Endocannabinoid functions controlling neuronal specification during brain development

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Abstract

Endocannabinoids (eCBs) regulate a broad range of physiological functions in the postnatal brain and are implicated in the neuropathogenesis of psychiatric and metabolic diseases. Accumulating evidence indicates that eCB signaling also serves key functions during neurodevelopment; and is inherently involved in the control of neurogenesis, neural progenitor proliferation, lineage segregation, and the migration and phenotypic specification of immature neurons. Recent advances in developmental biology define fundamental eCB-driven cellular mechanisms that also contribute to our understanding of the molecular substrates of prenatal drug, in particular cannabis, actions. Here, we summarize known organizing principles of eCB-signaling systems in the developing telencephalon, and outline the sequence of decision points and underlying signaling pathways upon CB1 cannabinoid receptor activation that contribute to neuronal diversification in the developing brain. Finally, we discuss how these novel principles affect the formation of complex neuronal networks.

Introduction

Our knowledge of the structural substrates, spatial composition, and functional significance of endocannabinoid (eCB) signaling has recently undergone rapid expansion because of the continued identification of novel eCBs and related lipid mediators, bioactive intermediates, metabolic enzymes, cannabinoid receptors, and context-dependent recruitment of signaling pathways downstream from cannabinoid receptors (Brown, 2007, Daigle et al., 2008, Egertova et al., 2007, Lauckner et al., 2008, Mackie and Stella, 2006, Wei et al., 2006). In the adult CNS, eCB-mediated retrograde synaptic signaling implies the selective recruitment of CB1 cannabinoid receptors (CB1Rs) to both inhibitory and excitatory presynaptic terminals thus allowing sensing of on-demand eCB release from postsynaptic neurons (Lutz, 2004). The activity-dependent release of eCBs thereby controls synaptic plasticity in many brain regions including the neocortex, hippocampus, cerebellum, and basal ganglia (Kreitzer and Regehr, 2001, Matyas et al., 2008, Ohno-Shosaku et al., 2002, Wilson and Nicoll, 2001b, Wilson et al., 2001a). Although the molecular machinery underscoring retrograde eCB release in the postnatal brain is well established (Piomelli, 2003), our understanding of eCB functions during neurodevelopment has just begun to unfold. Contemporary evidence indicates that in the developing central nervous system (CNS) anandamide (AEA) and 2-arachidonoylglycerol (2-AG), the main known eCBs, and Δ9-tetrahydrocannabinol (Δ9-THC), the major psychoactive component in cannabis (Cannabis spp.), target cannabinoid receptors differentially on neural progenitors (Arevalo-Martin et al., 2007, Molina-Holgado et al., 2007), immature neurons (Berghuis et al., 2005, Berghuis et al., 2007, Mulder et al., submitted for publication, Watson et al., in press), and glia (Aguado et al., 2006, Molina-Holgado et al., 2002) (Fig. 1). Functional studies have demonstrated that this family of lipid mediators is involved in the regulation of neural progenitor proliferation and lineage commitment (Galve-Roperh et al., 2006, Mulder et al., submitted for publication); instructs the migration and differentiation of immature neurons (Berghuis et al., 2005, Berghuis et al., 2007, Harkany et al., 2007, Mulder et al., submitted for publication); and affects the onset of synaptic communication in neonatal neuronal networks (Berghuis et al., 2007, Bernard et al., 2005, Mereu et al., 2003). While the concepts described herein are primarily derived from experimental data on mammalian expression systems (see also Watson et al., in press) with well-accepted ligands, metabolic enzymes, and CB1Rs in neurons, the recent expansion of metabolic pathways critical for eCB synthesis and degradation (Egertova et al., 2007, Liu et al., 2006, Mulder and Cravatt, 2006, Simon and Cravatt, 2006, Wei et al., 2006), and the identification of novel cannabinoid receptors, particularly the orphan G protein-coupled receptor GPR55 (Baker et al., 2006, Johns et al., 2007, Lauckner et al., 2008, Oka et al., 2007, Ryberg et al., 2007) suggest a future leap in our understanding of eCB functions during brain development.

Section snippets

Developmental specification of endocannabinoid signaling

The molecular organization of eCB metabolism and respective receptor systems during brain development is such that eCBs may effectively tune the cellular specification programs of both neural progenitors and lineage-committed neuronal precursors (Harkany et al., 2007). At present, a comprehensive neuroanatomical analysis of eCB-signaling components during brain development is lacking; which is primarily due to our restricted knowledge of key enzymes regulating eCB bioavailability, and of

Differential signaling through CB1 cannabinoid receptors underscores neuronal specification

CB1Rs belong to the superfamily of seven transmembrane domain-containing G protein-coupled receptors (GPCRs), and exhibit 44% overall homology to the CB2R (Munro et al., 1993). Recent advances in receptor biology argue that receptor multimers function as key signaling units (Devi, 2000), and accordingly, CB1Rs likely signal as homodimers (Wager-Miller et al., 2002). Receptor dimerization is a critical molecular phenomenon during neurodevelopment, as the diversity of interacting receptors, such

