The activation of cannabinoid receptors during early postnatal development reduces the expression of cell adhesion molecule L1 in the rat brain

Abstract

Cannabinoid CB 1 receptors and their ligands emerge early in brain development and are abundantly expressed in certain brain regions that play key roles in processes related to cell proliferation and migration, neuritic elongation and guidance, and synaptogenesis. This would support the notion that the cannabinoid system might play a modulatory role in the regulation of these processes. We have recently presented preliminary in vivo evidence showing that this modulatory action might be exerted, among others, through regulating the levels of several key elements in these processes, such as the L1 protein. This was observed in various white matter areas of the rat forebrain. Because these preliminary in vivo experiments focused only in fetal ages, we concentrated now in the period of early postnatal development. To this end, we analyzed the effects of the cannabinoid agonist Δ 9-tetrahydrocannabinol (Δ 9-THC) daily administered since the 5th day of gestation on mRNA levels for L1 in different brain structures of rat neonates at different postnatal ages (PND1, PND5 and PND12). Our results revealed that Δ 9-THC exposure affected the levels of L1 transcripts in specific brain structures only in PND1, these effects disappearing during further days. Thus, we found reduced L1-mRNA levels in grey matter regions, such as the cerebral cortex, septum nuclei, striatum, dentate gyrus and CA3 subfield of the Ammon horn. White matter areas and subventricular zones were, however, more resistant to Δ 9-THC exposure at this postnatal age in contrast with the previous data obtained in the fetal brain. Importantly, the effects were influenced by gender of animals, since the reductions were always more marked in females than males, also in contrast with the data reported for the fetal brain. In summary, the cannabinoid system seems to modulate the levels of L1 in several brain structures during specific periods of development [late gestation (previous data) and very early postnatal days (present data)], which correlates with the periods in which we had previously found an atypical distribution of CB 1 receptors in the developing brain. However, the magnitude of the effects of cannabinoids on L1 was influenced by two factors: gender and age of development. Considering the role played by L1 in different events related to neural development, our observations might support the occurrence of a physiological mechanism by which the cannabinoid system might regulate processes such as cell proliferation and migration, neuritic elongation and guidance, and synaptogenesis.