Aberrant location of inhibitory synaptic marker proteins in the hippocampus of dystrophin-deficient mice: implications for cognitive impairment in duchenne muscular dystrophy.

Elżbieta Krasowska,Dariusz C Górecki,Krzysztof Zabłocki,Jerome D Swinny,Jean-Luc Gaiarsa

doi:10.1371/journal.pone.0108364

Abstract

Duchenne muscular dystrophy (DMD) is a neuromuscular disease that arises from mutations in the dystrophin-encoding gene. Apart from muscle pathology, cognitive impairment, primarily of developmental origin, is also a significant component of the disorder. Convergent lines of evidence point to an important role for dystrophin in regulating the molecular machinery of central synapses. The clustering of neurotransmitter receptors at inhibitory synapses, thus impacting on synaptic transmission, is of particular significance. However, less is known about the role of dystrophin in influencing the precise expression patterns of proteins located within the pre- and postsynaptic elements of inhibitory synapses. To this end, we exploited molecular markers of inhibitory synapses, interneurons and dystrophin-deficient mouse models to explore the role of dystrophin in determining the stereotypical patterning of inhibitory connectivity within the cellular networks of the hippocampus CA1 region. In tissue from wild-type (WT) mice, immunoreactivity of neuroligin2 (NL2), an adhesion molecule expressed exclusively in postsynaptic elements of inhibitory synapses, and the vesicular GABA transporter (VGAT), a marker of GABAergic presynaptic elements, were predictably enriched in strata pyramidale and lacunosum moleculare. In acute contrast, NL2 and VGAT immunoreactivity was relatively evenly distributed across all CA1 layers in dystrophin-deficient mice. Similar changes were evident with the cannabinoid receptor 1, vesicular glutamate transporter 3, parvalbumin, somatostatin and the GABAA receptor alpha1 subunit. The data show that in the absence of dystrophin, there is a rearrangement of the molecular machinery, which underlies the precise spatio-temporal pattern of GABAergic synaptic transmission within the CA1 sub-field of the hippocampus.

Highlights

Duchenne muscular dystrophy (DMD) [1] is a neuromuscular disease that arises due to the absence of the protein dystrophin [2]
A large body of work mainly using the mdx mouse model of DMD indicates that the lack of dystrophin results in a decrease in the synaptic quotient of GABA-A receptors (GABAARs) [14], and altered GABAergic synaptic transmission [15,16,17,18]
The current study shows that the mouse models in which dystrophin is constitutively deleted present with a complex pattern of alterations in the location of proteins associated with both the pre- and postsynaptic elements of inhibitory synapses as well as those proteins located in the axon terminals of specific GABAergic interneuron classes

Summary

Introduction

Duchenne muscular dystrophy (DMD) [1] is a neuromuscular disease that arises due to the absence of the protein dystrophin [2]. Dystrophin functions to provide a scaffold for the formation of a complex of dystrophin-associated proteins (DAP), including dystroglycan and syntrophin, which provide a link between the cytoskeleton, cell membrane and extracellular matrix components [3]. Disruption of this protein complex results in muscle degeneration and the added burden of non-progressive cognitive impairment, which DMD patients suffer from, [1] [4,5]. A large body of work mainly using the mdx mouse model of DMD indicates that the lack of dystrophin results in a decrease in the synaptic quotient of GABA-A receptors (GABAARs) [14], and altered GABAergic synaptic transmission [15,16,17,18]

Methods

Results

Conclusion