Signal flow in the NMDA receptor–dependent phosphoproteome regulates postsynaptic plasticity for aversive learning

Structural plasticity of dendritic spines in the nucleus accumbens (NAc) is crucial for learning from aversive experiences. Activation of NMDA receptors (NMDARs) stimulates Ca<sup>2+</sup>-dependent signaling that leads to changes in the actin cytoskeleton, mediated by the Rho family of GTPases, resulting in postsynaptic remodeling essential for learning. We investigated how phosphorylation events downstream of NMDAR activation drive the changes in synaptic morphology that underlie aversive learning. Large-scale phosphoproteomic analyses of protein kinase targets in mouse striatal/accumbal slices revealed that NMDAR activation resulted in the phosphorylation of 194 proteins, including RhoA regulators such as ARHGEF2 and ARHGAP21. Phosphorylation of ARHGEF2 by the Ca<sup>2+</sup>-dependent protein kinase CaMKII enhanced its RhoGEF activity, thereby activating RhoA and its downstream effector Rho-associated kinase (ROCK/Rho-kinase). Further phosphoproteomic analysis identified 221 ROCK targets, including the postsynaptic scaffolding protein SHANK3, which is crucial for its interaction with NMDARs and other postsynaptic scaffolding proteins. ROCK-mediated phosphorylation of SHANK3 in the NAc was essential for spine growth and aversive learning. These findings demonstrate that NMDAR activation initiates a phosphorylation cascade crucial for learning and memory.

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Journal
Science Signaling
Published
2024-09-10
DOI
https://doi.org/10.1126/scisignal.ado9852
Citations
6
Primary Topic
Neuroscience and Neuropharmacology Research
Type
article
Field-Weighted Citation Impact
1.61
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article

Signal flow in the NMDA receptor–dependent phosphoproteome regulates postsynaptic plasticity for aversive learning

Masahiro Kawatani, Kozo Kaibuchi, Mutsuki Amano, You-Hsin Lin et al.
6 citations
Science Signaling
Neuroscience and Neuropharmacology Research
1.61
article

Signal flow in the NMDA receptor–dependent phosphoproteome regulates postsynaptic plasticity for aversive learning

Masahiro Kawatani, Kozo Kaibuchi, Mutsuki Amano, You-Hsin Lin, Daisuke Tsuboi, Yasuhiro Funahashi, Shinichi Nakamuta, Md Hasanuzzaman Shohag, Takayuki Yamashita, Tomoki Nishioka, Minhua Wu, Kenji Sakimura, Mengya Wu, Akira Yoshimi, Keisuke Kuroda, Md. Omar Faruk, Taku Nagai, Rijwan Uddin Ahammad, Huanhuan Wang, Xinjian Zhang, Li Xu, Kiyofumi Yamada, Emran Hossen, Shigeo Uchino, Yukihiko Noda
article en
6 citations

Abstract

Structural plasticity of dendritic spines in the nucleus accumbens (NAc) is crucial for learning from aversive experiences. Activation of NMDA receptors (NMDARs) stimulates Ca<sup>2+</sup>-dependent signaling that leads to changes in the actin cytoskeleton, mediated by the Rho family of GTPases, resulting in postsynaptic remodeling essential for learning. We investigated how phosphorylation events downstream of NMDAR activation drive the changes in synaptic morphology that underlie aversive learning. Large-scale phosphoproteomic analyses of protein kinase targets in mouse striatal/accumbal slices revealed that NMDAR activation resulted in the phosphorylation of 194 proteins, including RhoA regulators such as ARHGEF2 and ARHGAP21. Phosphorylation of ARHGEF2 by the Ca<sup>2+</sup>-dependent protein kinase CaMKII enhanced its RhoGEF activity, thereby activating RhoA and its downstream effector Rho-associated kinase (ROCK/Rho-kinase). Further phosphoproteomic analysis identified 221 ROCK targets, including the postsynaptic scaffolding protein SHANK3, which is crucial for its interaction with NMDARs and other postsynaptic scaffolding proteins. ROCK-mediated phosphorylation of SHANK3 in the NAc was essential for spine growth and aversive learning. These findings demonstrate that NMDAR activation initiates a phosphorylation cascade crucial for learning and memory.

Science SignalingVol. 17(853)
Fujita Health University (JP), Utsunomiya University (JP), Nagoya University Hospital (JP), Nagoya University (JP), Niigata University (JP), Teikyo University (JP), Southern States University (US), Meijo University (JP)
Openalex Percentile: Top 17%
Neuroscience and Neuropharmacology Research
1.61
DOISourceOpenAlex
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