Endocannabinoid System and Adult Neurogenesis: a Focused Review

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Endocannabinoid system and adult neurogenesis: a focused review

1,2 2 2,3

Sergio Oddi , Lucia Scipioni and Mauro Maccarrone

The endocannabinoid system (eCB) is a ubiquitous lipid multipotent progenitor cells — were identiﬁed within

signaling system composed of at least two receptors, their speciﬁc niches of the central nervous system, in particular

endogenous ligands, and the enzymes responsible for their the subventricular zone (SVZ), along the lateral ventricular

synthesis and degradation. Within the brain, the eCB system is wall, and in the subgranular zone (SGZ) of dentate gyrus of

highly expressed in the hippocampus and controls basic the hippocampus [2]. At present, conclusive evidence

biological processes, including neuronal proliferation, that also human brain can generate new neurons post-

migration and differentiation, which are intimately linked with developmentally and throughout adulthood is lacking

embryonal neurogenesis. Accumulated preclinical evidence [3]. In this context, two studies have recently reported

has indicated that eCBs play a major role also in regulating conﬂicting results on the actual presence of adult neuro-

adult neurogenesis. Increased cannabinoid receptor activity, genesis in humans, highlighting the methodological pitfalls

either by increased eCB content or by pharmacological inherent to human brain research [4,5].

blockade of their degradation, produces neurogenic effects

alongside rescue of phenotypes in animal models of different Although the biological role of adult neurogenesis is far

psychiatric and neurological disorders. Therefore, in the light of frombeing fullyelucidated,thereisnowsolidevidencethat

the higher therapeutic potential of adult neurogenesis adult-born neurons from SVZ and SGZ are functionally

compared to the embryonic one, here we sought to summarize incorporated into the olfactory bulb and hippocampus,

the most recent evidence pointing towards a neurogenic role respectively, where they can participate in the control of

for eCBs in the adult brain, both under normal and pathological olfactory inputs and memory processing throughout the life

conditions. of the organism [2]. From a pharmacological point of view,

the possibility of generating new functional neurons for the

Addresses

replacement of those lost during neurodegenerative

Faculty of Veterinary Medicine, University of Teramo, Via Balzarini 1,

disorders or age-related cognitive decline, could be the

64100 Teramo, Italy

2 basis for the development of future potential therapies for

European Center for Brain Research (CERC)/Santa Lucia Foundation,

Via del Fosso di Fiorano 64, 00143 Rome, Italy many neurological and psychiatric conditions [6,7].

Department of Medicine, Campus Bio-Medico University of Rome,

Via A´ lvaro del Portillo 21, 00128 Rome, Italy

The research on the mechanistic aspects of adult neuro-

genesis has revealed that generation of functional neurons

Corresponding authors: Oddi, Sergio ([email protected]),

is a very complex and coordinated process, that involves

Sergio, Mauro ([email protected])

survival, proliferation, differentiation and migration of

NSCs, as well as synaptic integration of the newborn

Current Opinion in Pharmacology 2020, 50:25–32

neurons into the existing circuitry [2]. Thus, a number of

This review comes from a themed issue on Neurosciences: intrinsic and extrinsic factors have been identiﬁed that play

neurogenesis

essential roles in various aspects of adult neurogenesis.

Edited by Annalisa Buffo and Stefania Ceruti Among them endocannabinoids (eCBs), a specialized

class of bioactive lipids, have emerged as key regulators

of neurogenesis, eliciting cell signaling cascades such as

mitogen-activated protein kinases (MAPKs) and mamma-

https://doi.org/10.1016/j.coph.2019.11.002 lian target of rapamycin (mTOR), that are primarily

In the last few years, the regulatory role of the eCB

signaling in embryonic and adult neurogenesis has been

extensively investigated in rodents, and recently

discussed in comprehensive reviews [9,10]. Here, in

Introduction the light of the higher therapeutic potential of adult

Adult neurogenesis is the process by which functional neurogenesis compared to the embryonic one, we sought

neurons are continuously generated in the nervous system, to summarize the most recent evidence pointing towards

after embryonal development and throughout the animal a neurogenic role for eCBs in the adult brain, both under

life [1]. Such a process has been well documented in normal and pathological conditions. To this aim, we give

rodents, where neural stem cells (NSCs) — self-renewing, also a brief overview of the key components of the eCB

