PT  - JOURNAL ARTICLE
AU  - Kunimichi Suzuki
AU  - Jonathan Elegheert
AU  - Inseon Song
AU  - Hiroyuki Sasakura
AU  - Oleg Senkov
AU  - Wataru Kakegawa
AU  - Amber J. Clayton
AU  - Veronica T. Chang
AU  - Maura Ferrer-Ferrer
AU  - Eriko Miura
AU  - Rahul Kaushik
AU  - Masashi Ikeno
AU  - Yuki Morioka
AU  - Yuka Takeuchi
AU  - Tatsuya Shimada
AU  - Shintaro Otsuka
AU  - Stoyan Stoyanov
AU  - Masahiko Watanabe
AU  - Kosei Takeuchi
AU  - Alexander Dityatev
AU  - A. Radu Aricescu
AU  - Michisuke Yuzaki
TI  - A synthetic synaptic organizer protein restores glutamatergic neuronal circuits
AID  - 10.1101/2020.02.27.967836
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.02.27.967836
4099  - http://biorxiv.org/content/early/2020/02/27/2020.02.27.967836.short
4100  - http://biorxiv.org/content/early/2020/02/27/2020.02.27.967836.full
AB  - Neuronal synapses undergo structural and functional changes throughout life, essential for nervous system physiology. However, these changes may also perturb the excitatory/inhibitory neurotransmission balance and trigger neuropsychiatric and neurological disorders. Molecular tools to restore this balance are highly desirable. Here, we report the design and characterization of CPTX, a synthetic synaptic organizer combining structural elements from cerebellin-1 and neuronal pentraxin-1 to interact with presynaptic neurexins and postsynaptic AMPA-type ionotropic glutamate receptors. CPTX induced the formation of excitatory synapses in vitro and in vivo and restored synaptic functions, motor coordination, spatial and contextual memories, and locomotion in mouse models for cerebellar ataxia, Alzheimer’s disease and spinal cord injury, respectively. Thus, CPTX represents a prototype for novel structure-guided biologics that can efficiently repair or remodel neuronal circuits.One Sentence Summary Structural biology information was used to design CPTX, a synthetic protein that induces functional excitatory synapses and restores normal behaviors in mouse models of neurological diseases.