamic Acid