Endocannabinoids regulate neuronal commitment and cell migration

During brain development, the establishment of eCB-signaling networks coincides with the expansion of neural progenies and their engagement in establishing neuronal diversity (Galve-Roperh et al., 2006). Functional eCB signaling in neurogenic proliferative zones, represented by DAGL and CB1R/CB2R expression (Aguado et al., 2005, Molina-Holgado et al., 2007, Mulder et al., submitted for publication), suggests that eCBs could provide extracellular cues instructing the cellular program of neural

CB1 cannabinoid receptors are targeted to developing axons

The subcellular domains where CB1Rs are momentarily accessible to their ligands define the physiological functions eCB signaling subserves whilst regulating neuronal differentiation. It has recently been demonstrated that domain-specific endocytosis, a key mechanism limiting the surface expression of a range of axonal proteins (Sampo et al., 2003, Wisco et al., 2003), determines the cell-surface availability of CB1Rs in neurons (Leterrier et al., 2006, McDonald et al., 2007a): CB1Rs on the

Endocannabinoids shape neuronal connectivity

The survival of neurochemically defined sets of neurons requires the correct patterning of axons and the establishment of functional synapses. Accordingly, the concept has recently evolved that eCB signaling through CB1Rs controls the initial phase of neurochemical specification and exerts differential effects on growth cone navigation, axonal elongation, and synaptogenesis of inhibitory interneurons and excitatory (pyramidal) cells in the mammalian cerebrum (Berghuis et al., 2004, Berghuis et

Conclusions

Multiple levels of evidence from complementary disciplines of developmental biology, molecular genetics, electrophysiology, neuropharmacology and the neurosciences demonstrate that eCB signaling modulates CNS patterning by tuning the size of neural progenitors pools generating neurons and glia, by defining the sizes of neuronal contingents undergoing radial or tangential migration to populate the developing cerebrum, and by controlling the morphological and functional specification of

Acknowledgements

This work was supported by grants from the Swedish Medical Research Council (T.H.), Hjärnfonden (Sweden, T.H.), Alzheimer's Association (T.H.), EMBO Young Investigator Programme (T.H.), the Scottish Universities Life Science Alliance (SULSA Cell Biology; T.H.) and European Community 7th Framework Programme (HEALTH-F2-2007-201159; T.H.). K.B. is recipient of a long-term Eötvös Fellowship of the Hungarian Scholarship Board. J.M. is supported by a postdoctoral fellowship from the Alzheimer's

References (104)

  • A.C. Huizink et al.

    Maternal smoking, drinking or cannabis use during pregnancy and neurobehavioral and cognitive functioning in human offspring

    Neurosci. Biobehav. Rev.

    (2006)
  • J.D. Jordan et al.

    Cannabinoid receptor-induced neurite outgrowth is mediated by Rap1 activation through G(alpha)o/i-triggered proteasomal degradation of Rap1GAPII

    J. Biol. Chem.

    (2005)
  • A.C. Kreitzer et al.

    Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells

    Neuron

    (2001)
  • R. Kurihara et al.

    Effects of peripheral cannabinoid receptor ligands on motility and polarization in neutrophil-like HL60 cells and human neutrophils

    J. Biol. Chem.

    (2006)
  • C. Leterrier et al.

    Constitutive endocytic cycle of the CB1 cannabinoid receptor

    J. Biol. Chem.

    (2004)
  • B. Lutz

    On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures

    Biochem. Pharmacol.

    (2004)
  • F. Matyas et al.

    Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area

    Neuropharmacology

    (2008)
  • N.A. McDonald et al.

    Generation and functional characterization of fluorescent N-terminally tagged CB(1) receptor chimeras for live-cell imaging

    Mol. Cell Neurosci.

    (2007)
  • S. Oka et al.

    Identification of GPR55 as a lysophosphatidylinositol receptor

    Biochem. Biophys. Res. Commun.

    (2007)
  • D. Rueda et al.

    The endocannabinoid anandamide inhibits neuronal progenitor cell differentiation through attenuation of the Rap1/B-Raf/ERK pathway

    J. Biol. Chem.

    (2002)
  • E. Ryberg et al.

    Identification and characterisation of a novel splice variant of the human CB1 receptor

    FEBS Lett.

    (2005)
  • B. Sampo et al.

    Two distinct mechanisms target membrane proteins to the axonal surface

    Neuron

    (2003)
  • M. Sawzdargo et al.

    Identification and cloning of three novel human G protein-coupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively expressed in human brain

    Brain Res. Mol. Brain Res.

    (1999)
  • G. Turu et al.

    The role of diacylglycerol lipase in constitutive and angiotensin AT1 receptor-stimulated cannabinoid CB1 receptor activity

    J. Biol. Chem.

    (2007)
  • N. Ueda et al.

