Ppp2r1a haploinsufficiency increases excitatory synaptic transmission and decreases spatial learning by impairing endocannabinoid signaling
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
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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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 10

Reduced 2-AG release mediates increased presynaptic Pr and learning deficits in NEX-het-cKO mice.

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Reduced 2-AG release mediates increased presynaptic Pr and learning defi...
(A) Diagram showing synthesis and degradation pathways of 2-AG and AEA, together with related inhibitors. (B–D) The 2-AG was the principal eCB evoked by electrical stimulation. Representative traces (B and C) and summary (D) showing that DO34 (1 μM) abolished GRABeCB2.0 signals (n = 5 mice). (E–L) The 2-AG release was significantly reduced in NEX-het-cKO mice (Control, n = 5 mice; NEX-het-cKO, n = 6 mice). (E) Schematic of GRAB2-AG1.2 activation by 2-AG but not by AEA. (F) Schematic of AAV-Syn-DIO-2-AG1.2 injection in the mPFC of NEX-Cre (Control) or NEX-het-cKO mice. Heatmap (G) and average traces (H) of GRAB2-AG1.2 signals evoked by increasing stimulation intensities in control. (I and J) Same as in G and H but for NEX-het-cKO mice. (K) Input/output plot of GRAB2-AG1.2 signals versus stimulation intensity. (L) Slope of input/output relationship. (M and N) MAGL inhibitor JZL184 rescued the reduced EPSC PPRs in NEX-het-cKO mice (Control, n = 18 neurons; NEX-het-cKO, n = 21 neurons). (O and P) FAAH inhibitor URB597 did not affect the reduced EPSC PPRs in NEX-het-cKO mice (Control, n = 17 neurons; NEX-het-cKO, n = 19 neurons). (Q–T) JZL184 ameliorated spatial learning and memory deficits in NEX-het-cKO mice (Control, n = 13 mice; NEX-het-cKO, n = 10 mice; NEX-het-cKO + JZL184, n = 10 mice). Green asterisks, control versus NEX-het-cKO; red asterisks, NEX-het-cKO versus NEX-het-cKO + JZL184. (Q) Number of primary errors. (R) Primary latency. (S) Primary path length. (T) Percentage of strategy used. Statistical comparisons were performed using 2-tailed unpaired Student’s t test (L), 2-tailed paired Student’s t test (D), 1-way ANOVA followed by 2-tailed Bonferroni’s t test (Serial and Mixed; T), Kruskal-Wallis test followed by Dunn’s test (Direct; T), and 2-way ANOVA followed by Bonferroni’s post hoc test (K, N, P, and Q–S). Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.