RRC ID 75813
Author Obi-Nagata K, Suzuki N, Miyake R, MacDonald ML, Fish KN, Ozawa K, Nagahama K, Okimura T, Tanaka S, Kano M, Fukazawa Y, Sweet RA, Hayashi-Takagi A.
Title Distorted neurocomputation by a small number of extra-large spines in psychiatric disorders.
Journal Sci Adv
Abstract Human genetics strongly support the involvement of synaptopathy in psychiatric disorders. However, trans-scale causality linking synapse pathology to behavioral changes is lacking. To address this question, we examined the effects of synaptic inputs on dendrites, cells, and behaviors of mice with knockdown of SETD1A and DISC1, which are validated animal models of schizophrenia. Both models exhibited an overrepresentation of extra-large (XL) synapses, which evoked supralinear dendritic and somatic integration, resulting in increased neuronal firing. The probability of XL spines correlated negatively with working memory, and the optical prevention of XL spine generation restored working memory impairment. Furthermore, XL synapses were more abundant in the postmortem brains of patients with schizophrenia than in those of matched controls. Our findings suggest that working memory performance, a pivotal aspect of psychiatric symptoms, is shaped by distorted dendritic and somatic integration via XL spines.
Volume 9(23)
Pages eade5973
Published 2023-6-9
DOI 10.1126/sciadv.ade5973
PMID 37294752
PMC PMC10256173
MeSH Animals Brain Dendritic Spines* / physiology Humans Memory, Short-Term / physiology Mice Neurons / physiology Schizophrenia* / pathology
IF 13.117
Mice RBRC03709