Nature communications

399009002025050520250525

2041-17231612025Feb03Nature communicationsNat CommunDuchenne muscular dystrophy: recent insights in brain related comorbidities.12981298129810.1038/s41467-025-56644-wDuchenne muscular dystrophy (DMD), the most common childhood muscular dystrophy, arises from DMD gene mutations, affecting the production of muscle dystrophin protein. Brain dystrophin-gene products are also transcribed via internal promoters. Their deficiency contributes to comorbidities, including intellectual disability ( ~ 22% of patients), autism ( ~ 6%) and attention deficit disorders ( ~ 18%), representing a major unmet need for patients and families. Thus, improvement of their diagnosis and treatment is needed. Dystrophic mouse models exhibit similar phenotypes, where genetic therapies restoring brain dystrophins improve their behaviour. This suggests that future genetic therapies could address both muscle and brain dysfunction in DMD patients.© 2025. The Author(s).VaillendCyrilleCUniversité Paris-Saclay, CNRS, Institut des Neurosciences Paris-Saclay, 91400, Saclay, Paris, France.AokiYoshitsuguY0000-0002-9038-7506Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, 187-8502, Japan.MercuriEugenioEDepartment of Paediatric Neurology, Catholic University, Rome, Italy.HendriksenJosJKempenhaeghe Centre for Neurological Learning Disabilities, Heeze, the Netherlands; Maastricht University, School for Mental Health and Neuroscience, Maastricht, the Netherlands. hendriksenj@kempenhaeghe.nl.TetorouKonstantinaKUniversity College London Great Ormond Street Institute of Child Health, London, UK.GoyenvalleAurelieA0000-0003-3938-1165Université Paris-Saclay, UVSQ, Inserm, END-ICAP, 78000, Versailles, France. aurelie.goyenvalle@uvsq.fr.MuntoniFrancescoF0000-0002-9102-5232University College London Great Ormond Street Institute of Child Health, London, UK. f.muntoni@ucl.ac.uk.engJournal ArticleReview20250203

EnglandNat Commun1015285552041-17230DystrophinIMMuscular Dystrophy, DuchennegeneticstherapyepidemiologyAnimalsHumansDystrophingeneticsmetabolismBrainmetabolismpathologyphysiopathologyComorbidityMiceDisease Models, AnimalIntellectual DisabilitygeneticsepidemiologyAutistic DisordergeneticsepidemiologyAttention Deficit Disorder with HyperactivitygeneticsepidemiologyGenetic TherapyMutationCompeting interests: The authors declare the following competing interests. F.M. has received grants, speaker, and consultancy honoraria from Sarepta Therapeutics, Roche, PTC Therapeutics, Dyne Therapeutics, and Pfizer. E.M. has received grants, speaker, and consultancy honoraria from Sarepta Therapeutics, Roche, Italfarmaco. Y.A. has received grants and consultancy honoraria from Nippon Shinyaku Co., Ltd. and grants from Shionogi & Co., Ltd. C.V., J.H., K.T. and A.G., declare no competing interests.202462720251202025240212025240202025232325202523epublish39900900PMC1179095210.1038/s41467-025-56644-w10.1038/s41467-025-56644-wCrisafulli, S. et al. Global epidemiology of Duchenne muscular dystrophy: an updated systematic review and meta-analysis. Orphanet. J. Rare Dis.15, 141 (2020).PMC727532332503598Markati, T. et al. Emerging therapies for Duchenne muscular dystrophy. Lancet Neurol.21, 814–829 (2022). 10.1016/S1474-4422(22)00125-935850122Duchenne, G.