    N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: a novel enzyme of the beta-lactamase fold family releasing anandamide and other N-acylethanolamines

    Life Sci.

    (2005)
  • J. Wager-Miller et al.

    Dimerization of G protein-coupled receptors: CB1 cannabinoid receptors as an example

    Chem. Phys. Lipids

    (2002)
  • M. Waldhoer et al.

    The carboxyl terminus of human cytomegalovirus-encoded 7 transmembrane receptor US28 camouflages agonism by mediating constitutive endocytosis

    J. Biol. Chem.

    (2003)
  • X. Wang et al.

    Preferential limbic expression of the cannabinoid receptor mRNA in the human fetal brain

    Neuroscience

    (2003)
  • B.Q. Wei et al.

    A second fatty acid amide hydrolase with variable distribution among placental mammals

    J. Biol. Chem.

    (2006)
  • H. Abe et al.

    Epithelial localization of green fluorescent protein-positive cells in epididymis of the GAD67-GFP knock-in mouse

    J. Androl.

    (2005)
  • T. Aguado et al.

    The endocannabinoid system drives neural progenitor proliferation

    FASEB J.

    (2005)
  • T. Aguado et al.

    The endocannabinoid system promotes astroglial differentiation by acting on neural progenitor cells

    J. Neurosci.

    (2006)
  • A. Arevalo-Martin et al.

    Cannabinoids modulate Olig2 and polysialylated neural cell adhesion molecule expression in the subventricular zone of post-natal rats through cannabinoid receptor 1 and cannabinoid receptor 2

    Eur. J. Neurosci.

    (2007)
  • P. Berghuis et al.

    Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor

    Proc. Natl. Acad. Sci. U.S.A.

    (2005)
  • P. Berghuis et al.

    Hardwiring the brain: endocannabinoids shape neuronal connectivity

    Science

    (2007)
  • C. Bernard et al.

    Altering cannabinoid signaling during development disrupts neuronal activity

    Proc. Natl. Acad. Sci. U.S.A.

    (2005)
  • F. Berrendero et al.

    Analysis of cannabinoid receptor binding and mRNA expression and endogenous cannabinoid contents in the developing rat brain during late gestation and early postnatal period

    Synapse

    (1999)
  • T. Bisogno et al.

    Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain

    J. Cell Biol.

    (2003)
  • A.J. Brown

    Novel cannabinoid receptors

    Br. J. Pharmacol.

    (2007)
  • A.A. Coutts et al.

    Agonist-induced internalization and trafficking of cannabinoid CB1 receptors in hippocampal neurons

    J. Neurosci.

    (2001)
  • B.F. Cravatt et al.

    Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides

    Nature

    (1996)
  • A.M. D’Antona et al.

    Mutations of CB1 T210 produce active and inactive receptor forms: correlations with ligand affinity, receptor stability, and cellular localization

    Biochemistry

    (2006)
  • P. Derkinderen et al.

    Regulation of a neuronal form of focal adhesion kinase by anandamide

    Science

    (1996)
  • P. Derkinderen et al.

    Regulation of extracellular signal-regulated kinase by cannabinoids in hippocampus

    J. Neurosci.

    (2003)
  • T.P. Dinh et al.

    Brain monoglyceride lipase participating in endocannabinoid inactivation

    Proc. Natl. Acad. Sci. U.S.A.

    (2002)
  • M. Egertova et al.

    Localization of N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) expression in mouse brain: a new perspective on N-acylethanolamines as neural signaling molecules

    J. Comp Neurol.

    (2007)
  • I. Galve-Roperh et al.

    The endocannabinoid system and neurogenesis in health and disease

    Neuroscientist

    (2007)
  • I. Galve-Roperh et al.

    Endocannabinoids: a new family of lipid mediators involved in the regulation of neural cell development

    Curr. Pharm. Des.

    (2006)
  • I. Galve-Roperh et al.

    Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation

    Nat. Med.

    (2000)
  • M. Guzman

    Cannabinoids: potential anticancer agents

    Nat. Rev. Cancer

    (2003)
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      In rodents, gestational CB1 receptor expression peaks in cortical excitatory pyramidal cells at E 14–15, whereas expression in inhibitory interneurons remains relatively low until late gestation/birth (Mulder et al., 2008), suggestive of a cell-type specific role of CB1 receptor signalling in neuronal development. Although the current understanding of CB1 receptor expression patterns in the postnatal brain is far from complete, the available evidence suggests that the ECS continues to develop into adolescence and adulthood (Fride, 2008; Harkany et al., 2008; Lee and Gorzalka, 2015). In both male and female rats, CB1 receptor expression in midbrain and limbic regions increased from PND 10 to peak expression in early-adolescence (PND 30–40), then gradually decreased to stable adult-typical levels by PND 70 (de Fonseca et al., 1994).

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