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

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

  • Nat Commun. 2025 Mar 4;16(1):2174. doi: 10.1038/s41467-025-57445-x.
Xin Zhang # 1,  Chao Yang # 1 2 3 4,  Chengle Zhang # 1,  Junqiang Wu 1,  Xiang Zhang 5 6,  Jiayang Gao 7,  Xuejie Wang 1 2,  Leung Ting Chan 1,  Yiren Zhou 1,  Yujun Chen 1,  Sindy Sing Ting Tam 1 5,  Shuhang Chen 2 5,  Yuqian Ma 8,  Wing-Ho Yung 9,  Liting Duan 10,  Liwen Jiang 7,  Yiwen Wang 5 6,  Kai Liu 11 12 13 14 15
Affiliations

Affiliations

  • 1 Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China.
  • 2 Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
  • 3 Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China.
  • 4 Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute; Shenzhen-Hong Kong Institute of Brain Science, Shenzhen, Guangdong, China.
  • 5 Department of Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong, China.
  • 6 Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, China.
  • 7 School of Life Sciences, Centre for Cell & Developmental Biology and State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, Sha Tin, China.
  • 8 Hefei National Research Center for Physical Sciences at the Microscale, CAS Key Laboratory of Brain Function and Disease, Biomedical Sciences and Health Laboratory of Anhui Province, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 9 Department of Neuroscience, City University of Hong Kong, Hong Kong, China.
  • 10 Department of Biomedical Engineering, The Chinese University of Hong Kong, Hong Kong, Sha Tin, China.
  • 11 Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China. kailiu@ust.hk.
  • 12 Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China. kailiu@ust.hk.
  • 13 Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China. kailiu@ust.hk.
  • 14 Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute; Shenzhen-Hong Kong Institute of Brain Science, Shenzhen, Guangdong, China. kailiu@ust.hk.
  • 15 Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, China. kailiu@ust.hk.
  • # Contributed equally.
PMID: 40038284 DOI: 10.1038/s41467-025-57445-x
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.

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