Imaging and Genetic Tools for the Investigation of the Endocannabinoid System in the CNS
Abstract
:1. The Endocannabinoid System (ECS)
1.1. Cannabinoid Receptors
Intracellular Organelle-Associated CB1R
1.2. Endocannabinoids: Endogenous CBR Ligands
1.3. The Enzymes
2. Imaging the ECS
2.1. The Most Used Tools in ECS Imaging
2.2. CB1R Imaging
Technique | Advantages | Disadvantages | References |
---|---|---|---|
Radioligands | |||
[18F] radioactive ligands coupled with PET 1 and autoradiography |
|
| [54,55,56] |
[11C] radioactive ligands coupled with PET 1 and autoradiography |
|
| [57,72] |
Optical microscopy | |||
Fluorescence light microscopy (immunocytochemistry and immunohistochemistry) |
|
| [61,62] |
Fluorescent probes |
|
| [47] |
FRET 2 |
|
| [48,63] |
Electron microscopy | |||
TEM 3 |
|
| [12,65,66,67,68] |
Super-resolution microscopy | |||
STORM 4 |
|
| [69,70,71] |
2.3. CB2R
Technique | Advantages | Disadvantages | References |
---|---|---|---|
Radioligands | |||
[18F] and [11C] radioactive ligands coupled with PET 1 and autoradiography |
|
| [74,75] |
Optical microscopy | |||
Fluorescence light microscopy (immunocytochemistry and immunohistochemistry) |
|
| [76,77] |
Fluorescent probes |
|
| [78,79,80] |
FRET 2 |
|
| [48,81] |
Electron microscopy | |||
TEM 3 |
|
| [82,83,84] |
2.4. Imaging the Endocannabinoids
2.5. Imaging eCB Metabolic Enzymes
Technique | Advantages | Disadvantages | References |
---|---|---|---|
Radioligands | |||
[18F] and [11C] radioactive ligands coupled with PET 1 and autoradiography |
|
| [90,91,92] |
Optical microscopy | |||
Fluorescence light microscopy (immunocytochemistry and immunohistochemistry) |
|
| [99,100] |
Fluorescent probes |
|
| [96,97,98] |
Electron microscopy | |||
TEM 2 |
|
| [102,103] |
3. The Best Genetic Models to Investigate the ECS
3.1. C. elegans as a Model
3.1.1. The Endocannabinoid System in C. elegans
3.1.2. Genetic Approaches
3.2. Zebrafish as a Model for ECS Studies
3.2.1. The Endocannabinoid System in Zebrafish
3.2.2. Genetic Approaches for ECS Manipulation in Zebrafish
3.2.3. CB1R Models in Zebrafish
Target Sequence of cnr1 | Annotations | References |
---|---|---|
5′-CGGACTTTGAGGCCGGGAACAGCAT-3′ | Translation-blocking | [127] |
5′-CTAGAGGAAACCTGTCGGAGGAAAT-3′ | Translation-blocking | [127,139] |
5′-GAATGACTACGCTTACATGGACATC-3′ | Target the 5′UTR | [132] |
5′-AACAGCATGGTCAGAGATGCTCTAG-3′ | Translation-blocking | [132] |
5′-GTGCTATCAACAACATACCTTTGTG-3 | Splice-blocking | [133,145] |
5′-CTTTGAGGCCGGGAACAGCATGGTC-3 | Splice-blocking | [145] |
5′-GAACAGCATGGTCAGAGATGCTCTA-3′ | Translation-blocking | [136] |
5′-TCAGAACCATCACCTCCG-3′ 5′-TCAGAACCATCACCTCCG-3′ | Target first exon | [146] |
3.2.4. CB2R Models in Zebrafish
3.3. Mouse Models
3.3.1. CB1R Mouse Models
Genetic Background | General Phenotype | Outcome | References |
---|---|---|---|
Spontaneous Behaviour | |||
CD1 (Ledent group) | Significantly higher anxiety-like and aggressive behaviour, increased affected maternal care | Increased locomotor activity and time spent exploring unknown objects; decreased spontaneous alteration in the Y-maze | [154] |
Increased anxiety-like behaviour | [170] | ||
Increased AMT 1 and FAAH 2 activity with age; mild-anxiety-like behaviour of young mice compared to old mice | [152] | ||
Increased anxiety-like effect under unfamiliar environment | [171] | ||
Increased anxiety-like behaviour in the elevated plus maze | [155] | ||
High level of anxiety with different types of anxiogenic stimuli under unfamiliar conditions | [153] | ||
