Postsynaptic proteins play critical roles in synaptic development, function, and plasticity. Dysfunction of postsynaptic proteins is strongly linked to neurodevelopmental and psychiatric disorders. SAP90/PSD95-associated protein 4 (SAPAP4; also known as DLGAP4) is a key component of the PSD95–SAPAP–SHANK excitatory postsynaptic scaffolding complex, which plays important roles at synapses. However, the exact function of the SAPAP4 protein in the brain is poorly understood. Here, we report that Sapap4 knockout (KO) mice have reduced spine density in the prefrontal cortex and abnormal compositions of key postsynaptic proteins in the postsynaptic density (PSD) including reduced PSD95, GluR1, and GluR2 as well as increased SHANK3. These synaptic defects are accompanied by a cluster of abnormal behaviors including hyperactivity, impulsivity, reduced despair/depression-like behavior, hypersensitivity to low dose of amphetamine, memory deficits, and decreased prepulse inhibition, which are reminiscent of mania. Furthermore, the hyperactivity of Sapap4 KO mice could be partially rescued by valproate, a mood stabilizer used for mania treatment in humans. Together, our findings provide evidence that SAPAP4 plays an important role at synapses and reinforce the view that dysfunction of the postsynaptic scaffolding protein SAPAP4 may contribute to the pathogenesis of hyperkinetic neuropsychiatric disorder.

Excitatory (glutamatergic) synaptic transmission underlies many aspects of brain activity and the genesis of normal human behavior. The postsynaptic scaffolding proteins SAP90/PSD-95-associated proteins (SAPAPs), which are abundant components of the postsynaptic density (PSD) at excitatory synapses, play critical roles in synaptic structure, formation, development, plasticity, and signaling. The convergence of human genetic data with recent in vitro and in vivo animal model data indicates that mutations in the genes encoding SAPAP1–4 are associated with neurological and psychiatric disorders, and that dysfunction of SAPAP scaffolding proteins may contribute to the pathogenesis of various neuropsychiatric disorders, such as schizophrenia, autism spectrum disorders, obsessive compulsive disorders, Alzheimer’s disease, and bipolar disorder. Here, we review recent major genetic, epigenetic, molecular, behavioral, electrophysiological, and circuitry studies that have advanced our knowledge by clarifying the roles of SAPAP proteins at the synapses, providing new insights into the mechanistic links to neurodevelopmental and neuropsychiatric disorders.