In vivo endocannabinoid dynamics at the timescale of physiological and pathological neural activity

Farrell, Jordan S.; Colangeli, Roberto; Dong, Ao; George, Antis G.; Addo-Osafo, Kwaku; Kingsley, Philip J.; Morena, Maria; Wolff, Marshal D.; Dudok, Barna; He, Kaikai; Patrick, Toni A.; Sharkey, Keith A.; Patel, Sachin; Marnett, Lawrence J.; Hill, Matthew N.; Li, Yulong; Teskey, G. Campbell; Soltész, Iván

doi:10.1016/j.neuron.2021.05.026

Cited by 42 publications

(47 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, L-type Ca 2+ channel blockers are effective in abolishing postictal hypoxia whether administered prior to the seizure or immediately following their termination [83]. These findings are among the first to show that seizure-induced functional deficits reflect impaired blood perfusion during the postictal period and highlight the potential utility of L-type Ca 2+ channels, as well as the COX-2 signaling pathways as molecular targets for drug discovery and/or drug repurposing efforts [85].…”

Section: Neurovascular Coupling In Seizuresmentioning

confidence: 80%

Neurovascular Coupling in Seizures

Teskey

Tran

2021

Neuroglia

Self Cite

View full text Add to dashboard Cite

Neurovascular coupling is a key control mechanism in cerebral blood flow (CBF) regulation. Importantly, this process was demonstrated to be affected in several neurological disorders, including epilepsy. Neurovascular coupling (NVC) is the basis for functional brain imaging, such as PET, SPECT, fMRI, and fNIRS, to assess and map neuronal activity, thus understanding NVC is critical to properly interpret functional imaging signals. However, hemodynamics, as assessed by these functional imaging techniques, continue to be used as a surrogate to map seizure activity; studies of NVC and cerebral blood flow control during and following seizures are rare. Recent studies have provided conflicting results, with some studies showing focal increases in CBF at the onset of a seizure while others show decreases. In this brief review article, we provide an overview of the current knowledge state of neurovascular coupling and discuss seizure-related alterations in neurovascular coupling and CBF control.

show abstract

Section: Neurovascular Coupling In Seizuresmentioning

confidence: 80%

Neurovascular Coupling in Seizures

Teskey

Tran

2021

Neuroglia

Self Cite

View full text Add to dashboard Cite

show abstract

“…To measure 2-AG release in the SN in vivo , we stereotactically injected the AAVs carrying a genetically encoded eCB sensor named eCB2.0 29,30 in the dorsal striatum ( Fig. 3E, F ).…”

Section: Resultsmentioning

confidence: 99%

“…DAGLA protein is enriched in dendritic spines 21,22 ; however, the subcellular localization of DAGLB protein remains unclear due to a lack of specific antibodies for tissue staining. Considering that the CB1-positive axon fibers form close contact with the dendrites and cell bodies of ventral nigral DANs 12 and 2-AG acts within a short range (∼10 μm) from the release sites 29,30 , it is reasonable to assume that DAGLB is distributed in the soma and dendrites of DANs for local 2-AG production and release. The strenuous rotarod training paradigm appears to promote the somatodendritic release of 2-AG from the nigral DANs more pronouncedly during the early phase of motor learning.…”

Section: Discussionmentioning

confidence: 99%

Deficiency in endocannabinoid synthase DAGLB contributes to Parkinson’s disease and dopaminergic neuron dysfunction

