Kainate receptors (KAR) are a subtype of ionotropic glutamate receptors implicated in excitatory transmission and neuronal excitability in the CNS. A number of KAR interacting proteins have been identified including, GRIP1, PICK1 and syntenin (Garcia et aI., 1998; Hirbec et aI., 2003) all of which have been shown to directly interact with KAR GluR5/6 subunits via a C-terminus PDZ domain protein-protein interaction. These proteins are thought to playa role in KAR trafficking. In this study I have investigated the effects on the surface expression of KAR subunits when over expressing the PDZ domain containing KAR interacting proteins. Over expressing GRIP1 or syntenin resulted in an increased surface expression of GluR6 and KA2 subunits. To investigate this mechanism further, lentiviral RNA interference (RNAi) was developed to enable short hairpin RNA (shRNA)-mediated specific knockdown of KAR interacting proteins. RNAi a natural innate mechanism in cells which can be mimicked experimentally to specifically reduce target protein levels via post transcriptional gene silencing. Lentiviral delivery of shRNA constructs has been successfully validated in both cortical cultured cells in vitro, in long term hippocampal slices and in the perirhinal cortex in vivo. In proof of concept experiments significant PICK1 knockdown caused marked morphological changes in neurons and PICK1 is thought to be involved in Arp2/3 mediated inhibition of actin polymerisation (Rocca et aI., 2008). These initial experiments demonstrate lentiviral RNAi is a powerful approach that can be used to study the specific roles of targeted proteins in KAR trafficking which, in turn, is a key mechanism for regulating synaptic strength and synaptic plasticity.