Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning

Department of Neuroscience, Retzius väg 8, and Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Scheeles väg 1, Karolinska Institutet, 17177 Stockholm, Sweden.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2008; 105(25):8760-5. DOI: 10.1073/pnas.0803545105
Source: PubMed


Endocannabinoids (eCBs) have recently been identified as axon guidance cues shaping the connectivity of local GABAergic interneurons in the developing cerebrum. However, eCB functions during pyramidal cell specification and establishment of long-range axonal connections are unknown. Here, we show that eCB signaling is operational in subcortical proliferative zones from embryonic day 12 in the mouse telencephalon and controls the proliferation of pyramidal cell progenitors and radial migration of immature pyramidal cells. When layer patterning is accomplished, developing pyramidal cells rely on eCB signaling to initiate the elongation and fasciculation of their long-range axons. Accordingly, CB(1) cannabinoid receptor (CB(1)R) null and pyramidal cell-specific conditional mutant (CB(1)R(f/f,NEX-Cre)) mice develop deficits in neuronal progenitor proliferation and axon fasciculation. Likewise, axonal pathfinding becomes impaired after in utero pharmacological blockade of CB(1)Rs. Overall, eCBs are fundamental developmental cues controlling pyramidal cell development during corticogenesis.

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    • "The endocannabinoid system includes endogenous ligands, cannabinoid type 1 (CB1R) and 2 receptors, and synthesizing and degrading enzymes (Piomelli, 2003; Basavarajappa, 2007; Subbanna et al., 2013a). A substantial amount of previous research has demonstrated multiple ways in which the endocannabinoid system regulates synaptic events (Ohno-Shosaku et al., 2001; Wilson and Nicoll, 2001; Bacci et al., 2004) in the developing (Berghuis et al., 2007; Mulder et al., 2008; Subbanna et al., 2013a) and adult brain (see Basavarajappa et al., 2009). Research findings from animal and human studies imply that the endocannabinoid system is one of the most relevant biochemical systems mediating the action of ethanol in multiple brain regions (Basavarajappa et al., 1998, 2003, 2006, 2008; Basavarajappa and Hungund, 1999a, 1999b; Roberto et al., 2010; DePoy et al., 2013; Hirvonen et al., 2013; Subbanna et al., 2013a; Ceccarini et al., 2014). "
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    ABSTRACT: Ethanol exposure to rodents during postnatal day 7 (P7), which is comparable to the third trimester of human pregnancy, induces long-term potentiation and memory deficits. However, the molecular mechanisms underlying these deficits are still poorly understood. In the present study, we explored the potential role of epigenetic changes at cannabinoid type 1 (CB1R) exon1 and additional CB1R functions, which could promote memory deficits in animal models of fetal alcohol spectrum disorder. We found that ethanol treatment of P7 mice enhances acetylation of H4 on lysine 8 (H4K8ace) at CB1R exon1, CB1R binding as well as the CB1R agonist-stimulated GTPγS binding in the hippocampus and neocortex, two brain regions that are vulnerable to ethanol at P7 and are important for memory formation and storage, respectively. We also found that ethanol inhibits cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation and activity-regulated cytoskeleton-associated protein (Arc) expression in neonatal and adult mice. The blockade or genetic deletion of CB1Rs prior to ethanol treatment at P7 rescued CREB phosphorylation and Arc expression. CB1R knockout mice exhibited neither ethanol-induced neurodegeneration nor inhibition of CREB phosphorylation or Arc expression. However, both neonatal and adult mice did exhibit enhanced CREB phosphorylation and Arc protein expression. P7 ethanol-treated adult mice exhibited impaired spatial and social recognition memory, which were prevented by the pharmacological blockade or deletion of CB1Rs at P7. Together, these findings suggest that P7 ethanol treatment induces CB1R expression through epigenetic modification of the CB1R gene, and that the enhanced CB1R function induces pCREB, Arc, spatial, and social memory deficits in adult mice. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 10/2014; 18(5). DOI:10.1093/ijnp/pyu028 · 4.01 Impact Factor
