In neurons, postsynaptic density (PSD) refers to an electron dense structure underneath the plasma membrane at the postsynaptic site, containing various protein molecules essential for responding to the presynaptic signals, including ion channels, scaffold proteins, signaling molecules, and cytoskeletons. The scaffold proteins provide the linkage among ion channels, signaling molecules and the cytoskeleton. Accumulating data indicate that the membrane associated guanylate kinase (MAGUK) proteins are important postsynaptic scaffold proteins involved in synaptic targeting, clustering and signaling of ion channels (Sheng and Sala 2001; Kim and Sheng 2004; Montgomery, Zamorano and Garner 2004). Calcium/calmodulin-dependent serine protein kinase (CASK) belongs to MAGUK protein family. Although CASK contains a CaMK-like domain, it doesn’t possess kinase activity. Instead, like other MAGUK proteins, CASK functions as multidomain scaffolding protein. Recent studies showed that CASK not only performs its function at the postsynaptic site but also enters the nuclei of neurons and regulates gene expression via the interaction with transcriptional factor T-brain-1 (Tbr-1) and nucleosome assembly protein CINAP (CASK-interacting nucleosome assembly protein). The Tbr-1-CASK-CINAP complex modulates expression of NMDA receptor subunit 2b (NR2b). More interestingly, CINAP protein levels in neurons are controlled by synaptic activity. The studies with the Tbr-1-CASK-CINAP complex provide a novel feedback mechanism that explains how synaptic activity regulates gene expression. In this chapter, the molecular characteristics of CASK, Tbr-1, and CINAP proteins will be described first, followed by a discussion of the regulation of NR2b expression by the CINAP-CASK-Tbr-1 protein complex.