title: Aberrant location of inhibitory synaptic marker proteins in the hippocampus of dystrophin-deficient mice: implications for cognitive impairment in duchenne muscular dystrophy.
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.
authors.affiliation: Laboratory of Cellular Metabolism, Nencki Institute of Experimental Biology, Warsaw, Poland; School of Pharmacy and Biomedical Sciences, Institute for Biomedical and Biomolecular Sciences, University of Portsmouth, Portsmouth, United Kingdom.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Krasowska
authors.affiliation: Laboratory of Cellular Metabolism, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Zabłocki
authors.affiliation: School of Pharmacy and Biomedical Sciences, Institute for Biomedical and Biomolecular Sciences, University of Portsmouth, Portsmouth, United Kingdom.
authors.forename: Dariusz C
authors.initials: DC
authors.lastname: Górecki
authors.affiliation: School of Pharmacy and Biomedical Sciences, Institute for Biomedical and Biomolecular Sciences, University of Portsmouth, Portsmouth, United Kingdom.
authors.forename: Jerome D
authors.initials: JD
authors.lastname: Swinny
mesh_terms: D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism*; D016189:Dystrophin / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism*; D051379:Mice; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000150:complications / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009433:Neural Inhibition / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D016189:Dystrophin; D009419:Nerve Tissue Proteins; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; C098003:neuroligin 2