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    • "Thus, different neurotransmitters and neuromodulators have been shown to influence neural progenitor proliferation and neurogenesis. In particular, the CB 1 cannabinoid receptor, the most important mediator of endocannabinoid actions on key neurobiological processes (Castillo et al. 2012), exerts a regulatory role in neuronal differentiation and long-range connectivity (Berghuis et al. 2007; Mulder et al. 2008; Diaz- Alonso et al. 2012). In addition, CB 1 receptors are known to control neural progenitor cell proliferation in vitro and in vivo, both in the developing brain and in adult neurogenic areas (Jin et al. 2004; Aguado et al. 2005, 2007; Trazzi et al. 2010). "
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    ABSTRACT: The CB1 cannabinoid receptor regulates cortical progenitor proliferation during embryonic development, but the molecular mechanism of this action remains unknown. Here, we report that CB1-deficient mouse embryos show premature cell cycle exit, decreased Pax6- and Tbr2-positive cell number, and reduced mammalian target of rapamycin complex 1 (mTORC1) activation in the ventricular and subventricular cortical zones. Pharmacological stimulation of the CB1 receptor in cortical slices and progenitor cell cultures activated the mTORC1 pathway and increased the number of Pax6- and Tbr2-expressing cells. Likewise, acute CB1 knockdown in utero reduced mTORC1 activation and cannabinoid-induced Tbr2-positive cell generation. Luciferase reporter and chromatin immunoprecipitation assays revealed that the CB1 receptor drives Tbr2 expression downstream of Pax6 induction in an mTORC1-dependent manner. Altogether, our results demonstrate that the CB1 receptor tunes dorsal telencephalic progenitor proliferation by sustaining the transcriptional activity of the Pax6-Tbr2 axis via the mTORC1 pathway, and suggest that alterations of CB1 receptor signaling, by producing the missexpression of progenitor identity determinants may contribute to neurodevelopmental alterations.
    Cerebral Cortex 03/2014; 25(9). DOI:10.1093/cercor/bhu039 · 8.67 Impact Factor
    • "The CB 1 R is expressed by a wide range of developing neurons in their axons and growth cones, dynamic neurite tips that sense and respond to guidance cues (Hohmann & Herkenham, 1999; Mulder et al., 2008; Vitalis et al., 2008; Wu et al., 2010; Argaw et al., 2011; Keimpema et al., 2013; Simon et al., 2013). DAGLa is expressed mainly in growth cones while MGL accumulates in the stabilized axon segment (Mulder et al., 2008; Keimpema et al., 2013). The lack of MGL expression in the growth cone allows the production of focal 2-AG, in addition to A B Fig. 2. Endocannabinoid signalling in development and adulthood. "
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    ABSTRACT: Neurotrophins are traditionally known for their roles in neuronal development, function and survival. More recent data has highlighted the importance of neurotrophin signalling in adult signalling contexts, including the regulation of synaptic transmission. In addition, neurotrophin levels are increased in inflammatory and neuropathic pain leading to sensitization to painful stimuli. Endocannabinoid (eCB) signalling was initially studied in the context of synaptic transmission and pain alleviation whilst recently gaining attention due to its involvement in the development of the nervous system. Similar to neurotrophins, eCB levels also rise during pain perception but result in diminished pain sensations. The overlap of cellular functions between neurotrophins and eCB signalling leads to the hypothesis that these signalling systems are positioned to regulate each other and narrow the multitude of actions that both systems can promote to the specific need of the cell. Therefore, in this review, we examine to what extent the involvement of these two signalling systems is co-ordinated as opposed to being coincidental, and causal to neuronal circuit modifications in pain. Available data point to numerous direct molecular interactions between the neurotrophin and eCB signalling systems in developmental and adult contexts, including receptor-level interplay, transcriptional control and synergistic regulation of downstream signalling cascades. Although experimental observations specifically in pain circuits are limited, the universality of downstream signalling systems from both neurotrophin and endocannabinoid receptors suggest an interdependent relationship between these two diverse signalling systems.
    European Journal of Neuroscience 02/2014; 39(3):334-43. DOI:10.1111/ejn.12431 · 3.18 Impact Factor
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