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

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 similar to 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 CB(1)Rs 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.