No significant alterations in anxiety-like behaviours under total darkness conditions | [172] | ||
Delayed pup retrieval and fewer ultrasonic vocalizations | [173] | ||
Higher levels of offensive aggression when housed in group | [174] | ||
C57BL/6J (Zimmer group) | Hypoactive, increased mortality, reduced anxiety | Reduced locomotion and rearing in open-field test | [158] |
Increased mortality rate and ring catalepsy; reduced locomotor activity and hypoalgesia | [142] | ||
Less burying behaviour and fewer contacts with the probe in the shock-probe burying test | [175] | ||
C57BL/6N (Lutz group) | Aversiveness-dependent anxiogenic-like phenotype and acute fear response, enhanced contextual fear memory, increased wakefulness | Reduced spontaneous caloric intake and decreased body weight | [176] (p. 200) |
Sustained fear response only after application of an intense foot shock (0.7 mA and 1.5 mA) | [166] | ||
Lack of within-session extinction during permanent tones and repeated tone presentations at variable intervals | [177] | ||
Decreased distance covered in the active and in the inactive phases of the cycle on wheel running activity | [178] | ||
Disrupted classical fear conditioning pattern by favouring passive responses | [179] | ||
Increased fear expression abolished by repeated social stress | [180] | ||
Enhanced freezing levels in the conditioning context and increased contextual fear after high-intensity conditioning foot shock (1.5 mA) | [181] | ||
Increased cortical excitability and reduced NREM 3 sleep and NREM 3 bout duration | [182] | ||
More time awake and less time in NREM 3 and REM 4; slower EEG 5 theta rhythm during REM 4 and habituated more rapidly to the arousing effect of the cage-switch test | [183] | ||
Hypoactivity, impaired eyeblink, and normal cerebellum-dependent locomotor coordination and learning | [162] | ||
In vivo response to drugs | |||
CD1 (Ledent group) | Insensitive to THC and CBD, sensitive to nicotine, ethanol, cocaine, and amphetamine | Insensitive to THC-induced antinociceptive properties, reduced horizontal activity, and decreased rectal temperature | [154] |
Sensitive to SR141716A anxiety reduction | [155] | ||
Enhanced nicotine-induced antinociceptive effects and absent rewarding effects | [184] | ||
Decreased ethanol self-administration with increased sensitivity to its acute intoxicating effects | [185] | ||
Decreased ethanol-induced conditional place preference and increased striatal dopamine D2 receptors | [186] | ||
Reduced ethanol self-administration and ethanol-conditioned place preference | [187] | ||
Decreased locomotor responses to cocaine and D-amphetamine | [188] | ||
Insensitive to CBD-induced anxiolytic actions | [157] | ||
C57BL/6J (Zimmer group) | Insensitive to cannabinoid drugs and sensitive to cocaine and ethanol; absence of ethanol withdrawal | Insensitive to THC-induced ring catalepsy, hypomobility, and hypothermia | [142] |
Insensitive to THC-, WIN 55,212-2-, and methanandamide; disruption in the working memory task | [159] | ||
No enhancement of growth rates or survival after CP55,940, WIN55,212-2, or 2-AG administration | [189] | ||
Reduced voluntary alcohol consumption and absent alcohol–dopamine release in the nucleus accumbens | [190] | ||
Absence of ethanol withdrawal symptoms and of foot-shock stress-induced alcohol preference | [191] | ||
Reduced ethanol preference and insensitive to SR141716A-induced reduction in ethanol preference in young mice | [192] | ||
Insensitive to THC- and O-1812-induced decrease in lever press; sensitive to methanandamide-, ethanol-, and morphine-induced decrease in lever press | [193] | ||
