Endocannabinoids via CB₁ receptors act as neurogenic niche cues during cortical development

Abstract

During brain development, neurogenesis is precisely regulated by the concerted action of intrinsic factors and extracellular signalling systems that provide the necessary niche information to proliferating and differentiating cells. A number of recent studies have revealed a previously unknown role for the endocannabinoid (ECB) system in the control of embryonic neuronal development and maturation. Thus, the CB(1) cannabinoid receptor in concert with locally produced ECBs regulates neural progenitor (NP) proliferation, pyramidal specification and axonal navigation. In addition, subcellularly restricted ECB production acts as an axonal growth cone signal to regulate interneuron morphogenesis. These findings provide the rationale for understanding better the consequences of prenatal cannabinoid exposure, and emphasize a novel role of ECBs as neurogenic instructive cues involved in cortical development. In this review the implications of altered CB(1)-receptor-mediated signalling in developmental disorders and particularly in epileptogenesis are briefly discussed.

Figure 1.

Expression pattern of the CB₁ cannabinoid receptor mRNA at different developmental stages. CB₁ mRNA in situ hybridization in the developing mouse nervous system is shown at the indicated stages. BG, basal ganglia; BS, brainstem; Cx, cortex; Hpc, hippocampus; Hth, hypothalamus; Pa, pallium; sPa, subpallium; SC, spinal cord. Published with permission of Allen Developing Mouse Brain Atlas, Seattle (WA), Allen Institute for Brain Science. Copyright ©2009. Available at: http://developingmouse.brain-map.org.

Figure 2.

CB₁ cannabinoid receptor expression during cortical development. The CB₁ receptor is present in the developing cortex, showing increasing expression levels from undifferentiated to differentiated projection neurons (PNs). The CB₁ receptor is present in Cajal–Retzius cells of the marginal zone (MZ) and apical and basal progenitors in the ventricular and subventricular (VZ/SVZ) proliferative area. Representative immunofluorescence images showing the colocalization of the CB₁ receptor in radial glial (RG) progenitors and intermediate amplifying progenitor cells (IPCs) as identified with Sox2 and Tbr2 antibodies, respectively [13] (copyright National Academy of Sciences, USA 2009). Higher expression levels of the CB₁ receptor are evident in maturing neurons that have reached the CP, that correspond to locally generated PNs. CB₁ receptor is present in certain interneuron (IN) populations that reach the pallium upon tangential migration from the ganglionic eminences. Image background corresponds to a representative in situ hybridization of the CNR1 mRNA at E.16.5 (by C. Hoffman and B. Lutz, Johannes Gutenberg University Mainz, Germany).

Figure 3.

CB₁ cannabinoid receptor signalling and regulation of neural stem/progenitor cell proliferation. CB₁ receptors are coupled to Gi proteins, thereby mediating the inhibition of adenylyl cyclase (AC) and protein kinase A (PKA). CB₁ receptor coupling to Gi signalling is also associated with activation of the extracellular signal-regulated kinase (ERK) pathway via different mechanisms (see text for details). Direct activation of the PI3K/Akt and ERK pathways by CB₁ receptors may converge, thus synergizing with their activation by other receptors such as growth factor receptors with tyrosine kinase activity (RTK). CB₁ receptor-induced activation of RTKs can occur by promoting the processing of membrane-bound growth factor inactive precursors to yield active growth factors, or by activating intracellular Src family protein kinases. In some circumstances, CB₁ activity can antagonize RTK-mediated ERK signalling (see [46,47] for further details). Activation of the CB₁ receptor ultimately controls different transcriptional regulators, including CREB, STAT-3, PAX-6 and β-catenin. The CB₁ receptor may also regulate mammalian target of rapamycin complex 1 (mTORC1) in NPs as it occurs in differentiated neurons.

Figure 4.

CB₁ cannabinoid receptor signalling and neuronal differentiation. CB₁ receptor activity in differentiating cortical neurons is coupled by as yet unknown mechanisms to the modulation of the neurogenic transcription factor code Ctip2-Satb2. CB₁ receptors are positively coupled to COUP-TF II interacting protein 2 (Ctip2) and negatively to Satb2-mediated repression of Ctip2. Thus, CB₁ receptor activity tunes the transcriptional neurogenic programme responsible for upper and lower cortical neuron differentiation. Transcription factors involved in cortical laminar specification regulated by CB₁ receptor are indicated in bold letters.