Dp71-Dystrophin Deficiency Alters Prefrontal Cortex Excitation-Inhibition Balance and Executive Functions
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In the Duchenne muscular dystrophy (DMD) syndrome, mutations affecting expression of Dp71, the main dystrophin isoform of the multipromoter dmd gene in brain, have been associated with intellectual disability and neuropsychiatric disturbances. Patients’ profile suggests alterations in prefrontal cortex-dependent executive processes, but the specific dysfunctions due to Dp71 deficiency are unclear. Dp71 is involved in brain ion homeostasis, and its deficiency is expected to increase neuronal excitability, which might compromise the integrity of neuronal networks undertaking high-order cognitive functions. Here, we used electrophysiological (patch clamp) and behavioral techniques in a transgenic mouse that display a selective loss of Dp71 and no muscular dystrophy, to identify changes in prefrontal cortex excitatory/inhibitory (E/I) balance and putative executive dysfunctions. We found prefrontal cortex E/I balance is shifted toward enhanced excitation in Dp71-null mice. This is associated with a selective alteration of AMPA receptor-mediated glutamatergic transmission and reduced synaptic plasticity, while inhibitory transmission is unaffected. Moreover, Dp71-null mice display deficits in cognitive processes that depend on prefrontal cortex integrity, such as cognitive flexibility and sensitivity of spatial working memory to proactive interference. Our data suggest that impaired cortical E/I balance and executive dysfunctions contribute to the intellectual and behavioral disturbances associated with Dp71 deficiency in DMD, in line with current neurobehavioral models considering these functions as key pathophysiological factors in various neurodevelopmental disorders. These new insights in DMD neurobiology also suggest new directions for therapeutic developments targeting excitatory neurotransmission, as well as for guidance of academic environment in severely affected DMD children.
KeywordsGlia Mouse models Intellectual disability Cortical network plasticity Working memory Cognitive flexibility
We are grateful to the Zootechnic platform of our institute for mouse breeding, care, and genotyping and to Glenn Dallérac for the advice in electrophysiology.
This work was supported by Centre National de la Recherche Scientifique (CNRS, France) and University Paris-Sud (France), and by grants from Association Française contre les Myopathies (AFM, France; grant number 15299) and Agence Nationale de la Recherche (ANR, France; grant number ANR-14-CE13-0037-01) to C.V. and by a PhD fellowship from Ministère de l’Enseignement Supérieur et de la Recherche (France) to R.C.
Compliance with Ethic Standards
Experiments involving animals were undertaken following the guidelines of the European Directive 2010/63/EU, French National Committee (87/848), and local mouse facility (agreement #D91–471-104), with official approval (#2635) from the CEEA59 ethical committee (Comité d’éthique en matière d’expérimentation animale Paris Centre et Sud) and Ministère de l’Enseignement Supérieur et de la Recherche (France).
Conflict of Interest
The authors declare they have no conflict of interest.
- 2.Desguerre I, Christov C, Mayer M, Zeller R, Becane HM, Bastuji-Garin S, Leturcq F, Chiron C et al (2009) Clinical heterogeneity of Duchenne muscular dystrophy (DMD): definition of sub-phenotypes and predictive criteria by long-term follow-up. PLoS One 4:e4347CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Daoud F, Angeard N, Demerre B, Martie I, Benyaou R, Leturcq F, Cossée M, Deburgrave N et al (2009a) Analysis of Dp71 contribution in the severity of mental retardation through comparison of Duchenne and Becker patients differing by mutation consequences on Dp71 expression. Hum Mol Genet 18:3779–3794CrossRefPubMedGoogle Scholar
- 20.Daoud F, Candelario-Martínez A, Billard JM, Avital A, Khelfaoui M, Rozenvald Y, Guegan M, Mornet D et al (2009b) Role of mental retardation-associated dystrophin-gene product Dp71 in excitatory synapse organization, synaptic plasticity and behavioral functions. PLoS One 4:e6574CrossRefPubMedCentralGoogle Scholar
- 24.Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, San DiegoGoogle Scholar
- 47.De Bellis M, Pisani F, Mola MG, Rosito S, Simone L, Buccoliero C, Trojano M, Nicchia GP et al (2017) Translational readthrough generates new astrocyte AQP4 isoforms that modulate supramolecular clustering, glial endfeet localization, and water transport. Glia 65(5):790–803CrossRefPubMedGoogle Scholar
- 48.Helleringer R, Le Verger D, Li X, Izabelle C, Chaussenot R, Belmaati-Cherkaoui M, Dammak R, Decottignies P, Daniel H, Galante M, Vaillend C (2018) Cerebellar synapse properties and cerebellum-dependent motor and non-motor performance in Dp71-null mice. Dis Model Mech 11(7).Google Scholar