title: Acetylcholine, GABA and neuronal networks: a working hypothesis for compensations in the dystrophic brain.
abstract: Duchenne muscular dystrophy (DMD), a genetic disease arising from a mutation in the dystrophin gene, is characterized by muscle failure and is often associated with cognitive deficits. Studies of the dystrophic brain on the murine mdx model of DMD provide evidence of morphological and functional alterations in the central nervous system (CNS) possibly compatible with the cognitive impairment seen in DMD. However, while some of the alterations reported are a direct consequence of the absence of dystrophin, others seem to be associated only indirectly. In this review we reevaluate the literature in order to formulate a possible explanation for the cognitive impairments associated with DMD. We present a working hypothesis, demonstrated as an integrated neuronal network model, according to which within the cascade of events leading to cognitive impairments there are compensatory mechanisms aimed to maintain functional stability via perpetual adjustments of excitatory and inhibitory components. Such ongoing compensatory response creates continuous perturbations that disrupt neuronal functionality in terms of network efficiency. We have theorized that in this process acetylcholine and network oscillations play a central role. A better understating of these mechanisms could provide a useful diagnostic index of the disease's progression and, perhaps, the correct counterbalance of this process might help to prevent deterioration of the CNS in DMD. Furthermore, the involvement of compensatory mechanisms in the CNS could be extended beyond DMD and possibly help to clarify other physio-pathological processes of the CNS.
authors.affiliation: Department of Clinical and Experimental Medicine, Physiological Sciences Section, University of Florence, Florence, Italy.
authors.forename: Erez James
authors.initials: EJ
authors.lastname: Cohen
authors.affiliation: Department of Clinical and Experimental Medicine, Physiological Sciences Section, University of Florence, Florence, Italy.
authors.forename: Eros
authors.initials: E
authors.lastname: Quarta
authors.affiliation: Laboratory of Experimental Pathology, Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy; Neural Development Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Fulgenzi
authors.affiliation: Department of Clinical and Experimental Medicine, Physiological Sciences Section, University of Florence, Florence, Italy. Electronic address: diego@unifi.it.
authors.forename: Diego
authors.initials: D
authors.lastname: Minciacchi
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000503:physiopathology*; D003072:Cognition Disorders / Q000503:physiopathology; D006801:Humans; D020388:Muscular Dystrophy, Duchenne / Q000503:physiopathology*; D009434:Neural Pathways / Q000503:physiopathology; D009474:Neurons / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D005680:gamma-Aminobutyric Acid; D000109:Acetylcholine
keywords: Acetylcholine; Duchenne muscular dystrophy; Network oscillations; Neuronal networks; mdx