A synthetic synaptic organizer protein restores glutamatergic neuronal circuits

• Published in: Science (American Association for the Advancement of Science) Vol. 369; no. 6507
• Main Authors: Suzuki, Kunimichi, Elegheert, Jonathan, Song, Inseon, Sasakura, Hiroyuki, Senkov, Oleg, Matsuda, Keiko, Kakegawa, Wataru, Clayton, Amber J, Chang, Veronica T, Ferrer-Ferrer, Maura, Miura, Eriko, Kaushik, Rahul, Ikeno, Masashi, Morioka, Yuki, Takeuchi, Yuka, Shimada, Tatsuya, Otsuka, Shintaro, Stoyanov, Stoyan, Watanabe, Masahiko, Takeuchi, Kosei, Dityatev, Alexander, Aricescu, A Radu, Yuzaki, Michisuke
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 28.08.2020; American Association for the Advancement of Science (AAAS)
• Subjects: Affinity; Alzheimer Disease - therapy; Alzheimer's disease; Anatomy; Animal diseases; Animal models; Animals; Ataxia; Autism; Autism Spectrum Disorders; Balance; Binding; Biochemistry, Molecular Biology; Brain; C-Reactive Protein - chemistry; C-Reactive Protein - pharmacology; C-Reactive Protein - therapeutic use; Cell adhesion; Cell adhesion & migration; Cell adhesion molecules; Cell differentiation; Cell surface; Cerebellar ataxia; Cerebellar Ataxia - therapy; Cerebellum; Circuit design; Circuits; Differentiation; Disease Models, Animal; Domains; Epilepsy; Gait; Granule cells; HEK293 Cells; Hippocampus; Humans; Individualized Instruction; Information retrieval; Injuries; Life Sciences; Locomotion; Long-term potentiation; Mental disorders; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - pharmacology; Nerve Tissue Proteins - therapeutic use; Nervous system; Neural networks; Neural Pathways - drug effects; Neurodegenerative diseases; Neurological disorders; Neurons; Neurotransmitters; Physiology; Protein Domains; Protein Precursors - chemistry; Protein Precursors - pharmacology; Protein Precursors - therapeutic use; Proteins; Receptors, AMPA - metabolism; Receptors, Glutamate - genetics; Recombinant Proteins - chemistry; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; Recovery of function; Schizophrenia; Spinal cord; Spinal cord injuries; Spine; Spine - drug effects; Spine - physiology; Structural Elements (Construction); Structural members; Synapses; Synapses - drug effects; Synaptogenesis; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.abb4853

Neuronal synapses undergo structural and functional changes throughout life, which are 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 designed and characterized CPTX, a synthetic synaptic organizer combining structural elements from cerebellin-1 and neuronal pentraxin-1. CPTX can interact with presynaptic neurexins and postsynaptic AMPA-type ionotropic glutamate receptors and induced the formation of excitatory synapses both in vitro and in vivo. CPTX 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 structure-guided biologics that can efficiently repair or remodel neuronal circuits.