-B. (1806-1875). A. du texte. De la paralysie musculaire pseudo-hypertrophique, ou paralysie myo-sclérosique / par le Dr Duchenne (de Boulogne). (1868).Pascual-Morena, C. et al. Global prevalence of intellectual developmental disorder in dystrophinopathies: A systematic review and meta-analysis. Dev. Med Child Neurol.65, 734–744 (2023). 10.1111/dmcn.1548136440509Darmahkasih, A. J. et al. Neurodevelopmental, behavioral, and emotional symptoms common in Duchenne muscular dystrophy. Muscle Nerve61, 466–474 (2020). 10.1002/mus.2680331909820Hendriksen, J. G. M. & Vles, J. S. H. Neuropsychiatric Disorders in Males With Duchenne Muscular Dystrophy: Frequency Rate of Attention-Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder, and Obsessive—Compulsive Disorder. 10.1177/0883073807309775 23, 477–481 (2008).18354150Muntoni, F., Torelli, S. & Ferlini, A. Dystrophin and mutations: One gene, several proteins, multiple phenotypes. Lancet Neurol.2, 731–740 (2003). 10.1016/S1474-4422(03)00585-414636778Doorenweerd, N. et al. Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy. Sci. Rep.7, 12575(2017).PMC562677928974727Birnkrant, D. J. et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol.17, 251 (2018). 10.1016/S1474-4422(18)30024-3PMC586970429395989García-Cruz, C. et al. Tissue-and cell-specific whole-transcriptome meta-analysis from brain and retina reveals differential expression of dystrophin complexes and new dystrophin spliced isoforms. Hum. Mol. Genet32, 659–676 (2023). 10.1093/hmg/ddac236PMC989647936130212Hildyard, J. C. W. et al. Single-transcript multiplex in situ hybridisation reveals unique patterns of dystrophin isoform expression in the developing mammalian embryo. Wellcome Open Res5, 32724863 (2020).PMC737231332724863Sánchez, A., Aragón, J., Ceja, V., Rendon, A. & Montanez, C. Nuclear transport and subcellular localization of the dystrophin Dp71 and Dp40 isoforms in the PC12 cell line. Biochem Biophys. Res Commun.630, 125–132 (2022). 10.1016/j.bbrc.2022.09.03536155058Bar, S. et al. A novel product of the Duchenne muscular dystrophy gene which greatly differs from the known isoforms in its structure and tissue distribution. Biochem. J.272, 557–560 (1990). 10.1042/bj2720557PMC11497402176467Tennyson, C. N., Dally, G. Y., Ray, P. N. & Worton, R. G. Expression of the dystrophin isoform Dp71 in differentiating human fetal myogenic cultures. Hum. Mol. Genet5, 1559–1566 (1996). 10.1093/hmg/5.10.15598894689Durbeej, M., Jung, D., Hjalt, T., Campbell, K. P. & Ekblom, P. Transient expression of Dp140, a product of the Duchenne muscular dystrophy locus, during kidney tubulogenesis. Dev. Biol.181, 156–167 (1997). 10.1006/dbio.1996.84309013927Holder -Masato Maeda, E. & Bies, R. D. Expression and regulation of the dystrophin Purkinje promoter in human skeletal muscle, heart, and brain. Hum. Genet97, 232–239 (1996). 10.1007/BF022652728566960Suzuki, Y., Higuchi, S., Aida, I., Nakajima, T. & Nakada, T. Abnormal distribution of GABAA receptors in brain of duchenne muscular dystrophy patients. Muscle Nerve55, 591–595 (2017). 10.1002/mus.2538327543743Knuesel, I. et al. Short communication: altered synaptic clustering of GABAA receptors in mice lacking dystrophin (mdx mice). Eur. J. Neurosci.11, 4457–4462 (1999). 10.1046/j.1460-9568.1999.00887.x10594673Sekiguchi, M. et al. A deficit of brain dystrophin impairs specific amygdala GABAergic transmission and enhances defensive behaviour in mice. Brain132, 124–135 (2009). 