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.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.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.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.
