Unraveling endocannabinoid signaling disruption in a preclinical model of neurodevelopmental disorders
Nephi Stella
Nephi Stella
Published September 2, 2025
Citation Information: J Clin Invest. 2025;135(17):e196707. https://doi.org/10.1172/JCI196707.
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Commentary

Unraveling endocannabinoid signaling disruption in a preclinical model of neurodevelopmental disorders

Abstract

The search for transformative medicines has continuously uncovered select diseases associated with the disruption of the endocannabinoid (eCB) signaling system in the brain and emphasized the therapeutic value of small molecules that rescue this signaling system. In this issue of JCI, Wang et al. report that genetic disruption of PPP2R1A function in mouse forebrain, a preclinical mouse model of neurodevelopmental disorders, resulted in pronounced impairment of eCB signaling. Notably, small-molecule inhibitors of eCB inactivation rescued both eCB signaling and cognitive dysfunction in this model, providing a solid foundation to move such transformative therapeutic approaches based on targeting eCB signaling toward human clinical trial testing.

Authors

Nephi Stella

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Figure 1

Impaired eCB signaling underlies synaptic alterations and spatial learning and memory deficits in Ppp2r1a-deficient mice.

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Impaired eCB signaling underlies synaptic alterations and spatial learni...
The eCB 2-AG is produced by postsynaptic neurons and normally acts on presynaptic CB1R to reduce glutamate release. Wang et al. leveraged the recently developed GRABeCB2.0 sensor to detect the subcellular dynamics of 2-AG signaling via the fluorescence induced when extrasynaptic 2-AG binds to the sensor. (A) Heterozygotic genetic deletion of Ppp2r1a in mouse brain led to impaired 2-AG/CB1R signaling alongside increased excitatory synaptic strength and ensuing impairments in spatial learning in this model. (B) The sorted RNA-Seq data identified the upregulation of mRNA encoding for the presynaptic enzyme MAGL, which regulates tonic levels of 2-AG, in the Ppp2r1a-deficient mouse forebrain. Wang et al. showed that pharmacological inhibition of MAGL rescued 2-AG signaling, leading to normalization of excitatory synaptic strength and spatial learning and memory.