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26 Neurosciences: neurogenesis

system, as well as of its main signaling pathways that can [9,10]. In NSCs and their descendant neurons, the

impact post-developmental neurogenesis. Then, we expression of CB1 and CB2 receptors changes during

describe preclinical research conducted over the last ﬁve the different stages of neuronal differentiation, with

years supporting the notion that targeted manipulation of CB1 increasing along neural maturation and CB2

eCB signaling may represent a valuable strategy for being more abundant in less committed cells [8 ].

developing new adult neurogenesis-based treatments to Moreover, NSCs possess all the enzymes involved

improve brain health (Table 1). in eCB metabolism and produce AEA and 2-AG in

response to increased intracellular Ca concentration

The eCB system [8 ]. Furthermore, in vitro studies demonstrated that

The eCB system is a pro-homeostatic modulator of basic the eCB tone contributes to basal and stimulus-induced

biological processes, including cell choice between survival neuronal proliferation, primarily via CB1 and CB2 [8 ].

and death, immune response, neuronal maturation, neuro-

transmission, energy homeostasis and reproduction [11 ]. In NSCs, CB1 and CB2 receptors display an extremely

Widely distributed throughout the body and highly expressed intricate signaling activity through which they modulate a

within the central nervous system, the eCB system comprises variety of cellular processes that include survival, prolif-

a group of phospholipid-derived neuromodulatory lipids, also eration, lineage differentiation, migration, maturation of

known as eCBs that mainly include N-arachidonoylethano- NSCs and their descendants (Figure 2). In particular,

lamine (AEA) and 2-arachidonoylglycerol (2-AG), in addition both cannabinoid receptors are coupled to heterotrimeric

to at least two G protein-coupled receptors (GPCRs), named Gi/o proteins through which they modulate multiple

type 1 (CB1) and type 2 (CB2) cannabinoid receptors; in signal transduction pathways, including (i) inhibition of

addition, the eCB system includes two main biosynthetic adenylyl cyclase and cyclic AMP-protein kinase A (PKA);

enzymes, N-acylphosphatidylethanolamine-speciﬁc phos- (ii) activation of extracellular signal-regulated kinase 1

pholipase D (NAPE-PLD) and diacylglycerol lipase (ERK1) and ERK2; (iii) activation of p38 MAPK and

(DAGL), for AEA and 2-AG respectively, and two main JUN N-terminal kinases (JNKs); and (iv) activation of

degradative enzymes, fatty acid amide hydrolase (FAAH) phosphatidylinositol 3-kinase-Akt-mTOR (PI3K/Akt/

and monoacylglycerol lipase (MAGL), for AEA and 2-AG mTOR) [8 ]. Moreover CB1, but also CB2, were shown

respectively (Figure 1). Unlike classical neurotransmitters, to regulate membrane potential of neurons and other

within neurons AEA and 2-AG are formed ‘on demand’ from excitable cells, by modulating the opening of speciﬁc

2+ +

membrane precursors, rather than being stored in synaptic Ca and K ion channels [14,15], thus further expanding

vesicles [11 ]. The mechanisms by which cells release the complexity of the signaling pathways by which both

and take up these bioactive lipids, have not been fully receptors control cellular functions.

understood yet, but it is likely to involve putative eCB

membrane transporters, intracellular carriers and/or passive Role of the eCB system in adult neurogenesis

diffusion (Figure 1). CB1-dependent effects

The evidence from the latest research conﬁrmed the pro-

CB1 receptor is the most abundant GPCR in the central neurogenic role of CB1 in the two germinal areas of adult

nervous system, and is highly expressed in brain areas rodents, both under normal and pathological conditions.