10.1093/brain/awn25318927146Pereira da Silva, J. D. et al. Altered release and uptake of gamma-aminobutyric acid in the cerebellum of dystrophin-deficient mice. Neurochem. Int. 118, 105–114 (2018). 10.1016/j.neuint.2018.06.00129864448Vaillend, C. & Billard, J. M. Facilitated CA1 hippocampal synaptic plasticity in dystrophin-deficient mice: Role for GABAA receptors? Hippocampus12, 713–717 (2002). 10.1002/hipo.1006812542223Wu, W. C., Bradley, S. P., Christie, J. M. & Pugh, J. R. Mechanisms and consequences of cerebellar purkinje cell disinhibition in a mouse model of duchenne muscular dystrophy. J. Neurosci.42, 2103–2115 (2022). 10.1523/JNEUROSCI.1256-21.2022PMC891675335064002Kreko-Pierce, T. & Pugh, J. R. Altered synaptic transmission and excitability of cerebellar nuclear neurons in a mouse model of duchenne muscular dystrophy. Front Cell Neurosci.16, 926518 (2022). 10.3389/fncel.2022.926518PMC929460635865113Zarrouki, F. et al. Abnormal expression of synaptic and extrasynaptic gabaa receptor subunits in the dystrophin-deficient mdx mouse. Int J. Mol. Sci.23, 23 (2022).10.3390/ijms232012617PMC960407336293496Vaillend, C. & Chaussenot, R. Relationships linking emotional, motor, cognitive and GABAergic dysfunctions in dystrophin-deficient mdx mice. Hum. Mol. Genet26, 1041–1055 (2017). 28087735Bianchi, R. et al. Hippocampal synaptic and membrane function in the DBA/2J-mdx mouse model of Duchenne muscular dystrophy. Mol. Cell. Neurosci.104, 103482 (2020). 10.1016/j.mcn.2020.10348232171922Araki, E. et al. Targeted Disruption of Exon 52 in the Mouse Dystrophin Gene Induced Muscle Degeneration Similar to That Observed in Duchenne Muscular Dystrophy. Biochem Biophys. Res Commun.238, 492–497 (1997). 10.1006/bbrc.1997.73289299538Hashimoto, Y. et al. Brain Dp140 alters glutamatergic transmission and social behaviour in the mdx52 mouse model of Duchenne muscular dystrophy. Prog. Neurobiol.216, 10.1016/j.pneurobio.2022.102288 (2022).35654209Leyva-Leyva, M. et al. Identification of Dp140 and α1-syntrophin as novel molecular interactors of the neuronal CaV2.1 channel. Pflug. Arch.475, 595–606 (2023).10.1007/s00424-023-02803-136964781Belmaati Cherkaoui, M. et al. Dp71 contribution to the molecular scaffold anchoring aquaporine-4 channels in brain macroglial cells. Glia69, 954–970 (2021). 10.1002/glia.2394133247858Lange, J. et al. Dystrophin deficiency affects human astrocyte properties and response to damage. Glia70, 466–490 (2022). 10.1002/glia.2411634773297Pascual-Morena, C. et al. Dystrophin genotype and risk of neuropsychiatric disorders in dystrophinopathies: a systematic review and meta-analysis. J. Neuromuscul. Dis.10, 159 (2023). 10.3233/JND-221586PMC1004143136565132Weerkamp, P. M. M. et al. Wechsler scale intelligence testing in males with dystrophinopathies: a review and meta-analysis. Brain Sci12, 10.3390/brainsci12111544 (2022).PMC968831936421868von Gontard, A. et al. Intelligence and cognitive function in children and adolescents with spinal muscular atrophy. Neuromuscul. Disord.12, 130–136 (2002). 10.1016/S0960-8966(01)00274-711738354D’alessandro, R. et al. Assessing cognitive function in neuromuscular diseases: A pilot study in a sample of children and adolescents. J. Clin. Med10, 10 (2021).10.3390/jcm10204777PMC853702734682900Lee, I. et al. The hidden disease: delayed diagnosis in duchenne muscular dystrophy and co-occurring conditions. J. Dev. Behav. Pediatr.43, e541–e545 (2022). 