Project summary: The signaling specification of the post synaptic membrane known as the post-synaptic density (PSD), is one of the most complex signaling machineries in the neuron. Many of the genes that have been implicated as risk factors for the psychiatric disorders are thought to affect PSD proteins. Yet with these genetic discoveries, there has been a gap in defining underlying biological mechanisms that contribute to dysfunction at the PSD in complex brain disorders. Our primary objectives are to determine how mutations associated to schizophrenia (SCZ), disrupts protein interaction networks (PINs) at the PSD, how risk factors are functionally organized in PINs and how they are regulated by synaptic activity. We will use mouse genetic models, including the protein kinase TNiK and a mutant -model of SHANK3 found in patients with SCZ, mass spectrometry analysis, biochemical assays, and computational approaches to explore not only the normal function of PSD PIN in responding to synaptic activity, but also translate the human genetic findings into knowledge of how the function of this network is affected by mutations associated with psychiatric disease.