Abolished CP55,940-induced antinociceptive effects and associated motor deficits | [194] | ||
Absent THC-induced expression of ΔFosB in the striatum | [195] | ||
Sensitive to the locomotor-stimulant effects of RTI-371 (a cocaine analogue) | [196] | ||
Absence of ethanol-induced activation of caspase 3 and of reduction in DNMT1 6, DNMT3A 6, and DNA methylation | [197] | ||
C57BL/6N (Lutz group) | Sensitive to KA 7 and insensitive to THC, reduced sensitivity to rewarding properties. | KA 7 injection induced more severe seizures and decreased survival rate | [164] |
Decreased sucrose consumption under operant conditions or a two-bottle free choice; decreased sensitivity to rewarding properties of sucrose | [198] | ||
Insensitive to cannabinoid-induced neurosphere generation | [199] | ||
Insensitive to THC-induced tetrad effects | [200] | ||
Insensitive to THC-induced increase in pregnenolone in the nucleus accumbens | [201] | ||
Learning and aging | |||
CD1 (Ledent group) | Defective neurogenesis, increased aggressiveness and conditioned responses | Increased aggressive response, higher sensitivity to exhibit depressive-like responses, and increased conditioned responses in the active avoidance model | [202] |
Enhanced retention of the habituation task | [203] | ||
Reduction in bromodeoxyuridine-labelled cells in dentate gyrus and subventricular zone | [204] | ||
C57BL/6J (Zimmer group) | Impaired extinction, age-related memory decline, accelerated decline in cognitive function | Increased perseverance in a reversal task | [159] |
Similar or better performance on 6–7-week-old mice and worst performance on 3–5-month-old mice in several learning and memory paradigms | [205] | ||
Impaired extinction process in the Morris water maze using a spaced extinction procedure | [206] | ||
Enhanced habituation (non-associative learning) displayed with decreased number of ambulations | [207] | ||
Impaired delay eyeblink conditioning performance | [208] | ||
Deficits in a sensory-selective reinforcer devaluation task | [209] | ||
Improved performance in the Morris water maze at 6 weeks old and inferior performance at 12 months old | [161] | ||
Superior learning ability in the eight-arm radial maze at 2 months old and impaired performance at 12 months old | [160] | ||
C57BL/6N (Lutz group) | Impaired extinction of aversive memories and of fear, impaired habituation | Strongly impaired short-term and long-term extinction in auditory fear-conditioning tests, with unaffected memory acquisition and consolidation | [163] |
Normal extinction of the stimulus–response association in an appetitively motivated learning task | [165] | ||
Severely impaired in extinction and in habituation of the fear response to a tone | [166] |
3.3.2. Conditional CB1R Deletions
Strain Designation | Cell-Type-Specific Deletion | Outcome | References |
---|---|---|---|
CB1RCaMKIIa-Cre | Forebrain principal neurons | More severe KA 1-induced seizures and decreased survival | [36,164] (p. 200) |
Sustained fear response only after intense electric shock | [214] | ||
CB1RDlx5/6-Cre | GABAergic neurons | No change in KA 1-induced seizures | [213] |
Impaired target selection of cortical GABAergic interneurons | [217] | ||
CB1R is localized on presynaptic boutons of about 30% in alBNST 2 | [218] | ||
Neuronal loss and increased neuroinflammation in the hippocampus | [161] | ||
Abolished anxiogenic effect under a high-dose treatment of CB1R agonist (CP-55940) | [219] | ||