10.1097/DBP.000000000000110535943375Chieffo, D. P. R. et al. A longitudinal follow-up study of intellectual function in duchenne muscular dystrophy over age: is it really stable? J. Clin. Med12, 12 (2023).10.3390/jcm12020403PMC986507436675332Norcia, G. et al. Early gross motor milestones in duchenne muscular dystrophy. J. Neuromuscul. Dis.8, 453 (2021). 10.3233/JND-210640PMC838550933935100Chesshyre, M. et al. Investigating the role of dystrophin isoform deficiency in motor function in Duchenne muscular dystrophy. J. Cachexia Sarcopenia Muscle13, 1360 (2022). 10.1002/jcsm.12914PMC897797735083887Coratti, G. et al. Longitudinal natural history in young boys with Duchenne muscular dystrophy. Neuromuscul. Disord.29, 857–862 (2019). 10.1016/j.nmd.2019.09.01031629611Pane, M. et al. Early neurodevelopmental assessment in Duchenne muscular dystrophy. Neuromuscul. Disord.23, 451–455 (2013). 10.1016/j.nmd.2013.02.01223535446Wijekoon, N. et al. Duchenne muscular dystrophy from brain to muscle: the role of brain dystrophin isoforms in motor functions. J. Clin. Med12, 5637 (2023). 10.3390/jcm12175637PMC1048849137685704Zambon, A. A. et al. Peak functional ability and age at loss of ambulation in Duchenne muscular dystrophy. Dev. Med Child Neurol.64, 979 (2022). 10.1111/dmcn.15176PMC930318035385138Coratti, G. et al. Age, corticosteroid treatment and site of mutations affect motor functional changes in young boys with Duchenne Muscular Dystrophy. PLoS One17, N/A-N/A (2022).PMC933763635905042Pascual-Morena, C. et al. Intelligence quotient–genotype association in dystrophinopathies: A systematic review and meta-analysis. Neuropathol. Appl Neurobiol.49, e12914 (2023). 10.1111/nan.1291437312416Fee, R. J., Montes, J., Stewart, J. L. & Hinton, V. J. Executive Skills and Academic Achievement in the Dystrophinopathies. J. Int. Neuropsychological Soc.24, 928–938 (2018).10.1017/S135561771700133330375314Battini, R. et al. Longitudinal data of neuropsychological profile in a cohort of Duchenne muscular dystrophy boys without cognitive impairment. Neuromuscul. Disord.31, 319–327 (2021). 10.1016/j.nmd.2021.01.01133658162Billard, C., Gillet, P., Barthez, M. A., Hommet, C. & Bertrand, P. Reading ability and processing in Duchenne muscular dystrophy and spinal muscular atrophy. Dev. Med Child Neurol.40, 12–20 (1998). 10.1111/j.1469-8749.1998.tb15351.x9459212Hendriksen, J. G. M. & Vles, J. S. H. Are Males With Duchenne Muscular Dystrophy at Risk for Reading Disabilities? Pediatr. Neurol.34, 296–300 (2006). 10.1016/j.pediatrneurol.2005.08.02916638505Astrea, G. et al. Reading impairment in Duchenne muscular dystrophy: A pilot study to investigate similarities and differences with developmental dyslexia. Res Dev. Disabil.45–46, 168–177 (2015). 10.1016/j.ridd.2015.07.02526255617Schmidt-Kastner, R. Genomic approach to selective vulnerability of the hippocampus in brain ischemia-hypoxia. Neuroscience309, 259–279 (2015). 10.1016/j.neuroscience.2015.08.03426383255Ricotti, V. et al. Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations. Dev. Med Child Neurol.58, 77–84 (2016). 10.1111/dmcn.1292226365034Pane, M. et al. Attention deficit hyperactivity disorder and cognitive function in duchenne muscular dystrophy: Phenotype-genotype correlation. J. Pediatrics161, 705–709.e1 (2012).10.1016/j.jpeds.2012.03.02022560791Pascual-Morena, C. et al. Prevalence of Neuropsychiatric Disorders in Duchenne and Becker Muscular Dystrophies: A Systematic Review and Meta-analysis. Arch. Phys. Med Rehabil.103, 2444–2453 (2022). 