associated with emotionality, cognition and memory like The chronic stimulation of CB1 by arachidonyl-2-

brain cortex, limbic system, substantia nigra and chloroethylamide (ACEA), a highly selective CB1 agonist,

hippocampus [11 ]. Of note, CB1 is also responsible produced a robust neural proliferation in the SGZ [16,17]

for the pharmacological and psychotropic effects of and an increased neuroblast migration along the rostral

natural and synthetic cannabinoids, such as the migratory stream towards the olfactory bulb [18].

main ingredient of cannabis (Cannabis sativa) extracts, Similarly, chronic administration of 2-AG ether, another

D -tetrahydrocannabinol. Instead, CB2 receptor is selective CB1 agonist, promoted neurogenesis in mouse

mainly located in immune cells, where it exerts various olfactory epithelium [19], an effect that was blocked by

immunosuppressive actions [12], but there is growing the speciﬁc CB1 antagonist AM251 and was absent in

evidence that it is also expressed by some neurons, both CB1/CB2 double knockout mice [19].

under physiological conditions and upon acute and

chronic stress [13,14]. Notably, even though to a minor In a more pathological context, Andres-Mach et al. found

extent CB1 is also co-expressed with CB2 in glial that CB1 chronic stimulation by ACEA had a strong impact

elements, such as astrocytes and microglial cells on proliferation, migration and differentiation of newly

[11 ,12–15], thus further conﬁrming essential and born cells in the hippocampus of a mouse model of epilepsy

pleiotropic roles of eCB signaling in brain neuroimmune [16]. Interestingly, they described that administration of

physiology and pathology. valproate, an anti-epileptic drug, had no signiﬁcant impact

on neurogenesis on this model; instead, combination of

Emerging evidence has revealed the eCB system as a key valproate with ACEA markedly enhanced neurogenesis in

player in controlling NSC biology in the adult brain the SGZ [16]. In keeping with these observations, studies

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Endocannabinoid signaling in adult neurogenesis Oddi, Scipioni and Maccarrone 27

Table 1

Effects of manipulating the eCB system on adult neurogenesis

Target Model Treatment Biological activity Effect Ref.

CB1 Mouse model of ACEA, 10 mg/kg, i.p., Alone or co-treated with an anti-epileptic [16]

epilepsy (pilocarpine) 10 days drug (valproate) enhances neurogenesis

in the SGZ

Rat model of ethanol- ACEA, 3 mg/kg, i.p., Reverts ethanol-induced anti-proliferative [20]

induced neurotoxicity 5 days Agonist effects on NSCs in the SGZ, but not in SVZ

Adolescent CB57/BL ACEA, 10 mg/kg, i.p., Compared to control mice, increases [30]

male mice 10 days neurogenesis in the SGZ

ACEA, 0.5 mM, 2 hour Stimulates neuroblasts migration towards

Mouse brain slice cultures, the olfactory bulb

and rostral migratory AM251, 1 M, 2 hour Antagonist/ Interferes with neuroblasts migration [18]

stream explants inverse agonist (reduce the motility and the percentage of

cells migrating towards the olfactory bulb)

Cultures of human and ACEA, 1 mM, 2 days Agonist Reduces cell death of human NSCs [21 ]

murine NSCs mediated by Gp120

ACEA, 0.1, 0.3 and 1 mM, Agonist Promotes neurogenesis in SVZ cells

24 hour

Rat SVZ and DG WIN55,212-2, 0.1, Non-selective Promotes neurogenesis in SGZ, but not in

[22 ]

neurospheres 0.3 and 1 M, 24 hour CB1/CB2 agonist SVZ stem/progenitor cells

AM251, 1 mM, 24 hour Antagonist/ Reverts the neurogenic effects of ACEA in

inverse agonist SVZ cells

2-AG ether, 1, 5 and Agonist Promotes neurogenesis in the olfactory

10 mM, i.n., 2 days epithelium in a dose-dependent manner

WIN55, 212-2, 10 mM, Non-selective Promotes neurogenesis in the olfactory

Swiss Webster and i.n., 2 days CB1/CB2 agonist epithelium

C57BL/6 mice AM251, 10 M, i.n., Antagonist/ Decreases the neurogenesis in the olfactory

