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

Aims: The endocannabinoid system with its type 1 cannabinoid receptor (CB₁ R) expressed in postmitotic neuroblasts is a critical chemotropic guidance module with its actions cascading across neurogenic commitment, neuronal polarization and synaptogenesis in vertebrates. Here, we present the systematic analysis of regional CB₁ R expression in the developing human brain from gestational week 14 until birth. In parallel, we diagrammed differences in CB₁ R development in Down syndrome fetuses and identified altered CB₁ R signalling.

Methods: Fetal brains with normal development or with Down’s syndrome were analysed using standard immunohistochemistry, digitalized light microscopy and image analysis (NanoZoomer). CB₁ R 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 CB₁ Rs gradually decreased during the second and third trimesters in the neocortex. In contrast, CB₁ R density was maintained, or even increased, in the hippocampus. We found the onset of CB₁ R expression being delayed by ≥1 month in age-matched fetal brains with Down’s syndrome. In vitro, CB₁ R excitation induced excess microtubule stabilization 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.