30 July 2012. A new study published June 11 in Proceedings of the National Academy of Sciences plunges into the depths of neuregulin 1 (NRG1) signaling, and emerges with PIK3CD as a potential therapeutic target for schizophrenia. Amanda Law and colleagues at the National Institute for Mental Health in Bethesda, Maryland, probed the downstream workings of NRG1 and its receptor, ErbB4, which are involved in many cellular processes, including neural development and synaptic plasticity, and which have both been implicated in schizophrenia with genetic studies. As previously presented in 2011 at a New York Academy of Sciences meeting on Advancing Drug Discovery in Schizophrenia (see SRF related conference story), the team found signs of aberrant NRG1-ErbB4 signaling in schizophrenia, and reported that pharmacologically inhibiting a downstream protein encoded by PIK3CD blocks schizophrenia-related behaviors in rodents.
Drawing from human lymphoblastoid cell lines (LCLs) derived from patients with schizophrenia and controls, the researchers found an overabundance of an ErbB4 isoform, called CYT-1, in schizophrenia, and this isoform can bind to and activate phosphoinositide 3-kinase (PI3K). PIK3CD, which encodes a catalytic subunit of PI3K, was also elevated by 40 percent in schizophrenia compared to controls. Blocking PIK3CD might rectify this, and just such an inhibitor prevented amphetamine-induced locomotion in mice, and prepulse inhibition deficits in a rat model. Two family-based genetic studies also turned up single nucleotide polymorphisms in PIK3CD associated with schizophrenia. These and other data build a case for PIK3CDís involvement in schizophrenia, which the authors suggest may offer a way to fine-tune NRG1-ErbB4 signaling without messing with the myriad other processes governed by the pathway.—Michele Solis.
Law AJ, Wang Y, Sei Y, O'Donnell P, Piantadosi P, Papaleo F, Straub RE, Huang W, Thomas CJ, Vakkalanka R, Besterman AD, Lipska BK, Hyde TM, Harrison PJ, Kleinman JE, Weinberger DR. Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy. Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):12165-70. Abstract