2 days inverse agonist epithelium compared to vehicle-treated [19]

Swiss Webster mice; reverses the

neurogenic effects of WIN55,212-2

CB1/CB2 double Show no change in neurogenic levels in

knock-out mice response to any cannabinoid

pharmacological manipulation

CB2 Mouse model of Parkinson’s AM1241, 0.75 Agonist Dose-dependently increases survival of [25 ]

disease (MPTP mice) 12 mg/kg, i.p., 12 days neurotoxin-damaged neurons in the

substantia nigra

Mouse model of HIV- AM1241, 10 mg/kg, Agonist Prevents deﬁcits in neurogenesis in SGZ

associated encephalitis i.p., 20 days, analyzed at and reduces neuroinﬂammation

9 months of age

AM1241, 100 nM, 7–21 Agonist Inhibits Gp120-mediated neurotoxicity and

[21]

days apoptosis of NSCs and increased their

Cultures of human and

survival and differentiation

murine NSCs

AM630, 1 mM, Antagonist Reverts the effects of AM1241 in mouse

7–21 days NSCs treated with Gp120

CB2 knock-out mice and Compared to wildtype genotype, CB2 [23]

wildtype littermates deﬁciency does not inﬂuence basal adult

neurogenesis in SGZ

Mouse model of Alzheimer’s MDA7 Agonist Restores Sox2 expression and increases [26]

disease (APP/PS1) neurogenesis in hippocampal DG

JWH133, 1.5 mg/kg, Agonist Does not affect neurogenesis in vivo, but

i.p., 7, 14, 28 days increases the migration of NPCs in vitro

SR144528, 5 mg/kg, Antagonist/ Decreases the migration of neuroblasts

Mouse model of stroke

i.p., 7, 14, 28 days inverse agonist towards the boundary of the infarct region

(middle cerebral artery [27]

CB2 knock-out mice Compared to wild-type mice, display lower

occlusion)

number of new neurons (NeuN+/BrdU

+ cells) in peri-infarct cortex 28 days after

stroke

HU-308, 1 mM, 24 hour Agonist Promotes SVZ neuronal differentiation; in

co-treatment with ACEA, results in DG cell

proliferation

Rat SVZ and DG

AM630 Antagonist/ Blocks the HU-308-mediated SVZ neuronal [22 ]

neurospheres

inverse agonist differentiation; reverts the neurogenic

effects of CB1/CB2 co-activation in the DG

cells

Rat model of ethanol- JWH133, 0.2 mg/kg, Agonist Counteracts the anti-neurogenic effects of [20]

induced neurotoxicity i.p., 5 days ethanol in the SVZ and SGZ

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28 Neurosciences: neurogenesis

Table 1 (Continued )

Target Model Treatment Biological activity Effect Ref.

Metabolic Cultures of human NSCs URB597, 100 nM, Inhibitor of FAAH Increases differentiation of human NSCs [21 ]

enzymes 2 weeks

Rat model of ethanol- URB597, 0.3 mg/kg, Does not revert the toxic effects of alcohol [20]

induced neurotoxicity i.p., 5 days on neurogenesis

Rats URB597, 0.3 mg/kg, Acute treatment increases neurogenesis in [30]

i.p., 5 days SVZ, but not in SGZ. Chronic treatment

Inhibitor of FAAH

reduces neurogenesis in SGZ and lowers

the expression of CB1 gene

URB597, 100 mM, i.n.,

Swiss Webster and C57BL/6 2 days Co-administered with JZL184 increases

[19]

mice JZL184, 10 M, i.n., neurogenesis in olfactory epithelium

2 days

Mouse model of chronic JZL184, 8 mg/kg, i.p., Inhibitor of MAGL Prevents the chronic stress-induced [31 ]

unpredictable stress- 21 days impairment of neurogenesis in the SGZ and

induced depression ameliorates the depressive-like behaviors

conducted on a rat model of alcohol intoxication demon- co-activation of CB1 and CB2 by WIN 55,212-2, a synthetic

strated that ACEA reversed impairment of neurogenesis CB1/CB2 agonist, exerted a mitogenic effect in SGZ, but not

induced by ethanol in the SGZ, but not in SVZ [20]. in SVZ cells, indicating the presence ofa context-dependent

interplay between these two cannabinoid receptors [22 ].

