Specific Dystrophins Selectively Associate with Inhibitory and Excitatory Synapses of the Mouse Cerebellum and their Loss Alters Expression of P2X7 Purinoceptors and Pro-Inflammatory Mediators

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dc.cclicenceCC-BYen
dc.contributor.authorJackson, Torquil
dc.contributor.authorSeifi, Mohsen
dc.contributor.authorGórecki, Dariusz C.
dc.contributor.authorSwinny, Jerome D.
dc.date.acceptance2021-05-27
dc.date.accessioned2021-06-30T08:20:55Z
dc.date.available2021-06-30T08:20:55Z
dc.date.issued2021-06-08
dc.descriptionopen access articleen
dc.description.abstractDuchenne muscular dystrophy (DMD) patients, having mutations of the DMD gene, present with a range of neuropsychiatric disorders, in addition to the quintessential muscle pathology. The neurobiological basis remains poorly understood because the contributions of different DMD gene products (dystrophins) to the different neural networks underlying such symptoms are yet to be fully characterised. While full-length dystrophin clusters in inhibitory synapses, with inhibitory neurotransmitter receptors, the precise subcellular expression of truncated DMD gene products with excitatory synapses remains unresolved. Furthermore, inflammation, involving P2X purinoceptor 7 (P2RX7) accompanies DMD muscle pathology, yet any association with brain dystrophins is yet to be established. The aim of this study was to investigate the comparative expression of different dystrophins, alongside ionotropic glutamate receptors and P2RX7s, within the cerebellar circuitry known to express different dystrophin isoforms. Immunoreactivity for truncated DMD gene products was targeted to Purkinje cell (PC) distal dendrites adjacent to, or overlapping with, signal for GluA1, GluA4, GluN2A, and GluD2 receptor subunits. P2X7R immunoreactivity was located in Bergmann glia profiles adjacent to PC-dystrophin immunoreactivity. Ablation of all DMD gene products coincided with decreased mRNA expression for Gria2, Gria3, and Grin2a and increased GluD2 immunoreactivity. Finally, dystrophin-null mice showed decreased brain mRNA expression of P2rx7 and several inflammatory mediators. The data suggest that PCs target different dystrophin isoforms to molecularly and functionally distinct populations of synapses. In contrast to muscle, dystrophinopathy in brain leads to the dampening of the local immune system.en
dc.funderOther external funder (please detail below)en
dc.funder.otherTJ was supported by a PhD studentship from the University of Portsmouth. Aspects of this work were supported by the Kościuszko grant (523/2017/DA) from the Polish Ministry of National Defense (D.C.G.).en
dc.identifier.citationJackson, T., Seifi, M., Górecki, D.C. and Swinny, J.D. (2021) Specific Dystrophins Selectively Associate with Inhibitory and Excitatory Synapses of the Mouse Cerebellum and their Loss Alters Expression of P2X7 Purinoceptors and Pro-Inflammatory Mediators. Cellular and Molecular Neurobiology, 42, pp 2357–2377.en
dc.identifier.doihttps://doi.org/10.1007/s10571-021-01110-6
dc.identifier.issn0272-4340
dc.identifier.urihttps://dora.dmu.ac.uk/handle/2086/21072
dc.language.isoenen
dc.peerreviewedYesen
dc.projectid523/2017/DAen
dc.publisherSpringeren
dc.researchinstituteLeicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)en
dc.subjectAMPAen
dc.subjectDelta 2 receptoren
dc.subjectDuchenne muscular dystrophyen
dc.subjectNMDAen
dc.subjectNeuroinflammationen
dc.subjectP2RX7en
dc.titleSpecific Dystrophins Selectively Associate with Inhibitory and Excitatory Synapses of the Mouse Cerebellum and their Loss Alters Expression of P2X7 Purinoceptors and Pro-Inflammatory Mediatorsen
dc.typeArticleen

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