Conserved impairment of SWM 3 and in vivo LTD 4 of synaptic strength at CA3-CA1 synapses caused by an acute exposure to exogenous cannabinoids | [36] | ||
Abolished CB1R agonist (CP-55940)-induced increase in HVS 5 | [220] | ||
Insensitive to quinolinic-acid-induced neurotoxicity | [136] | ||
Insensitive to THC-induced memory impairment in novel object recognition | [221,222] | ||
CB1RNex-Cre | Glutamatergic cortical neurons | Aberrant fasciculation and pathfinding in both corticothalamic and thalamocortical axons | [223] |
Absence of neuronal loss and increased neuroinflammation in the hippocampus | [161] | ||
Unbalanced neurogenic fate determination | [224] | ||
Conserved impairment of SWM 3 and in vivo LTD 4 of synaptic strength at CA3-CA1 synapses caused by an acute exposure to exogenous cannabinoids | [36] | ||
Reduced decrease in fast ECoG 6 oscillations and stronger cannabinoid-induced increase in HVS 5 | [220] | ||
Sensitive to excitotoxic damage induced with quinolinic acid administration | [136] | ||
CB1RD1-Cre | Neurons expressing dopamine D1 receptors | Insensitive to THC-induced catalepsy | [200] |
Abolished CB1R agonist (CP-55940)-induced increase in HVS 5 | [220] | ||
CB1Rsns-Cre | Dorsal root ganglia neurons | Reduced LTD 4 at dorsal horn nociceptor synapses | [215] |
CB1RGabra6-Cre | Cerebellar granule cells | Abolition of short-term plasticity at parallel fibre synapses and lack of LTD | [225] |
Activated cerebellar microglia and increased cerebellar neuroinflammation | [226] | ||
Normal eyeblink conditioning and normal cerebellum-dependent locomotor coordination and learning | [162] | ||
CB1RGfap-CreERT2 | Astrocytes | Abolished impairment of SWM 3 and in vivo LTD 4 of synaptic strength at CA3-CA1 synapses | [36] |
Impaired object recognition memory and decreased LTP 7 at CA3-CA1 synapses | [37] | ||
CB1RSim1-Cre | Neurons expressing Sim 1 8 (hypothalamus and mediobasal amygdala) | Increased locomotor activity in open field, unconditioned anxiety, and cued fear expression under basal conditions | [216] |
CB1RTph2-CreERT2 | Central serotoninergic neurons | Anxiety and decreased cued fear expression | [180] |
3.3.3. MtCB1R Models
Genetic Background | General Phenotype | Outcome | References |
---|---|---|---|
C57BL/6N DN22-CB1R 1-KI | Specific impairment of mtCB1R and of cannabinoid effects on mitochondrial dynamics but no influence on CB1R general functions | mtCB1R decreases synaptic activity and induces catalepsy | [27] |
mtCB1R mediates corticosterone-induced memory impairment | [26] | ||
Astroglial mtCB1R reduces mitochondrial respiration with complex I destabilization | [25] | ||
C57BL/6N GFAP 2-CB1R-KO | Specific impairment of mtCB1R and of cannabinoid effects on mitochondrial dynamics but no influence on CB1R general functions | Astroglial mtCB1R reduces mitochondrial respiration with complex I destabilization | [25] |
3.3.4. CB2R Mouse Models
Genetic Background | General Phenotype | Outcome | References |
---|---|---|---|
Neurodegeneration, neuroinflammation, and synaptic plasticity | |||
C57BL/6J CB2R −/− Buk | Increased neurodegenerative symptoms, impaired neuroprogenitor proliferation, impairment of neuroprotective proteins | Protective role for CB2R in experimental autoimmune encephalitis | [231] |
Augmented multiple sclerosis severity (similar to pharmacological inhibition) | [232] | ||
Link between CB2R and the onset of Huntington’s disease | [233] | ||
Amelioration of Alzheimer’s disease-like pathology | [234] | ||
CB2R-mediated modulation of cocaine action | [235] | ||
Incomplete activation of microglia in neuroinflammation | [236] | ||