In vitro, ACEA inhibited HIV-1/Gp120-mediated Taken together, these results conﬁrm the multifaceted role

apoptosis, and enhanced the survival of human NSCs of eCB signaling in neurogenesis, and suggest that some

[21 ], while in primary cultures of rat neurospheres it conﬂicting results could be due, at least in part, to the

promoted proliferation of SVZ-derived NSCs [22 ]. By crosstalk between CB1 and CB2 receptors.

contrast, ACEA alone was not sufﬁcient to stimulate

proliferation of SGZ-derived NSCs, an effect that was CB2-dependent effects

reached only uponco-administered with HU-308, aselective Recent studies suggest a more complex role in adult

CB2 agonist. Notably, in the same experimental paradigm neurogenesis for CB2 than for CB1. In particular,

Figure 1

AEA 2-AG

CB1/CB2 CB1/CB2 NAPE DAGs DAGL NAPE-PLD AEA 2-AG

2+ Ca 2+ Ca FAAH External or internal MAGL stimuli External or internal stimuli

Ethanolamine Glycerol Arachidonic acid

Current Opinion in Pharmacology

Schematic representation of the main elements of the eCB system within the cell. See text for details. 2-AG, 2-arachidonoylglycerol; AEA, N-

arachidonoylethanolamine; CB1/CB2, type 1 and type 2 cannabinoid receptors; DAGs, diacylglycerols; DAGL, diacylglycerol lipase; EMT, purported

“eCB membrane transporter”; FAAH, fatty acid amide hydrolase; MAGL, monoacylglycerol lipase; NAPE, N-acyl-phosphatidylethanolamine; NAPE-

PLD, N-acyl-phosphatidylethanolamine-specific phospholipase D.

Current Opinion in Pharmacology 2020, 50:25–32 www.sciencedirect.com

Endocannabinoid signaling in adult neurogenesis Oddi, Scipioni and Maccarrone 29

Mensching et al. have recently found that genetic ablation apoptosis and promoted proliferation and differentiation

of CB2 in four-month-old healthy mice did not signiﬁcantly of human NSCs.

alter SGZ neurogenesis compared to wild-type animals

[23]. These ﬁndings are at variance with previous studies In a study performed in a mouse model of Parkinson’s

showing reduced basal levels of cell proliferation in the disease, Shi et al. found that AM1241 dose-dependently

SGZ of CB2 knockout mice at embryonic day 17.5, and at increased survival of neurons damaged by the neurotoxin

two-months of age [24]. Although this discrepancy could 1-methyl-4-phenylpyridinium, along with normalizing

be due to the different age of the animals, it is also possible the levels of dopamine and serotonin and stimulating

that inadults CB2 might be more physiologically relevantin neurogenesis in the substantia nigra [25 ]. These

coping with brain injury than in maintaining basal CB2-dependent effects appeared to involve activation

neurogenesis. Indeed, in the last few years it has been of PI3K/Akt/MEK pathway, and to be mediated via

clearly documented that CB2 agonism promotes neurogen- enhanced expression of Parkin/PINK1, two proteins that

esis in different models of neuropathological conditions, function in mitochondrial quality control [25 ].

primarily by normalizing key-processes known to compro-

mise neuronal homeostasis and survival, like apoptosis, Moreover, long-term administration of a selective CB2 ago-

oxidative stress and inﬂammation (Figure 2). nist, MDA7, in a mouse model of Alzheimer’s disease was

found to enhance neurogenesis in the hippocampus along

Speciﬁcally, ina mousemodelofHIV-1-associated enceph- with (i) promoting Ab plaque clearance, (ii) suppressing

alitis, where mice exhibit decreased adult neurogenesis microglial activation, (iii) strengthening hippocampal synap-

in the hippocampus, chronic treatment with AM1241, a tic plasticity, and (iv) ameliorating cognitive decline [26].

