Abstract
BackgroundDuchenne 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.Methodology/Principal FindingsComplementary 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/SignificanceResults 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.
Highlights
Mental retardation (MR) is a clinical feature in a third of patients suffering from Duchenne muscular dystrophy (DMD), an X-linked genetic disease caused by mutations in the dystrophin gene [1]
The data provide evidence for an association of Dp71-dystrophin-associated protein complexes (DAPC) with the multi-protein scaffolds that cluster glutamate receptors and organize signaling proteins required for synaptic transmission and plasticity, including NMDA subtype of glutamate receptors (NMDAr) and AMPA glutamate receptor (AMPAr) subunits, and other PDZcontaining proteins such as PSD-95 and nNOS
Dp71-DAPC is associated with key signaling proteins such as focal adhesion kinase (FAK), c-Src and Grb2, proteins known to contribute to neurite outgrowth, dendritic spine morphogenesis and synaptic plasticity [24,25,26]
Summary
Mental retardation (MR) is a clinical feature in a third of patients suffering from Duchenne muscular dystrophy (DMD), an X-linked genetic disease caused by mutations in the dystrophin gene [1]. As Dp71 is the most abundant dystrophingene product in adult brain [4,5] and as DMD patients with mutations located in Dp71 genomic region display severe MR, Dp71 loss-of-function, mostly due to translation-terminating mutations, has emerged as a major contributing factor [2,6]. One third of DMD patients 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; the specific function of Dp71 is poorly understood
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