Growing evidence implicates synaptic proteins in the pathogenesis of neuropsychiatric disorders such as autism spectrum disorder (ASD), intellectual disability (ID) and schizophrenia. In fact, mutations in genes encoding synaptic proteins are enriched and overlap among different conditions highlighting the complex and pleiotropic nature of these disorders. In this review, we discuss recently described candidate genes that affect excitatory synapse function and result in changes in spine number and morphology. Spine pathology has been observed in several animal models of disease and in human brain post-mortem samples from ID, ASD, and schizophrenia patients. Recent data point to convergent mechanisms, such as dysregulation of the actin cytoskeleton and dysfunction of microglia synaptic remodeling, underlying dendritic spine dysgenesis. Interestingly, the reversion of important pathologic features, including spine abnormalities, has been observed in adult animal models of neuropsychiatric disorders, suggesting that therapies may not be restricted to a specific developmental window. Shedding light on the specific mechanisms impacted in neuropsychiatric disorders will undeniably contribute to the development of more directed and personalized therapies.
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