Concerted Action of CB1 Cannabinoid Receptor and Deleted in Colorectal Cancer in Axon Guidance

Abstract

Endocannabinoids (eCBs) are retrograde neurotransmitters that modulate the function of many types of synapses. The presence of eCBs, their CB1 receptor (CB1R), and metabolizing enzymes at embryonic and early postnatal periods have been linked to developmental processes such as neuronal proliferation, differentiation, and migration, axon guidance, and synaptogenesis. Here, we demonstrate the presence of a functional eCB system in the developing visual system and the role of CB1R during axon growth and retinothalamic development. Pharmacological treatment of retinal explants and primary cortical neuron cultures with ACEA, a selective CB1R agonist, induced a collapse of the growth cone (GC). Furthermore the application of AM251, a CB1R inverse agonist, to the neuronal cultures increased the surface area of GC. In vivo, intraocular injection of ACEA diminished retinal projection growth, while AM251 promoted growth and caused aberrant projections. In addition, compared with their wild-type littermates, CB1R-deficient adult mice revealed a lower level of eye-specific segregation of retinal projections in the dorsal lateral geniculate nucleus. Finally, we found that pharmacological modulation of CB1R affected the trafficking of Deleted in colorectal cancer (DCC) receptor to the plasma membrane in a PKAdependent manner. Moreover, pharmacological inhibition or genetic inactivation of DCC abolished the CB1R-induced reorganization of the GC. Overall, these findings establish a mechanism by which the CB1R influences GC behavior and nervous system development in concerted action with DCC.

Type-1 Cannabinoid Receptor Signaling in Neuronal Development

“…CB1R is strongly expressed in projection axons during neuronal development of embryonic chicken [5,6], zebrafish [6], mice [7,8,10], rats [9] and in mouse retina [11]. Interestingly, this expression is dynamically regulated in cortical projection neurons during brain development [6,7,8,12].…”

“…Developmental studies have shown that, from zebrafish to mammals, CB1R is highly expressed in the developing brain [5,6,7,8,9,10,11]. Remarkably, after birth, when synaptic contacts of axons consolidate, CB1R expression is greatly reduced in structures such as cortical projection neurons [7,8,12].…”

“…This peculiar expression pattern opens the possibility that neuronal eCBs may play important novel roles, different from their established roles in synaptic regulation. Indeed, currently eCBs and CB1R are known to be involved in brain development at the synaptic [7,12,13,14,15], neuronal [7,8,9,10,11,12,15,16,17,18,19] and network level [5,10,20]. …”

Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons

“…2-AG liberated from postsynaptic neurons serves as a retrograde messenger to limit neurotransmitter release from many mature presynapses (1). However, 2-AG signaling also emerges as a molecular determinant of cortical development (2)(3)(4). Despite recent advances, the contribution of endocannabinoids (specifically 2-AG) to neuronal diversification and the development of synaptic connectivity in subcortical territories remains unknown.…”

Altered patterns of filopodia production in CHO cells heterologously expressing zebra finch CB1cannabinoid receptors

“…19-21 CB 1 -mediated signaling is known to be involved in the control of axonal migration and growth cone structure in the developing retina 22 and cortex. [23][24][25][26] We have recently discovered that developmental, but not adult cannabinoid exposure increases dendritic spine densities in song control regions of zebra finch telencephalon.…”