Physiological Rules of Endocannabinoid Action During Fetal and Neonatal Brain Development

The endocannabinoid system is chiefly recognized as a homeostatic regulator of synaptic neurotransmission, primarily through the modulation of presynaptic CB₁ cannabinoid neurons. Accordingly, the use of plant-derived cannabinoids received significant attention recently given the broad spectrum of physiological and pathobiological processes the endocannabinoid system is involved in. Nevertheless, a parallel line of research from a number of developmental biology groups has uncovered fundamental, evolutionarily conserved, and molecularly unique processes that endocannabinoids drive during development of the central nervous system. This lecture transcript is a concise summary of nearly 20 years of research on endocannabinoid-gated mechanisms of neurogenic specification events, which particularly define the numbers, placement, and connectivity of cortical neurons. A summary of both CB₁ and alternative cannabinoid receptor contributions to neural differentiation is also discussed. Besides, insights are given into how phytocannabinoids can bypass physiologically timed and pivoted endocannabinoid action to inflict developmental errors that can significantly compromise the adaptive and computational ability of neurocircuits. By discussing specific subcellular targets of phytocannabinoid action and inferring errant glia versus neuron fate decisions and communication, a cellular basis is outlined for lifelong psychiatric phenotypes in offspring that associate with maternal cannabis seeking during pregnancy.