10.1016/j.apmr.2022.05.01535839922Trimmer, R. E., Mandy, W. P. L., Muntoni, F. & Maresh, K. E. Understanding anxiety experienced by young males with Duchenne muscular dystrophy: a qualitative focus group study. Neuromuscul. Disord.34, 95–104 (2024). 10.1016/j.nmd.2023.12.00238159461Maresh, K. et al. Startle responses in Duchenne muscular dystrophy: a novel biomarker of brain dystrophin deficiency. Brain146, 252–265 (2023). 10.1093/brain/awac048PMC982559435136951Hendriksen, J. G. M. et al. 249th ENMC International Workshop: The role of brain dystrophin in muscular dystrophy: Implications for clinical care and translational research, Hoofddorp, The Netherlands, November 29th–December 1st 2019. Neuromuscul. Disord.30, 782–794 (2020). 10.1016/j.nmd.2020.08.35732912717Doorenweerd, N. et al. Reduced cerebral gray matter and altered white matter in boys with Duchenne muscular dystrophy. Ann. Neurol.76, 403–411 (2014). 10.1002/ana.2422225043804Cheng, B. et al. Connectomic disturbances in Duchenne muscular dystrophy with mild cognitive impairment. Cereb. Cortex33, 6785–6791 (2023). 10.1093/cercor/bhac54236627244Biagi, L. et al. Neural substrates of neuropsychological profiles in dystrophynopathies: A pilot study of diffusion tractography imaging. PLoS One16, 10.1371/journal.pone.0250420 (2021).PMC809276633939732Doorenweerd, N. et al. Resting-state functional MRI shows altered default-mode network functional connectivity in Duchenne muscular dystrophy patients. Brain Imaging Behav.15, 2297 (2021). 10.1007/s11682-020-00422-3PMC850088033389442Preethish-Kumar, V. et al. In Vivo Evaluation of White Matter Abnormalities in Children with Duchenne Muscular Dystrophy Using DTI. 10.3174/ajnr.A6604.PMC735765332616576Demirci, H. et al. Cognition of the mothers of patients with Duchenne muscular dystrophy. Muscle Nerve62, 710–716 (2020). 10.1002/mus.2705732893363Rose, M. et al. A randomised controlled trial of acceptance and commitment therapy for improving quality of life in people with muscle diseases. Psychol. Med53, 3511 (2023). 10.1017/S0033291722000083PMC1027776935192788Adan, R. A. H. et al. Nutritional psychiatry: Towards improving mental health by what you eat. Eur. Neuropsychopharmacol.29, 1321–1332 (2019). 10.1016/j.euroneuro.2019.10.01131735529Wolf, T. G., Faerber, K. A., Rummel, C., Halsband, U. & Campus, G. Functional changes in brain activity using hypnosis: a systematic review. Brain Sci12, 10.3390/brainsci12010108 (2022).PMC877377335053851Hellebrekers, D. M. J. et al. Computerized working memory training in males with Duchenne muscular dystrophy: A single case experimental design study. Neuropsychol. Rehabil.33, 1325–1348 (2023). 10.1080/09602011.2022.209608035876193Cortese, S. et al. Psychopharmacology in children and adolescents: unmet needs and opportunities. Lancet Psychiatry11, 143–154 (2024). 10.1016/S2215-0366(23)00345-038071998Brusa, C. et al. Psychopharmacological treatments for mental disorders in patients with neuromuscular diseases: a scoping review. Brain Sci.12, 10.3390/brainsci12020176 (2022).PMC887061935203936Lionarons, J. M. et al. Methylphenidate use in males with Duchenne muscular dystrophy and a comorbid attention-deficit hyperactivity disorder. Eur. J. Paediatr. Neurol.23, 152–157 (2019). 