A growing number of synaptic proteins have recently been associated with diverse neuropsychiatric disorders including autism spectrum disorders (ASDs), schizophrenia, attention deficit hyperactivity disorder (ADHD), and mood disorders. ASDs represent a group of neurodevelopmental disorders with a prevalence of ~1% and are characterized by core symptoms including impaired social interaction, impaired social communication, and restricted/repetitive behaviors and interests. Although a large number of ASD-related genes and mutations have been identified, a few of them have been verified by approaches including mouse genetics. In addition, neural mechanisms underlying the development of ASDs remain largely unknown, explaining the lack of efficient medications for the treatment of autism. Synaptic scaffolding proteins at excitatory synapses interact with various synaptic proteins including receptors and signaling molecules, and promote the physical and functional coupling of receptor activation with downstream signaling events. In this presentation, I will discuss how defects in synaptic signaling scaffolds affect synaptic transmission, signaling, and plasticity, and how these defects are associated with ASD-like behavioral abnormalities in mice.