C57BL/6J CB2R −/− Del | Higher corticosterone levels after stress in the prefrontal cortex (PFC), higher hippocampal and PFC neuron excitability | CB2R activation mediates PFC neuron excitability | [237] |
Chronic CB2R activation in the hippocampus increases excitatory synaptic transmission | [238] | ||
C57BL/6J CB2R−/− Lop | Increased neurodegenerative symptoms, agonist treatment can reduce inflammatory phenotypes | Development of a new reporter mouse line and involvement in neuroinflammation | [230] |
Tau protein levels increase CB2R during early stages of neurodegeneration | [239] | ||
CB2R depletion reduces inflammatory pain behaviours and markers of neuroinflammation | [240] | ||
Nociception and neuropathic pain | |||
C57BL/6J CB2R −/− Buk | Normal cannabidiol analgesia, altered opioid receptor expression | Neuropathic pain is mediated by glycinergic neurons | [241] |
CB2R mediates analgesic effects in neuroinflammation, neuropathies | [242] | ||
C57BL/6J CB2R −/− Del | Reduced morphine analgesia, no effect of AM1710 on paclitaxel-induced allodynia | Chronic CB2R activation reverses paclitaxel-induced neuropathy | [243] |
Activation of CB2R alone or with CB1R decreases neuropathic-pain-related behaviour in mice | [244] | ||
Possible mechanism to suppress chemotherapy-induced neuropathy | [245] | ||
Behaviour | |||
C57BL/6J CB2R −/− Buk | Impaired memory consolidation, schizophrenic behavioural phenotypes | Induces schizophrenia-related behaviours such as locomotor activities, anxiety- and depressive-like behaviours, and cognitive deficits | [246] |
CB2R role in cognitive processes, particularly in short- and long-term memory | [247] | ||
CB2R is expressed in red nucleus glutamate receptors and modulates motor behaviour | [248] | ||
C57BL/6J CB2R −/− Del | Impairment of contextual long-term memory, enhancement of spatial working memory, decrease in neuropathic pain-related behaviour in mice | CB2R plays different roles in regulating memory with different outcomes depending on the brain areas | [249] |
3.3.5. CB1R × B2R Genetic Models
3.3.6. Genetic Mouse Models of eCB Metabolic Enzymes
3.3.7. 2-AG Biosynthesis and Catabolism
Genetic Background | General Phenotype | Outcome | References |
---|---|---|---|
C57BL/6N DAGLα−/− Tanimura | Improved learning habituation, increased seizure risk | Reduced 2-AG; abolished DSE 1 | [258] |
Abolished DSE 1 at MC-GC 2 | [266] | ||
Improved odour habituation; enhanced LTP 3 | [267] | ||
Unchanged CB1R-G protein signalling, compensatory 2-AG synthesis | [268] | ||
Localization: Mostly post-synaptic | [269] | ||
C57BL/6 DAGLα−/− Gao | Impaired spatial learning and memory | 80% 2-AG reduction; impaired synaptic plasticity; reduced neurogenesis | [259] |
Main contribution to brain 2-AG and eicosanoid synthesis | [261] | ||
Decreased 2-AG; decreased LTD 4; impaired learning and memory | [270] | ||
2-AG signals preferentially to neurons in short-distance synaptic regulation | [34] | ||
Unspecified DAGLα-KOLex; gene trap | No overt phenotype reported | Reduced 2-AG; small AEA reduction; abolished DSI 5 | [260] |
C57BL/6N DAGLα−/− | Sex-specific pro-anxiety and anhedonia | CB1R-dependent anxiety; anhedonia | [262] |
C57BL/6J DAGLα−/− | Anxiety and fear similar to CB1R-KO | Increased fear, anxiety; loss of maternal care | [263] |
Unspecified DAGLαfl/fl | Increased susceptibility to post-traumatic stress | Decreased stress resilience (AAV 6 directed in basolateral amygdala) | [264] |
129SvEv × C57BL/6 DAGLβ-GTLex; gene trap | Reduced macrophage response, reduced hepatic eCB | 50% 2-AG reduction; impaired synaptic plasticity; reduced neurogenesis | [259] |
