Defective Adult Neurogenesis in CB1 Cannabinoid Receptor Knockout Mice

Jin, Kunlin; Xie, Lin; Kim, Sun Hee; Parmentier-Batteur, Sophie; Sun, Yunjuan; Mao, Xiao Ou; Childs, Jocelyn; Greenberg, David A.

doi:10.1124/mol.66.2.204

Cited by 252 publications

(224 citation statements)

References 43 publications

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“…First, the coincident expression of eCB synthesis enzymes and receptors in cortical progenitor zones demonstrates the existence of operational eCB signaling networks in neurogenic niches of the developing brain, where eCBs tune the rate of neural progenitor proliferation and the number of immature neurons committed to radial migration. Our findings indicate that eCB signaling is instrumental for embryonic neurogenesis, as also reported in adult brain (21), and data from knockout mice support a role for CB 1 Rs in committing SVZ progenitors to a pyramidal cell fate (10). Our in vitro morphometric and biochemical data also extend previous findings showing that both DAGL␣/␤ are recruited to elongating glutamatergic axons (9) with DAGL␣ being the primary enzyme concentrating in axonal growth cones.…”

Section: Discussionsupporting

confidence: 79%

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

Mulder

Aguado²,

Keimpema³

et al. 2008

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

279

356

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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 longrange 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 (CB1R) null and pyramidal cellspecific conditional mutant (CB 1R 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 1Rs. Overall, eCBs are fundamental developmental cues controlling pyramidal cell development during corticogenesis.excitation ͉ glutamate ͉ layer patterning ͉ neocortex ͉ neurogenesis P yramidal cell specification follows a sequential scenario in the developing cerebrum: commitment of progenitor cells to the neuronal lineage occurs in the subcortical proliferative ventricular zone (VZ) and subventricular zone (SVZ). Immature pyramidal cells undergo radial migration to populate the cortical plate (CP) (1), where they acquire layer-specific neurochemical and morphological diversity (2). Pyramidal cell positioning and patterning of their corticofugal and intracortical axons is in part achieved via transcriptional control acting throughout cellular identification (2). However, epigenetic microenvironmental cues, provided by neural progenitors, radial glia, and immature neurons, are also fundamental in attaining cortical cell identity with particularly robust effects on pathfinding and directional growth of long-range axons (3).Endocannabinoids [eCBs; anandamide (AEA) and 2-arachidonoylglycerol] control various forms of synaptic plasticity at cortical glutamatergic synapses in the postnatal brain (4) through functional CB 1 cannabinoid receptors (CB 1 Rs) (5). During brain development, eCBs control neuronal fate decision (6), interneuron migration (7), and axonal specification (8). Developmental eCB actions are underpinned by a temporally defined assembly of functional eCB signaling networks with coincident expression of sn-1-diacylglycerol lipases (DAGL␣/␤) (9) and N-arachidonoyl-phosphatidyl ethanolamine (NAPE)-selective phospholipase D involved in eCB synthesis, fatty-acid amide hydrolase (FAAH) (an enzyme preferentially degrading AEA), and CB 1 Rs (8). The selective axonal targeting of CB 1 Rs and DAGLs in immature neurons suggests that eCBs may function in either cell-autonomous (6, 9) or target-derived (8) manner to control axonal elongation and postsynaptic target selection, respectively.Although recent findings in both mammals (8) and nonmammalian v...

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Section: Discussionsupporting

confidence: 79%

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

Mulder

Aguado²,

Keimpema³

et al. 2008

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

279

356

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“…It was shown that CB1 receptor activity is necessary for the upregulation of neurogenesis and proliferation after excitotoxic stress [220]. In good agreement with these findings, genetic deletion of CB1 receptors leads to defective neurogenesis [221]. The consequence of this effect on the learning phenotype is unclear but it is unrelated to the early loss of cognitive abilities in this strain [197].…”

Section: (D) Regulation Of Glial Activitysupporting

confidence: 70%

The endocannabinoid system in normal and pathological brain ageing

Bilkei-Gorzó

2012

Phil. Trans. R. Soc. B

121

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The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, proageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brainderived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing.

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“…While GFAP/Gp120 Tg mice exhibited impaired neurogenesis and a decrease in cells with proliferating cell nuclear antigen (PCNA), administration of AM1241 to GFAP/Gp120 Tg mice resulted in enhanced in vivo neurogenesis in the hippocampus. An endogenous metabolite of docosahexaenoic acid and its derivatives (N-docosahexaenoylethanolamine and N-docosahexaenoylethanolamide) were shown to stimulate neurite growth, synaptogenesis, glutamatergic synaptic activity and neuronal differentiation of neural cells in hippocampal neurons [50,51]. Results of subsequent studies also confirmed the influence of the endocannabinoid system on neural progenitor cells (NCPs) regulation.…”

Section: Neurogenesis and Cannabinoidssupporting

confidence: 61%

Endocannabinoid system and cannabinoids in neurogenesis – new opportunities for neurological treatment? Reports from experimental studies.

Drab¹,

Haratym-Maj²,

Zagaja³

et al. 2017

J Pre Clin Clin Res.

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Neurogenesis is one of the most important phenomenona affecting human life. This process consists of proliferation, migration and differentiation of neuroblasts and synaptic integrations of newborn neurons. Proliferation of new cells continues into old age, also in humans, although the most extensive process of cell formation occurs during the prenatal period. It is possible to distinguish two regions in the brain responsible for neurogenesis: the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ). Hippocampal neurogenesis is very sensitive to various physiological and pathological stimuli. The functional integration of the newly-born dentate granule cells into hippocampal circuitry, and their ability to mediate long-term potentiation in DG, has led to the hypothesis that neurogenesis in the adult brain may play a key role in learning and memory function, as well as cognitive dysfunction in some diseases. Brain disorders, such as neurodegenerative diseases or traumatic brain injuries, significantly affect migration, proliferation and differentiation of neural cells. In searching for the best neurological drugs protecting neuronal cells, stimulating neurogenesis, while also developing no side-effects, endocannabinoids proved to be a strong group of substances having many beneficial properties. Therefore, the latest data is reviewed of the various experimental studies concerning the analysis of the most commonly studied cannabinoids and their impact on neurogenesis.

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Defective Adult Neurogenesis in CB1 Cannabinoid Receptor Knockout Mice

Cited by 252 publications

References 43 publications

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

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

The endocannabinoid system in normal and pathological brain ageing

Endocannabinoid system and cannabinoids in neurogenesis – new opportunities for neurological treatment? Reports from experimental studies.

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