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AAV GRAB sensors
The complex function in the brain is inseparable from the efficient and specific information exchange and integration between neurons. Neurotransmitters (such as acetylcholine, dopamine, and neuropeptides ) are a key biological small molecules and participate in the process of information transmission mediated by chemical synapses between neurons, and are involved in a variety of physiological functions including development, information perception, motor regulation and higher-level cognitive behavior in the brain, and the devastating diseases will be caused once the malfunction of neurotransmitter, such as Parkinson's disease, Alzheimer's disease, addiction and epilepsy. Therefore, the study of neurotransmitter is essential for understanding the mechanism of brain function.
Sun, F., et al. Cell 2018
Li Yulong’s lab from Peking University develops cutting edge research tools, namely advanced imaging probes (GRAB sensors), including published dopamine (2018, Cell), acetylcholine (2018, Nature Biotechnology), and norepinephrine (2019, Neuron), to untangle the complexity of nervous system in space and in time, and helps to understand the changes of neurotransmitters in specific diseases, thus providing a new path for future precision medicine and new drug development.
 
The GRAB sensors could be expressed in specific cell-types and are able to detect dynamics of extracellular neurotransmitters in cultured cell, brain slice and living animal (e.g. fly, zebrafish, mice, rat, monkey etc.) by transfection, virus injection or construction of transgenic animals. For the aspect of instruments, GRAB sensors could perform well in epifluorescence microscopy, confocal microscopy, 2P microscopy and fiber photometry recording.

Features of published sensors
Name Neurotransmitters Version Color Backbones(From human) Affinity Signal Response Amplitude Dynamics Downstream Signal Coupling Reference
Ach2.0 Acetylcholine First generation Green M3 receptor EC50~1uM ΔF/F0~90% τon~200ms,
τoff~800ms
Weak [1]
Ach3.0 Acetylcholine Second generation Green M3 receptor EC50~2uM ΔF/F0~280% τon~112ms,
τoff~580ms
Hardly [2]
Ach3.0-mut Acetylcholine Control of Second generation Green M3 receptor EC50~0uM
(W200A mutation)
ΔF/F0~1.8% / / [2]
DA1m Dopamine First generation Green D2 receptor EC50~130nM
Medium affinity
ΔF/F0~90% τon~60ms,
τoff~700ms
Hardly [3]
DA1h Dopamine First generation Green D2 receptor EC50~10nM
High affinity
ΔF/F0~90% τon~140ms,
τoff~2500ms
Hardly [3]
DAmut(1st) Dopamine Control of First generation Green D2 receptor EC50~0uM
C118A and S193N mutation
No effect / / [3]
DA2m(DA4.4) Dopamine Second generation Green D2 receptor EC50~90nM
Medium affinity
ΔF/F0~340% τon~40ms,
τoff~1300ms
Little [4]
DA2h(DA4.3) Dopamine Second generation Green D2 receptor EC50~7nM
High affinity
ΔF/F0~280% τon~50ms,
τoff~7300ms
Little [4]
DAmut(2nd) Dopamine Control of Second generation Green D2 receptor EC50~0uM
C1183.36A and S1935.42N mutation
No effect / / [4]
rDA1m (rDA2.5m) Dopamine / Red D2 receptor EC50~95nM
Medium affinity
ΔF/F0~150% τon~80ms,
τoff~770ms
Little [4]
rDA1h (rDA2.5h) Dopamine / Red D2 receptor EC50~4nM
Medium affinity
ΔF/F0~100% τon~60ms,
τoff~2150ms
Little [4]
rDAmut (rDA2.5mut) Dopamine Control Red D2 receptor EC50~0uM
C1183.36A and S1935.42N mutation
No effect / / [4]
NE1m(NE2.1) Norepinephrine / Green a2A receptor EC50~930nM
Medium affinity
ΔF/F0~230% τon ~70ms,
τoff~ 750ms
Uncoupled [5]
NE1h(NE2.2) Norepinephrine / Green a2A receptor EC50~83nM
High affinity
ΔF/F0~130% τon ~30ms,
τoff~ 2000ms
Uncoupled [5]
NEmut Norepinephrine / Green a2A receptor EC50~0uM
S5.46A mutation
No effect / / [5]
Ado1.0 Adenosine Control Green a2A receptor EC50~60nM ΔF/F0~130% τon~36ms,
τoff~1890ms
Hardly [6]
Ado1.0mut Adenosine   Green a2A receptor EC50~0uM
F168A mutation
No effect / / [6]
5-HT1.0 Serotonin Control Green 5-HT2C receptor EC50~22nM ΔF/F0~250% τon~0.2s,
τoff~3.1s
Uncoupled [7]
5-HTmut Serotonin / Green 5-HT2C receptor EC50~0uM
D1343.32Q mutation
No effect / / [7]
 
The Yulong Li Lab has deposited sensor plasmids at BrainVTA for distribution to the research community, and all GRAB sensors (including the lastest ACh, DA, NE, 5-HT, Ado, ATP, VIP, CCK and eCB sensors) with AAV are available.If you require any further information, please click the Neurotransmitter sensors or contact sales@brainvta.com.
Note: please contact the Li Lab (yulonglilab2018@gmail.com) before ordering unpublished sensors.

FAQ:
1. What do the abbreviation h/m/l/mut mean, and what about the number?
h/m/l is the abbreviation of high/median/low, which indicates the sensors' apparent affinity towards transmitter. Most of the GRAB sensors have transmitter-insensitive mutant for comparison with GRAB sensors to check signal specificity. The number represents the version of sensor, the higher version, the better performance.

2. How to use GRAB sensors?
GRAB sensors are genetically encoded sensors for neurotransmitters, similar to other genetically encoded sensors (e.g. GCaMP). They could be expressed in specific cell-types and are able to detect dynamics of extracellular neurotransmitters in cultured cell, brain slice and living animal (e.g. fly, zebrafish, mice, rat, monkey etc.). For the aspect of instruments, GRAB sensors could perform well in epifluorescence microscopy, confocal microscopy, 2P microscopy and fiber photometry recording.

3. Can the sensors be expressed in vivo for a long-term period?
Yes. We can record good signals from GRAB sensor after expression for 3 to 6 months in mice brain by AAV infection.

4. Can GRAB sensors detect excitability of neurons?
No. The change of fluorescent intensity only indicates the dynamics of corresponding neurotransmitter, which has no direct correlation with excitability of neurons. Other approach is needed for detection of neuron excitability.
 
Reference
1. Jing, M., et al. (2018). "A genetically encoded fluorescent acetylcholine indicator for in vitro and in vivo studies." Nat Biotechnol 36(8): 726-737.
2. Jing, M., et al. (2020). "An optimized acetylcholine sensor for monitoring in vivo cholinergic activity." Nat Methods 17(11): 1139-1146.
3. Sun, F., et al. (2018). "A Genetically Encoded Fluorescent Sensor Enables Rapid and Specific Detection of Dopamine in Flies, Fish, and Mice." Cell 174(2): 481-496 e419.
4. Sun, F., et al. (2020). "Next-generation GRAB sensors for monitoring dopaminergic activity in vivo." Nat Methods 17(11): 1156-1166.
5. Feng, J., et al. (2019). "A Genetically Encoded Fluorescent Sensor for Rapid and Specific In Vivo Detection of Norepinephrine." Neuron 102(4): 745-761 e748.
6. Peng, W., et al. (2020). "Regulation of sleep homeostasis mediator adenosine by basal forebrain glutamatergic neurons." Science 369(6508).
7. Wan, J., et al. (2021). "A genetically encoded sensor for measuring serotonin dynamics." Nat Neurosci.





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