Nrg1 reverse signaling in cortical pyramidal neurons.

Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see Review of Chen et al. Schizophrenia is a severe neurological disorder characterized by psychotic symptoms , emotional distress, and cognitive deficits. It results from an amalgam of genetic , developmental, and environmental factors. In the last decade, several studies identified Nrg1 and its receptor ErbB4 as major schizophrenia-risk genes (Stefansson et al., 2002; Norton et al., 2006). Moreover , behavioral studies on different Nrg1 and ErbB4 mutant mice revealed various endophenotypes that are believed to be useful for modeling schizophrenia in mice (e.g., hyperactivity in response to novelty, hypersensitivity to psychostimulants, and deficits in working memory tasks). Similar phenotypes were shown in mice expressing mutated BACE-1 (the extracellular Nrg1-cleavage enzyme) (Savonenko et al., 2008) or Aph1B/C-␥-secretase (the Nrg1 intracel-lular proteolytic enzyme) (Dejaegere et al., 2008). Together, these findings suggest that perturbed Nrg1 signaling leads to functional deficits that correlate with schizophrenia. Nonetheless, Nrg1 and ErbB4 mutants do not display overt morphological defects in the brain and the precise role of Nrg1/ ErbB4 signaling in the nervous system remains elusive. In addition to canonical forward sig-naling via ErbB family receptors, the membrane-bound form of Nrg1 can also activate reverse signaling. Upon synaptic activation or receptor binding, membrane-associated type III Nrg1 is cleaved by ␥-secretase to release the intracellular domain (NRG1-ICD), which translocates to the nucleus where it regulates gene expression (Bao et al., 2003, 2004). Recently, it was shown that Nrg1/ErbB4 forward signaling promotes the formation of in-hibitory circuits in the cortex (Fazzari et al., 2010). Chen et al. (2010) show that Nrg1 reverse signaling is important for the development of the dendritic arbor of py-ramidal neurons (PNs). To address the function of type III Nrg1 in PNs in vivo, the authors compared the morphology of dendritic arbor of neurons in type III Nrg1-deficient and wild-type (WT) mice. The histological analysis of mutant and control brains revealed that the total length and number of branches of basal dendrites were greatly reduced in type III Nrg1-deficient versus WT neurons. Because axon length could not be measured efficiently in vivo, the authors used primary cortical cultures. Mimicking the in vivo data, the type …