Liu

Yang

Dong

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

2-arachidonoyl-glycerol (2-AG), the most abundant endocannabinoid (eCB) in the brain, regulates diverse neural functions. However, whether 2-AG deficiency contributes to Parkinson's disease (PD) and nigral dopaminergic neurons (DANs) dysfunction is unclear. Diacylglycerol lipase A and B (DAGLA and DAGLB) mediate the biosynthesis of 2-AG. Using homozygosity mapping and whole-exome sequencing, we linked multiple homozygous loss-of-function mutations in DAGLB to a form of early-onset autosomal recessive PD. We then used RNA sequencing and fiber photometry with genetically encoded eCB sensors to demonstrate that DAGLB is the main 2-AG synthase in nigral DANs. Genetic knockdown of Daglb by CRISPR/Cas9 in mouse nigral DANs substantially reduces 2-AG levels in the substantia nigra (SN). The SN 2-AG levels are markedly correlated with the vigor of movement during the acquisition of motor skills, while Daglb-deficiency impairs motor learning. Conversely, pharmacological enhancement of 2-AG levels increases nigral DAN activity and dopamine release and improves motor learning. Together, we demonstrate that DAGLB-deficiency contributes to the etiopathogenesis of PD, reveal the importance of DAGLB-mediated 2-AG biosynthesis in nigral DANs in regulating neural activity and dopamine release, and provide preclinical evidence for the beneficial effects of 2-AG augmentation in PD treatment.

show abstract

“…Furthermore, the GRABeCB2.0 sensor binds endocannabinoids such as 2-AG and AEA, but does not couple to the downstream G proteins and has no observable effects on cellular physiology ( Dong et al, 2021 ). These features enable us to use this sensor to observe physiological endocannabinoid release in cultures, brain slices and the brain of live animals during behavioral experiments ( Dong et al, 2021 ; Farrell et al, 2021 ). For example, spontaneous running induces an increase in the signal for 2-AG release in the pyramidal cell layer of the hippocampal CA1 in mice ( Farrell et al, 2021 ).…”

Section: Endocannabinoidsmentioning

confidence: 99%

“…These features enable us to use this sensor to observe physiological endocannabinoid release in cultures, brain slices and the brain of live animals during behavioral experiments ( Dong et al, 2021 ; Farrell et al, 2021 ). For example, spontaneous running induces an increase in the signal for 2-AG release in the pyramidal cell layer of the hippocampal CA1 in mice ( Farrell et al, 2021 ). Moreover, the increase was correlated with the increase in cellular activity observed using the calcium sensor jRGECO1a.…”

Section: Endocannabinoidsmentioning

confidence: 99%

Endocannabinoid-Mediated Control of Neural Circuit Excitability and Epileptic Seizures

Sugaya

Kano

2022

Front. Neural Circuits

View full text Add to dashboard Cite

Research on endocannabinoid signaling has greatly advanced our understanding of how the excitability of neural circuits is controlled in health and disease. In general, endocannabinoid signaling at excitatory synapses suppresses excitability by inhibiting glutamate release, while that at inhibitory synapses promotes excitability by inhibiting GABA release, although there are some exceptions in genetically epileptic animal models. In the epileptic brain, the physiological distributions of endocannabinoid signaling molecules are disrupted during epileptogenesis, contributing to the occurrence of spontaneous seizures. However, it is still unknown how endocannabinoid signaling changes during seizures and how the redistribution of endocannabinoid signaling molecules proceeds during epileptogenesis. Recent development of cannabinoid sensors has enabled us to investigate endocannabinoid signaling in much greater spatial and temporal details than before. Application of cannabinoid sensors to epilepsy research has elucidated activity-dependent changes in endocannabinoid signaling during seizures. Furthermore, recent endocannabinoid research has paved the way for the clinical use of cannabidiol for the treatment of refractory epilepsy, such as Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Cannabidiol significantly reduces seizures and is considered to have comparable tolerability to conventional antiepileptic drugs. In this article, we introduce recent advances in research on the roles of endocannabinoid signaling in epileptic seizures and discuss future directions.

show abstract

In vivo endocannabinoid dynamics at the timescale of physiological and pathological neural activity

Cited by 42 publications

References 25 publications

Neurovascular Coupling in Seizures

Neurovascular Coupling in Seizures

Deficiency in endocannabinoid synthase DAGLB contributes to Parkinson’s disease and dopaminergic neuron dysfunction

Endocannabinoid-Mediated Control of Neural Circuit Excitability and Epileptic Seizures

Contact Info

Product

Resources

About