Negligible contribution to brain 2-AG and eicosanoid synthesis | [261] | ||
C57BL/6N DAGLβ−/− | No overt phenotype reported | Normal 2-AG; DSE 1 normal | [258] |
Unspecified DAGLβ-GTLex; gene trap | No overt phenotype reported | Normal 2-AG; small AEA reduction | [260] |
Unspecified DAGLα-GTLex × DAGLβ-GTLex | Greater 2-AG reduction than single KO | Greater 2-AG reduction than single KO | [260] |
Unspecified RNAi DAGLα/β | No overt phenotype reported | Equal DAGLα/β contribution to autaptic CA1/3 neuron 2-AG levels | [265] |
129SvEv × C57BL/6J MAGL-GTLex; gene trap | Enhanced learning, analgesic CB1R agonist tolerance | CB1R desensitization; altered synaptic plasticity | [271] |
Altered synaptic plasticity; enhanced LTD 4; enhanced learning | [272] | ||
CB1R desensitization; prolonged climbing fibre DSE 1 | [273] | ||
C57BL6/Ntac MAGL−/− | CB1R agonist tolerance, analgesic tolerance | CB1R desensitization; lack of characteristic CB1R effects | [274] |
C57BL/6 MAGL−/− Taschler | CB1R agonist tolerance, anxious and obsessive-compulsive behaviour | Increased 2-AG; CB1R agonist tolerance; impaired lipolysis | [275] |
CB1R desensitization in all regions; compensatory serine hydrolase activity | [276] | ||
CB1R desensitization and disturbed E/I ratio in limbic pathways; stress-like cannabimimetic behaviour | [277] | ||
C57BL/6N MAGL−/− Uchigashima | CB1R agonist tolerance, analgesic tolerance | Low MAGL expression in MC-GC 2 spines, mostly astrocytic | [266] |
Unspecified GluN2C:MAGL−/− | No overt phenotype reported | Prolonged 2-AG signalling, but less than total KO | [278] |
C57BL/6 MAGLlox/lox | Floxed animals with no overt phenotype. Specific effect for neuronal, astrocytic cKO. No effect in microglial cKO | Neuron and astrocyte MAGL coordinate CB1R signalling termination; neuron-2-AG/astrocyte-AA 7 shuttle. | [40] |
Neuron and astrocyte MAGL both contribute to terminate synaptic eCB signalling; differential effects in different fibre types/synaptic events | [38] | ||
Neuron and astrocyte MAGL both contribute to terminate synaptic eCB signalling; effect restricted to molecular layer | [39] | ||
Increased 2-AG; decreased AA 7 and PGE/F 8 (global KO) | [85] | ||
C57BL/6N MAGLflox/flox | Decreased microglial inflammatory response | Cell-type-specific change in gene expression, astrocytic 2-AG promotes immune vigilance in microglia | [279] |
C57BL6/J CaMKII:MAGLTg | Lean and hypothermic response to hypercaloric diet | MAGL overexpression; decreased 2-AG correlated to weight loss and hyperthermia | [280] |
C57BL6/J GFAP:MAGL−/− | Decreased microglial inflammatory response | Reduced neuroinflammation independent of CB1R and total 2-AG | [281] |
3.3.8. AEA Synthesis and Catabolism
Genetic Background | General Phenotype | Outcome | References |
---|---|---|---|
129SvJ × C57BL/6 NAPE-PLD−/− Cravatt | Healthy and viable through lifespan, no significant AEA decrease | Decreased saturated and monounsaturated NAEs, no change in AEA | [284] |
Subcellular localization: Preferentially in dendrites | [269] | ||
Lower AEA; higher DHA/DHEA; significant effect of dietary fatty acids | [291] | ||
AEA signals preferentially to astrocytes; astrocytic Ca2+ mobilization and synaptic plasticity | [34] | ||
C57BL/6 × 129SV NAPE-PLD−/− Palmiter | Healthy and viable throughout, significant AEA decrease | Decreased AEA/NAE levels, ABDH4 as main compensatory synthesizer | [285] |
Region- and lipid-specific NAE/MAG alteration; decreased NAE | [255] | ||
