Ppp2r1a haploinsufficiency increases excitatory synaptic transmission and decreases spatial learning by impairing endocannabinoid signaling
Yirong Wang, … , Bo Xiong, Man Jiang
Yirong Wang, … , Bo Xiong, Man Jiang
Published August 21, 2025
Citation Information: J Clin Invest. 2025;135(17):e185602. https://doi.org/10.1172/JCI185602.
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Research Article Development Neuroscience

Ppp2r1a haploinsufficiency increases excitatory synaptic transmission and decreases spatial learning by impairing endocannabinoid signaling

Abstract

Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase in the brain. Mutations in PPP2R1A, encoding the scaffolding subunit, are linked to intellectual disability, although the underlying mechanisms remain unclear. This study examined mice with heterozygous deletion of Ppp2r1a in forebrain excitatory neurons (NEX-het-conditional knockout [NEX-het-cKO]). These mice exhibited impaired spatial learning and memory, resembling Ppp2r1a-associated intellectual disability. Ppp2r1a haploinsufficiency also led to increased excitatory synaptic strength and reduced inhibitory synapse numbers on pyramidal neurons. The increased excitatory synaptic transmission was attributed to increased presynaptic release probability, likely due to reduced levels of 2-arachidonoyl glycerol (2-AG). This reduction in 2-AG was associated with increased transcription of monoacylglycerol lipase (MAGL), driven by destabilization of enhancer of zeste homolog 2 (EZH2) in NEX-het-cKO mice. Importantly, the MAGL inhibitor JZL184 effectively restored both synaptic and learning deficits. Our findings uncover an unexpected role of PPP2R1A in regulating endocannabinoid signaling, providing fresh molecular and synaptic insights into the mechanisms underlying intellectual disability.

Authors

Yirong Wang, Weicheng Duan, Hua Li, Zhiwei Tang, Ruyi Cai, Shangxuan Cai, Guanghao Deng, Liangpei Chen, Hongyan Luo, Liping Chen, Yulong Li, Jian-Zhi Wang, Bo Xiong, Man Jiang

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Figure 5

Ppp2r1a haploinsufficiency alters the transcription of eCB enzymes.

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Ppp2r1a haploinsufficiency alters the transcription of eCB enzymes. (A)...
(A) Workflow of sorted RNA-Seq experiments. (B) Volcano plot showing transcriptomic changes in NEX+ neurons of NEX-het-cKO mice. Pink dots represent upregulated DEGs with log2 (fold change) > 1 and P.adj < 0.05, and blue dots represent downregulated DEGs with log2 (fold change) < –1 and P.adj < 0.05 (green, eCB-associated enzymes; yellow, synaptic molecules). (C) Schematic of key enzymes involved in biosynthesis and degradation of 2-AG and AEA. VGCC, voltage-gated calcium channel; DAG, diacylglycerol, PGH2-G, prostaglandin H2-glycerol ester; PGH2-EA, Prostaglandin H2-ethanolamide; AA, arachidonic acid; EA, ethanolamine; NAT, N-acetyltransferase. (D) Bar graph showing mRNA expression levels (transcripts per million) of enzymes involved in eCB synthesis and degradation, alongside CB1R, based on sorted RNA-Seq of NEX+ neurons from control (n = 3) and NEX-het-cKO (n = 4) mice. Abhd6: α/β hydrolase domain containing 6; Cnr1, cannabinoid receptor 1. Statistical comparisons were performed using the negative binomial distribution model of DESeq2 (B) (also see Supplemental Table 1) and 2-tailed unpaired Student’s t test (D). All data are presented as mean ± SEM. *P < 0.05.