10.1016/j.ejpn.2018.09.00530287260Lee, A. J., Buckingham, E. T., Kauer, A. J. & Mathews, K. D. Descriptive phenotype of obsessive compulsive symptoms in males with Duchenne Muscular Dystrophy. J. Child Neurol.33, 572 (2018). 10.1177/0883073818774439PMC602759329779439Weerkamp, P. M. M. et al. Psychopharmaceutical treatment for neurobehavioral problems in Duchenne muscular dystrophy: a descriptive study using real-world data. Neuromuscul. Disord.33, 619–626 (2023). 10.1016/j.nmd.2023.05.01137453172Gadaleta, G. et al. Adults living with Duchenne muscular dystrophy: old and new challenges in a cohort of 19 patients in their third to fifth decade. Eur. J. Neurol.31, e16060 (2024).PMC1123570937724986Nart, L., Desikan, M., Pietrusz, A., Savvatis, K. & Quinlivan, R. Neurodiversity, treatment compliance and survival in adults with Duchenne muscular dystrophy: a single-centre retrospective cohort review. Neuromuscul. Disord.35, 13–18 (2024). 10.1016/j.nmd.2023.12.00338194731Bouquillon, L. et al. Workshop report: Workshop on psychiatric prescribing and psychology testing and intervention in children and adults with Duchenne muscular dystrophy. Res. Ideas Outcomes 1010, e119243 (2024).10.3897/rio.10.e119243Kamenov, K., Twomey, C., Cabello, M., Prina, A. M. & Ayuso-Mateos, J. L. The efficacy of psychotherapy, pharmacotherapy and their combination on functioning and quality of life in depression: a meta-analysis. Psychol. Med47, 414–425 (2017). 10.1017/S0033291716002774PMC524444927780478DeRubeis, R. J., Siegle, G. J. & Hollon, S. D. Cognitive therapy versus medication for depression: treatment outcomes and neural mechanisms. Nat. Rev. Neurosci.9, 788–796 (2008).PMC274867418784657Van Putten, M. et al. Mouse models for muscular dystrophies: an overview. 10.1242/dmm.043562 (2020).PMC704445432224495Vaillend, C., Billard, J. M. & Laroche, S. Impaired long-term spatial and recognition memory and enhanced CA1 hippocampal LTP in the dystrophin-deficient Dmdmdx mouse. Neurobiol. Dis.17, 10–20 (2004). 10.1016/j.nbd.2004.05.00415350961Bellissimo, C. A. et al. Memory impairment in the D2.mdx mouse model of Duchenne muscular dystrophy is prevented by the adiponectin receptor agonist ALY688. Exp. Physiol.108, 1108–1117 (2023). 10.1113/EP091274PMC1098843037415288Phillips, R. G. & LeDoux, J. E. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci.106, 274–285 (1992). 10.1037/0735-7044.106.2.2741590953Nonneman, D. J., Brown-Brandl, T., Jones, S. A., Wiedmann, R. T. & Rohrer, G. A. A defect in dystrophin causes a novel porcine stress syndrome. BMC Genomics13, 1–9 (2012). 10.1186/1471-2164-13-233PMC346346122691118Caudal, D. et al. Characterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat model. PLoS One15, e0230083 (2020).PMC706577632160266Razzoli, M. et al. Social stress is lethal in the mdx model of Duchenne muscular dystrophy. EBioMedicine55, 102700 (2020). 10.1016/j.ebiom.2020.102700PMC725124732192914Saoudi, A. et al. Emotional behavior and brain anatomy of the mdx52 mouse model of Duchenne muscular dystrophy. Dis. Model Mech.14, dmm049028 (2021).PMC847681634546327Verhaeg, M. et al. Learning, memory and blood–brain barrier pathology in Duchenne muscular dystrophy mice lacking Dp427, or Dp427 and Dp140. Genes Brain Behav.23, 10.1111/gbb.12895 (2024).PMC1115103538837620Vaillend, C. et al. Spatial discrimination learning and CA1 hippocampal synaptic plasticity in mdx and mdx3cv mice lacking dystrophin gene products. Neuroscience86, 53–66 (1998). 