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Regional redistribution of CB1 cannabinoid receptors in human foetal brains with Down's syndrome and their functional modifications in Ts65Dn+/+ mice

Patthy, Ágoston ; Hanics, János ; Zachar, Gergely ; Kovács, Gábor G. ; Harkany, Tibor ; Alpár, Alán

Neuropathology and applied neurobiology, 2023-02, Vol.49 (1), p.e12887-n/a [Periódico revisado por pares]

England: Wiley Subscription Services, Inc

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  • Título:
    Regional redistribution of CB1 cannabinoid receptors in human foetal brains with Down's syndrome and their functional modifications in Ts65Dn+/+ mice
  • Autor: Patthy, Ágoston ; Hanics, János ; Zachar, Gergely ; Kovács, Gábor G. ; Harkany, Tibor ; Alpár, Alán
  • Assuntos: Animals ; Axonogenesis ; Brain - metabolism ; Cannabinoid CB1 receptors ; cannabinoid receptor ; Cannabinoids ; Chromosome 21 ; Coding ; developmental delay ; Down Syndrome - metabolism ; Down's syndrome ; Endocannabinoid system ; Endocannabinoids - metabolism ; genetic brain disease ; Humans ; Image processing ; Immunohistochemistry ; Light microscopy ; Medicin och hälsovetenskap ; Mice ; Mice, Transgenic ; Neocortex ; Neonates ; neurodevelopmental disorder ; Receptor, Cannabinoid, CB1 - metabolism ; Receptors, Cannabinoid - metabolism ; Synaptogenesis ; Telencephalon ; Transgenic mice ; trisomy
  • É parte de: Neuropathology and applied neurobiology, 2023-02, Vol.49 (1), p.e12887-n/a
  • Notas: Funding information
    This work was supported by the National Brain Research Program of Hungary (2017‐1.2.1‐NKP‐2017‐00002 and NAP2022‐I‐1/2022 to A.A.); the Excellence Program for Higher Education of Hungary (TKP‐EGA‐25, A.A.); the Swedish Medical Research Council (2018‐02838 to T.H.); Novo Nordisk Foundation (NNF20OC0063667 to T.H.); the NKFIH UNKP‐22‐23 and the FK 131966 grants (to G.Z.); Hjärnfonden (FO2019‐0277 to T.H.); and the European Research Council (FOODFORLIFE, 2020‐AdG‐101021016, and SECRET‐DOCK, 2022‐PoC2‐101082277 to T.H.).
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  • Descrição: Aims The endocannabinoid system with its type 1 cannabinoid receptor (CB1R) expressed in postmitotic neuroblasts is a critical chemotropic guidance module with its actions cascading across neurogenic commitment, neuronal polarisation and synaptogenesis in vertebrates. Here, we present the systematic analysis of regional CB1R expression in the developing human brain from gestational week 14 until birth. In parallel, we diagrammed differences in CB1R development in Down syndrome foetuses and identified altered CB1R signalling. Methods Foetal brains with normal development or with Down's syndrome were analysed using standard immunohistochemistry, digitalised light microscopy and image analysis (NanoZoomer). CB1R function was investigated by in vitro neuropharmacology from neonatal Ts65Dn transgenic mice brains carrying an additional copy of ~90 conserved protein‐coding gene orthologues of the human chromosome 21. Results We detected a meshwork of fine‐calibre, often varicose processes between the subventricular and intermediate zones of the cortical plate in the late first trimester, when telencephalic fibre tracts develop. The density of CB1Rs gradually decreased during the second and third trimesters in the neocortex. In contrast, CB1R density was maintained, or even increased, in the hippocampus. We found the onset of CB1R expression being delayed by ≥1 month in age‐matched foetal brains with Down's syndrome. In vitro, CB1R excitation induced excess microtubule stabilisation and, consequently, reduced neurite outgrowth. Conclusions We suggest that neuroarchitectural impairments in Down's syndrome brains involve the delayed development and errant functions of the endocannabinoid system, with a particular impact on endocannabinoids modulating axonal wiring. This study gives the regional distribution pattern of cannabinoid receptor type 1 expression in the human foetal brain. In Down's syndrome, receptor expression is delayed by at least a month. CB1R activation induces excess microtubule stabilisation in cortical neurons of infant Ts65Dn Down's syndrome model transgenic mice.
  • Editor: England: Wiley Subscription Services, Inc
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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