C57BL/6 NAPE-PLD−/− Tsuboi | Healthy and viable throughout, significant AEA decrease | Decreased AEA/NAE levels, compensatory synthesis pathways involved | [252] |
Decreased AEA/NAE levels, compensatory synthesis pathways involved | [292] | ||
C57BL/6 GDE1−/− | Healthy and viable through lifespan, no significant AEA decrease | Unchanged NAE/AEA levels | [287] |
C57BL/6 GDE1−/− × NAPE-PLD−/− | Healthy and viable through lifespan, no significant AEA decrease | Unchanged NAE/AEA levels | [287] |
129SvEv × C57BL/6 ABHD4-KO | Healthy and viable through lifespan, no significant AEA decrease | No significant AEA decrease; decreased GP/pNAPE | [288] |
129SvJ × C57BL/6 FAAH−/− | Significant AEA increase, pain and inflammation resistance, super sensitivity to AEA treatment | Increased AEA; CB1R-dependent sensitivity to AEA | [293] |
Increased GABAergic inhibition of synaptic transmission | [294] | ||
Decreased AEA transport; diffusion- and transporter-mediated systems | [295] | ||
CB1R-mediated hypoalgesia | [296] | ||
Increased neurogenesis (AEA-dependent) | [297] | ||
Decreased post-mortem AEA/EA accumulation | [298] | ||
Increased astrogliogenesis (CB1R-dependent) | [199] | ||
Alternative phosphocholine-NAE metabolic route | [299] | ||
Accumulation of N-acyltaurines, which act as TRPV1/4 agonists | [300] | ||
Resistance to acetaminophen analgesia, TRPV1-dependant | [301] | ||
NAE/NAT accumulation in CNS (primarily long-chain saturated forms) | [302] | ||
Altered iLTD | [303] | ||
Increased TRPV1 activity; modulated glutamate release | [304] | ||
Hyperalgesia to certain types of pain; analgesia to others | [305] | ||
Increased AEA and phosphamides; no changes in PGE/F effect | [85] | ||
129SvJ × C57BL/6 FAAH−/− × Eno2:FAAH | Wild-type pain responses, resistance to inflammation | Increased AEA in CNS; no change in periphery | [306] |
4. Concluding Remarks
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cannabinoid Receptors |
CB1R, CB2R, GPR55, GPR18, GPR119, TRPs, PPARs |
Endocannabinoids |
2-AG, AEA, PEA, DHEA, EPEA, OEA, NADA, 2-AGE, O-AEA |
Enzymes |
Biosynthesis: DAGLα/β, NAPE-PLD, ABHD4, GDE1, PLC, PLA, PTN22, SHIP1 Degradation: FAAH, MAGL, NAAA, ABHD6/12, COX-2, CYP2-4, 12/15-LO Transport process: EMT, FABP5/7, SCP2/x |
Technique | Advantages | Disadvantages | ECS Components |
---|---|---|---|
Radioligands | |||
Radioactive ligands coupled with PET 1, autoradiography, radioligand binding assays |
|
| CB1R, CB2R, enzymes |
Optical microscopy | |||
Fluorescence light microscopy (Immunocytochemistry and immunohistochemistry) |
|
| CB1R, CB2R, enzymes |
FRET 2 |
|
| CB1R, CB2R |
Electron microscopy | |||
TEM 3 |
|
| CB1R, CB2R, enzymes |
Super-resolution microscopy | |||
STORM 4 |
|
| CB1R |
Mass spectrometry imaging (MSI) | |||
MALDI 5 |
|
| eCB |
Bioengineered sensors | |||
GRABeCB2.0 6 |
|
| eCB |
Technique | Advantages | Disadvantages | References |
---|---|---|---|
Mass spectrometry imaging | |||
MALDI 1 |
|
| [88] |
Bioengineered sensors | |||
GRABeCB2.0 2 |
|
| [89] |
Zebrafish Stage | Genetic Approach | Technique | Outcome | References |
---|---|---|---|---|
Juvenile | cnr1 KO (total) | Morpholino | Defects in axonal growth and fasciculation | [128] |
Juvenile | cnr1 and cnr2 KO (total) | Morpholino | CART-3 1 expression and yolk sac size | [132] |
Juvenile | cnr1 KO (total) | Morpholino | Decreased locomotor activity and suppression of feeding behaviour | [133] |
Juvenile Adult | cnr1 overexpression (hepatic) | Tetoff transgenic system | Loss of lipid accumulation | [131] |
Juvenile | cnr2 KO (total) | CoDA ZFN 2 | Regulation of leukocyte migration | [134] |