10.1016/S0306-4522(98)00023-29692743Vaillend, C. & Ungerer, A. Behavioral characterization of mdx3cv mice deficient in C-terminal dystrophins. Neuromuscul. Disord.9, 296–304 (1999). 10.1016/S0960-8966(99)00029-210407849Chaussenot, R., Amar, M., Fossier, P. & Vaillend, C. Dp71-dystrophin deficiency alters prefrontal cortex excitation-inhibition balance and executive functions. Mol. Neurobiol.56, 2670–2684 (2019). 10.1007/s12035-018-1259-630051354Miranda, R. et al. Social and emotional alterations in mice lacking the short dystrophin-gene product, Dp71. Behav. Brain Funct.20, 10.1186/s12993-024-00246-x (2024).PMC1134492539182120Crawford, A. H., Hornby, N. L., de la Fuente, A. G. & Piercy, R. J. Brain magnetic resonance imaging in the DE50-MD dog model of Duchenne muscular dystrophy reveals regional reductions in cerebral gray matter. BMC Neurosci.24, 1–9 (2023). 10.1186/s12868-023-00788-2PMC1002436036932329Crawford, A. H. et al. Validation of DE50-MD dogs as a model for the brain phenotype of Duchenne muscular dystrophy. DMM Dis. Model. Mech.15, dmm049291 (2022).PMC890616935019137Stirm, M. et al. A scalable, clinically severe pig model for Duchenne muscular dystrophy. DMM Dis. Model. Mech.14, dmm049285 (2021).PMC868840934796900Goyenvalle, A. et al. Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers. Nat. Med. 2015 21:321, 270–275 (2015).25642938Dallérac, G. et al. Rescue of a dystrophin-like protein by exon skipping normalizes synaptic plasticity in the hippocampus of the mdx mouse. Neurobiol. Dis.43, 635–641 (2011). 10.1016/j.nbd.2011.05.01221624465Saoudi, A. et al. Partial restoration of brain dystrophin by tricyclo-DNA antisense oligonucleotides alleviates emotional deficits in mdx52 mice. Mol. Ther. Nucleic Acids32, 173–188 (2023). 10.1016/j.omtn.2023.03.009PMC1010673237078061Helleringer, R. et al. Cerebellar synapse properties and cerebellum-dependent motor and non-motor performance in Dp71-null mice. DMM Disease Models and Mechanisms11, 10.1242/dmm.033258 (2018).PMC607840729895670Miranda, R. et al. Altered social behavior and ultrasonic communication in the dystrophin-deficient mdx mouse model of Duchenne muscular dystrophy. Mol. Autism6, 10.1186/s13229-015-0053-9 (2015).PMC462761626527530Daoud, F. et al. Role of mental retardation-associated dystrophin-gene product dp71 in excitatory synapse organization, synaptic plasticity and behavioral functions. PLoS One4, e6574 (2009).PMC271870419649270Chaussenot, R. et al. Cognitive dysfunction in the dystrophin-deficient mouse model of Duchenne muscular dystrophy: A reappraisal from sensory to executive processes. Neurobiol. Learn Mem.124, 111–122 (2015). 10.1016/j.nlm.2015.07.00626190833Tetorou, K. Created in BioRender. https://BioRender.com/u06g263 (2024).Michael, N. & Karen, A. Dystrophin Dp71 and the Neuropathophysiology of Duchenne Muscular Dystrophy. Mol Neurobiol.57, 1748–1767 (2020).PMC706096131836945Tetorou, K. Created in BioRender. https://BioRender.com/w86l794 (2024).Tetorou, K. Created in BioRender. https://BioRender.com/y58j574 (2024).Tetorou, K. Created in BioRender. https://BioRender.com/q88i529 (2024).Tetorou, K. Created in BioRender. https://BioRender.com/b76v061 (2024).