selective CB2 agonist, prevented deﬁcits in SGZ neurogen-

esis [21 ]. In the same study, Avraham et al. found that, Using a model of focal brain ischemia, Bravo-Ferrer et al.

in vitro, AM1241 inhibited HIV-1/Gp120-mediated found that, after cortical stroke, activation of CB2 by

Figure 2

FAAH inhibitors MAGL inhibitors

Neural stem cell

PROLIFERATION

Astrocyte Microglial cell CHEMOTAXIS/ MIGRATION

ANTI-APOPTOTIC DEFENCES

ANTI-OXIDANT

Astrocyte DEFENCES

IMMUNOREGULATION

AUTOPHAGY/ MITOPHAGY

Phyto- and synthetic cannabinoids

Current Opinion in Pharmacology

Impact of targeting CB1, CB2, FAAH and MAGL on adult neurogenesis. See text for details.

www.sciencedirect.com Current Opinion in Pharmacology 2020, 50:25–32

30 Neurosciences: neurogenesis

JWH133, another selective CB2 agonist, promoted co-administered with JZL184, URB597 efﬁcaciously

neuroblast migration to (and differentiation at) the infarct increased neurogenesis in olfactory epithelium of adult

site [27]; these effects were reverted by the CB2 antago- mice, suggesting a synergic activity of AEA and 2-AG in

nist SR144528. In agreement with the pro-homeostatic the control of neuronal proliferation in this tissue [19].

role of CB2, absence of this receptor in knockout mice Interestingly, the same study reported that in the presence

was associated with robust reduction of stroke-induced of both FAAH and MAGL inhibitors the number of adult-

neurogenesis in peri-infarct cortex [27]. born neural cells reached its maximum value at two days, but

it was not maintained afterwards. Indeed, these newly

The key role of CB2 in modulating adult neurogenesis has proliferated cells underwent apoptosis before 14 days after

been further conﬁrmed in a model of ethanol-induced treatment, indicating that in olfactory epithelium the eCB

neurotoxicity, where CB2 receptor activation by JWH133 system regulatesthe proliferative state of NSCs, but not their

was found to counteract the anti-neurogenic effect of differentiation into mature neurons [19]. An opposite result

alcohol-exposure in SGZ and SVZ of the adult brain of was observed in vitro on human NSCs, where inhibition of

rats [20]. FAAH by URB597 led to their differentiation [21 ].

Overall, these results strengthen the notion that CB2 As a proof-of-principle that MAGL inhibition may

signaling may primarily participate in the control of adult represent a potential strategy for the development of

neurogenesis under pathological conditions, by eliciting pro-neurogenic treatments [10], it has been found that

mechanisms able to protect newborn neurons from chronic inhibition of this enzyme by JZL184 prevented

excitotoxic, oxidative and inﬂammatory damages, as it neurogenesis impairment in SGZ, restored long-term

has been widely observed in several models of brain potentiation in the hippocampus, and attenuated

injury [13,14]. depressive-like behaviors on mice that were subjected

to the chronic unpredictable stress model of depression

eCB metabolic enzymes-dependent effects [31 ]. Zhang et al. speculated that JZL184 produced these

A pharmacological strategy to circumvent the CB1-mediated neurogenic and antidepressant-like effects by reversing

psychotropic andCB2-mediatedimmunosuppressiveeffects a defective 2-AG signaling that, in turn, could lead to

associated with cannabinoid receptor agonism is to use CB1-mediated-activation of mTOR-dependent signal

inhibitors of eCB-degrading enzymes, namely FAAH and transduction in the hippocampus [31 ,32].