Juvenile | cnr2 KO (total) | Morpholino | Reduced runx1 expression and decreased HSCs 3 | [135] |
Juvenile | cnr1 KO (total) | Morpholino | Reduced microRNA dre-let-7d levels | [136] |
Juvenile Adult | cnr1 and cnr2 KO | Morpholino TALEN 4 | Smaller livers with fewer hepatocytes, reduced liver-specific gene expression and proliferation | [134] |
Juvenile Adult | cnrip1a and cnrip1b (total) | CRISPR 5/Cas9 | No phenotype is detected, fish lacking these genes both maternally and zygotically are viable. | [137] |
Juvenile | cnr2 KO (total) | CRISPR/Cas9 | Mutants show an anxiety-like behaviour: they show an altered PDR 6 and decreased CO 7 | [138] |
Juvenile | cnr1 KO (total) | Morpholino | Reduced number of GnRH3 neurons, fibre misrouting, and altered fasciculation | [139] |
Disorder | Model | Outcome | References |
---|---|---|---|
ALS 1 | FAAH−/− × SOD1-Tg | Attenuated symptoms; no increase in lifespan (CB1R-independent) | [308] |
Diet-induced obesity | ABHD6−/− | No changes in total MAG content | [283] |
ABHD6−/− | Increased 2-AG/CB1R signalling drives weight gain and hypothermia | [33] | |
CaMKII:MAGLTg | MAGL overexpression; decreased 2-AG correlated to weight loss and hyperthermia | [280] | |
EAE 2 model of MS 3 | FAAH−/− | Enhanced recovery/remission from EAE 2 | [309] |
Kainate-induced epilepsy | FAAH−/− | Increased seizure susceptibility | [310] |
DAGLα−/− Tanimura | Decreased CB1R DSI 4; increased seizure incidence | [311] | |
Pain and neuroinflammation (LPS 5 induced) | GFAP:MAGL−/− | Reduced neuroinflammation independent of CB1R and total 2-AG | [281] |
DAGLα−/− Gao | No effect on pain sensitization | [312] | |
DAGLβ-GTLex; gene trap | Reduced pain sensitization | [312] | |
Parkinson’s disease | MAGL-GTLex; gene trap | Reduced neuroinflammation; neuroprotection; prostaglandin and not ECS related | [32] |
DAGLβ-GTLex; gene trap | DAGLβ is main 2-AG synthesizer in SN 6; contributes to disease progression in mice and rare-variant patients | [313] | |
Stress + anxiety | DAGLαfl/fl | Decreased stress resilience (BLA 7 AAV 8-directed) | [264] |
DAGLαfl/fl | Reduced stress behaviour | [314] | |
DAGLα−/− | Increased anxiety; anhedonia | [262] | |
DAGLα−/− | Increased fear, anxiety; loss of maternal care | [263] | |
FAAH−/− | Reduced anxiety | [315] | |
Substance use disorders | FAAH−/− | Increased ethanol consumption and preference | [316] |
FAAH−/− | Increased alcohol sensitivity and withdrawal | [317] | |
FAAH−/− | Reduced morphine withdrawal | [318] | |
TBI 9 | DAGLβ-GTLex; gene trap | Sex-dependant increase in survival; attenuated sphingolipid TBI 9 markers | [319] |
GFAP:MAGLflox/flox | Reduced neuroinflammation, neuroprotection, CB1R-PPARγ-dependent | [320] |
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Kouchaeknejad, A.; Van Der Walt, G.; De Donato, M.H.; Puighermanal, E. Imaging and Genetic Tools for the Investigation of the Endocannabinoid System in the CNS. Int. J. Mol. Sci. 2023, 24, 15829. https://doi.org/10.3390/ijms242115829
Kouchaeknejad A, Van Der Walt G, De Donato MH, Puighermanal E. Imaging and Genetic Tools for the Investigation of the Endocannabinoid System in the CNS. International Journal of Molecular Sciences. 2023; 24(21):15829. https://doi.org/10.3390/ijms242115829
Chicago/Turabian StyleKouchaeknejad, Armin, Gunter Van Der Walt, Maria Helena De Donato, and Emma Puighermanal. 2023. "Imaging and Genetic Tools for the Investigation of the Endocannabinoid System in the CNS" International Journal of Molecular Sciences 24, no. 21: 15829. https://doi.org/10.3390/ijms242115829