Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor

Abstract

In utero exposure to ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC), the active component from marijuana, induces cognitive deficits enduring into adulthood. Although changes in synaptic structure and plasticity may underlie ⌬ 9 -THC-induced cognitive impairments, the neuronal basis of ⌬ 9 -THC-related developmental deficits remains unknown. Using a Boyden chamber assay, we show that agonist stimulation of the CB 1 cannabinoid receptor (CB1R) on cholecystokinin-expressing interneurons induces chemotaxis that is additive with brain-derived neurotrophic factor (BDNF)-induced interneuron migration. We find that Src kinase-dependent TrkB receptor transactivation mediates endocannabinoid (eCB)-induced chemotaxis in the absence of BDNF. Simultaneously, eCBs suppress the BDNF-dependent morphogenesis of interneurons, and this suppression is abolished by Src kinase inhibition in vitro. Because sustained prenatal ⌬ 9 -THC stimulation of CB1Rs selectively increases the density of cholecystokinin-expressing interneurons in the hippocampus in vivo, we conclude that prenatal CB 1R activity governs proper interneuron placement and integration during corticogenesis. Moreover, eCBs use TrkB receptor-dependent signaling pathways to regulate subtype-selective interneuron migration and specification.corticogenesis ͉ drug abuse ͉ neurotrophin E ndogenous cannabinoids, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), modulate synaptic plasticity by the retrograde control of neurotransmitter release (1). Accordingly, a compartmentalization of endocannabinoid (eCB) synthesis and action has been demonstrated in adult brain (1-3). eCBs are predominantly synthesized in dendritic compartments and signal through presynaptic G i/o protein-coupled CB 1 cannabinoid receptors (CB 1 Rs) (4-6). The adult phenotype of cannabinoid systems is achieved through a series of developmentally regulated events culminating in high CB 1 R expression on cholecystokinin (CCK)-containing GABAergic interneurons (CB 1 R ϩ cells) in the hippocampus and neocortex (3,5,6).Recent studies have demonstrated the existence of functional CB 1 Rs in developing cortical neurons (7). A coincidence of eCB synthesis and release and CB 1 R activation within axonal growth cones was postulated to provide an eCB-driven reinforcement loop that regulates axonal growth and guidance (8). Although the functional significance of CB 1 Rs during assembly of cortical neuronal circuitries is unknown, their developmental impact is illustrated by long-lasting cognitive, motor, and social disturbances in offspring exposed prenatally to cannabis (9, 10).The majority of cortical interneurons are derived from extracortical precursor pools and undergo long-distance migration before inhabiting specific cortical layers (11, 12). Interneuron specification is in part governed by epigenetic cues within the neocortex, including brain-derived neurotrophic factor (BDNF) (12-14). Considering that pyramidal cells in the juvenile neocortex harbor the capacity of eCB synthesis and release (15), we hypothesiz...

The endocannabinoid system in normal and pathological brain ageing

“…This hypothesis was supported by Marsicano showing that induction of BDNF expression contributes to the protective effect of CB1 receptor activity against excitotoxicity [209]. CB1 receptor activity can enhance TrkB signalling partly by activating MAP kinase/ERK kinase pathways [210] but also by directly transactivating the TrkB receptors [211]. The fact that genetic deletion of CB1 receptors leads to a decreased BDNF expression suggests that endogenous cannabinoids exert a tonic control over BDNF expression [212].…”

Endocannabinoids via CB1receptors act as neurogenic niche cues during cortical development

“…Later, CB 1 receptors are heterogeneously distributed through cortical layers and the hippocampus, in both excitatory glutamatergic projection neurons, as identified by vGlut1 expression, and cholecystokinin (CCK)-expressing GABAergic interneurons colabelled with vGlut3 [16][17][18]. CB 1 þ CCK þ interneurons derived from the ganglionic eminences follow tangential migratory routes from the ventral telencephalon and reach the developing cortex, hippocampus and amygdala [15,[19][20][21]. The regulatory role of the ECB system in development of excitatory and inhibitory neuronal lineages is also conserved in the adult brain, in which CB 1 receptors are functional in cortical excitatory projecting neurons and inhibitory GABAergic interneurons [8,22].…”

“…Accordingly, pharmacological regulation with selective CB 1 and CB 2 receptor agonists or antagonists exerts a positive or negative action, respectively, on NP cell division [29,30,34,40,45]. In vivo, CB 1 receptor loss of function induces alterations of cortical and hippocampal development [20,29] and, whereas CB 1 -null mice have reduced cortical progenitor proliferation, in FAAHdeficient mice the opposite is observed [13,29]. Abnormal cortical development in CB 1 -deficient mice is characterized by defective SVZ/VZ pyramidal progenitor proliferation and radial migration, deficits in axonal navigation and aberrant corticofugal projections [13].…”

Neurotrophin receptors: Old friends with new partners

“…Trk activation is associated with activation of a variety of G-protein coupled receptors (GPCRs) including A2a adenosine receptors (Lee and Chao, 2001), PAC1 receptors for the neuropeptide pituitary adenylate cyclase activating peptide (PACAP) (Lee et al, 2002), and endocannabinoid receptors (Berghuis et al, 2005). GPCRdependent Trk transactivation differs from neurotrophin-dependent Trk activation in one important respect.…”