MAGL, which allow to increase the levels of AEA and 2-AG,

respectively,onlyinthesites wheretheseeCBs areproduced Conclusions

and released. In the last ﬁve years, the use of URB597 In summary, adult neurogenesis is emerging as an

and JZL184, two speciﬁc inhibitors of FAAH and MAGL important player in brain homeostasis that could be

respectively,led toresults that are somewhat conﬂicting with involved in brain plasticity and repair in adulthood.

earlier data, again stressing the complexity of basal eCB tone Finding more about the regulatory mechanisms that

inregulatingneuralproliferation,differentiationandsurvival dictate NSC biology, and that can promote the process

in the adult brain. of generating new functional neurons in the adult brain,

may lead to strategies for preventive and/or therapeutic

It has been proposed that the inhibition of FAAH may be a approaches against cognitive decline, as well as against

promising strategy to promote neurogenesis as a conse- age-related brain disorders.

quence of enhanced AEA signaling [28,29]. However, recent

reports have disclosed a puzzling scenario where no effect, or Herein, we have discussed recent studies on the patho-

even anti-neurogenic effects, can be demonstrated by physiological relevance of eCB signaling both in health

inhibiting FAAH in vivo. Indeed, Rivera et al. showed that and in the context of different neuropathological condi-

chronic administration of URB597 speciﬁcally reduced tions accompanied by impaired neurogenesis, including

neurogenesis in the SGZ of adult rat brain [30], without stroke, epilepsy, alcohol intoxication, Alzheimer’s disease

reverting the anti-neurogenic effects of alcohol intake in a rat and Parkinson’s disease. A considerable body of evidence

model of ethanol-induced neurotoxicity [20]. Interestingly, now supports the intriguing possibility that the eCB

they also reported that acute administration of URB597 system is involved in the regulation of proliferation,

induced an increase of the neural proliferation in the SVZ survival and migration of NSCs and their progeny in

of the lateral ventricles in adult rats [30]. These authors the adult brain (Figure 2).

commented that this apparent discrepancy could be

explained by (i) URB597-induced downexpression of the However, the ubiquitous expression of this pro-homeostatic

hippocampal CB1 receptors, and (ii) putative participation system, along with the complexity of its signaling activity

of non-eCB signaling as a consequence of the activation of and pharmacology, makes it difﬁcult to fully characterize

additional AEA targets, such as transient receptor how its various components may contribute to control

potential vanilloid type-1 ion channels, and the nuclear genesis and functional integration of adult-born neurons

peroxisome proliferator-activated receptor a. Finally, when within the post-developmental brain. We believe that future

Current Opinion in Pharmacology 2020, 50:25–32 www.sciencedirect.com

Endocannabinoid signaling in adult neurogenesis Oddi, Scipioni and Maccarrone 31

13. Bisogno T, Oddi S, Piccoli A, Fazio D, Maccarrone M: Type-2

research on the precise role played by distinct components of

cannabinoid receptors in neurodegeneration. Pharmacol Res

the eCB system in NSC biology will contribute to improve 2016, 111:721-730.

our mechanistic understanding of adult neurogenesis, and

14. Chen D-J, Gao M, Gao F-F, Su Q-X, Wu J: Brain cannabinoid

could provide the basis for new therapeutic applications of receptor 2: expression, function and modulation. Acta

Pharmacol Sin 2017, 38:312-316.

eCB-based drugs.

15. Chevaleyre V, Takahashi KA, Castillo PE: Endocannabinoid-

mediated synaptic plasticity in the CNS. Annu Rev Neurosci

Conﬂict of interest statement 2006, 29:37-76.

Nothing declared.

16. Andres-Mach M, Zagaja M, Haratym-Maj A, Rola R, Maj M,

Haratym J, Dudra-Jastrze?bska M, Łuszczki J, Andres-Mach M,

Acknowledgements Zagaja M et al.: A long-term treatment with arachidonyl-2 -

chloroethylamide combined with valproate increases

This investigation was supported by the Ministero della Salute, under

neurogenesis in a mouse pilocarpine model of epilepsy. Int J

competitive grant EULAC Health JOINT CALL 20162017 to MM (ref:

Mol Sci 2017, 18:900.

EULACH16/T010132)

17. Andres-Mach M, Haratym-Maj A, Zagaja M, Rola R, Maj M,

Chroscïnska-Krawczyk M, Luszczki JJ: ACEA (a highly selective

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