Decoding Spine Nanostructure in Mental Disorders Reveals a Schizophrenia-Linked Role for Ecrg4

Dendritic spine dysfunction may contribute to the etiology and symptom expression of neuropsychiatric disorders. The intimate relationship between spine morphology and function suggests that decoding disease-related abnormalities from spine morphology can aid in developing synapse-targeted interventions. Here, we describe a population analysis of dendritic spine nanostructure applied to the objective grouping of multiple mouse models of neuropsychiatric disorders. This method has identified two major groups of spine phenotypes linked to schizophrenia and autism spectrum disorder (ASD). An increase in spine subpopulation with small volumes characterized the spines of schizophrenia mouse models, whereas a spine subset with large volumes increased in ASD models. Schizophrenia mouse models showed higher similarity in spine morphology, which was caused by a reduced speed of nascent spine growth. The expression of Ecrg4, a gene encoding small secretory peptides, was increased in schizophrenia mouse models, and functional studies confirmed its critical involvement in impaired spine dynamics and shape in schizophrenia mouse models. These results suggest that the population-level spine analysis provides rich information about the heterogeneous spine pathology, which facilitates identification of new molecular targets related to core synaptic dysfunction.