Functional optic tract rewiring via subtype- and target-specific axonal regeneration and presynaptic activity enhancement

Xin Zhang, Chao Yang, Chengle Zhang, Junqiang Wu, Xiang Zhang, Jiayang Gao, Xuejie Wang, Leung Ting Chan, Yiren Zhou, Yujun Chen, Sindy Sing Ting Tam, Shuhang Chen, Yuqian Ma, Wing-Ho Yung, Liting Duan, Liwen Jiang, Yiwen Wang and Kai Liu ()
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Xin Zhang: The Hong Kong University of Science and Technology
Chao Yang: The Hong Kong University of Science and Technology
Chengle Zhang: The Hong Kong University of Science and Technology
Junqiang Wu: The Hong Kong University of Science and Technology
Xiang Zhang: The Hong Kong University of Science and Technology
Jiayang Gao: The Chinese University of Hong Kong
Xuejie Wang: The Hong Kong University of Science and Technology
Leung Ting Chan: The Hong Kong University of Science and Technology
Yiren Zhou: The Hong Kong University of Science and Technology
Yujun Chen: The Hong Kong University of Science and Technology
Sindy Sing Ting Tam: The Hong Kong University of Science and Technology
Shuhang Chen: Hong Kong Center for Neurodegenerative Diseases
Yuqian Ma: University of Science and Technology of China
Wing-Ho Yung: City University of Hong Kong
Liting Duan: The Chinese University of Hong Kong
Liwen Jiang: The Chinese University of Hong Kong
Yiwen Wang: The Hong Kong University of Science and Technology
Kai Liu: The Hong Kong University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Mechanisms underlying functional axonal rewiring after adult mammalian central nervous system (CNS) injuries remain unclear partially due to limited models. Here we develop a mouse intracranial pre–olivary pretectal nucleus (OPN) optic tract injury model and demonstrate that Pten/Socs3 knockout and CNTF expression in retinal ganglion cells (RGCs) promotes optic tract regeneration and OPN reinnervation. Revealed by transmission electron microscopy, trans-synaptic labeling, and electrophysiology, functional synapses are formed in OPN mainly by intrinsically photosensitive RGCs, thereby partially restoring the pupillary light reflex (PLR). Moreover, combining with Lipin1 knockdown accelerates the recovery and achieves functional reconnection after chronic injury. PLR can be further boosted by increasing RGC photosensitivity with melanopsin overexpression, and it can also be enhanced by treatment of a voltage-gated calcium channel modulator to augment presynaptic release. These findings highlight the importance of neuronal types and presynaptic activity for functional reconnection after CNS injuries.

Date: 2025
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DOI: 10.1038/s41467-025-57445-x

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