| First Author | Yamahashi Y | Year | 2022 |
| Journal | Mol Psychiatry | Volume | 27 |
| Issue | 8 | Pages | 3479-3492 |
| PubMed ID | 35665767 | Mgi Jnum | J:350154 |
| Mgi Id | MGI:7662418 | Doi | 10.1038/s41380-022-01643-2 |
| Citation | Yamahashi Y, et al. (2022) Phosphoproteomic of the acetylcholine pathway enables discovery of the PKC-beta-PIX-Rac1-PAK cascade as a stimulatory signal for aversive learning. Mol Psychiatry 27(8):3479-3492 |
| abstractText | Acetylcholine is a neuromodulator critical for learning and memory. The cholinesterase inhibitor donepezil increases brain acetylcholine levels and improves Alzheimer's disease (AD)-associated learning disabilities. Acetylcholine activates striatal/nucleus accumbens dopamine receptor D2-expressing medium spiny neurons (D2R-MSNs), which regulate aversive learning through muscarinic receptor M1 (M1R). However, how acetylcholine stimulates learning beyond M1Rs remains unresolved. Here, we found that acetylcholine stimulated protein kinase C (PKC) in mouse striatal/nucleus accumbens. Our original kinase-oriented phosphoproteomic analysis revealed 116 PKC substrate candidates, including Rac1 activator beta-PIX. Acetylcholine induced beta-PIX phosphorylation and activation, thereby stimulating Rac1 effector p21-activated kinase (PAK). Aversive stimulus activated the M1R-PKC-PAK pathway in mouse D2R-MSNs. D2R-MSN-specific expression of PAK mutants by the Cre-Flex system regulated dendritic spine structural plasticity and aversive learning. Donepezil induced PAK activation in both accumbal D2R-MSNs and in the CA1 region of the hippocampus and enhanced D2R-MSN-mediated aversive learning. These findings demonstrate that acetylcholine stimulates M1R-PKC-beta-PIX-Rac1-PAK signaling in D2R-MSNs for aversive learning and imply the cascade's therapeutic potential for AD as aversive learning is used to preliminarily screen AD drugs. |
