PDE10A identified by cross-hemisphere visual cortex proteomics restores adult ocular dominance plasticity involving cAMP/CREB signaling

Ocular dominance plasticity (ODP) is robust during the critical period but is restricted in adulthood. The molecular programs that distinguish this permissive state and whether they can be pharmacologically engaged in adulthood remain unclear. Here, using quantitative proteomics of the left and right visual cortices from monocularly deprived (MD) juvenile mice, we identify phosphodiesterase 10 A (PDE10A) and the cAMP signaling pathway as molecular signatures of juvenile ODP.

Juvenile MD is associated with reduced PDE10A and increased phosphorylated CREB (pCREB) in the visual cortex contralateral to the deprived eye, whereas adult mice show no comparable response. In adult mice, systemic administration of the selective PDE10A inhibitor TAK-063 during MD reinstates an experience-dependent ocular dominance shift and reduces visual acuity in the deprived eye. This is accompanied by increased cortical cAMP and pPKA, an inverted-U pCREB response peaking at 0.3 mg/kg, and upregulation of plasticity-related synaptic proteins.

TAK-063 does not alter basal visual function, retinal electrophysiology, or locomotor behavior in non-deprived adults, excluding nonspecific sensory/motor confounds. These findings identify PDE10A as a candidate molecular regulator of visual cortical plasticity and support its pharmacological inhibition as a strategy to facilitate experience-dependent plasticity in the adult visual cortex. We thank the Editage team (https://www.editage.cn/) for assistance in improving the language quality of this manuscript.

This study was supported by the Joint TCM Science & Technology Projects of National Demonstration Zones for Comprehensive TCM Reform (Grant Nos. GZY-ZJ-KJ-24090 and GZY-ZJ-KJ-24089) and the National Natural Science Foundation of China (General Program, No. 82371042). These authors contributed equally: Yuanyuan Li, Zehui Zhu.

Eye Hospital and School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China Yuanyuan Li, Zehui Zhu, Jingyuan Xu, Sihan Dong, Er Mo, Qiyuan Li, Zhangliang Li, Yun-e Zhao & Pingjun Chang National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, China Eye Hospital of Wenzhou Medical University Hangzhou Branch, Hangzhou, China State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, China Eye Research Center, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Eye Hospital, Wenzhou Medical University, Hangzhou, China Correspondence to Yun-e Zhao or Pingjun Chang. The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material.