Research ReportNeuregulin 1 transgenic mice display reduced mismatch negativity, contextual fear conditioning and social interactions
Introduction
Schizophrenia is a devastating psychiatric illness that affects about 1% of the world's population (Lewis and Levitt, 2002). Recent molecular genetics studies have identified multiple candidate genes for susceptibility for schizophrenia, such as Neuregulin-1 (NRG1), DISC1, Dysbindin, COMT, and GAD67 (Guidotti et al., 2000, Harrison and Weinberger, 2005, O'Tuathaigh et al., 2007a).
NRG1 is of particular interest because much of its physiological and molecular activity has been characterized previously and is relevant to the proposed pathophysiology of schizophrenia (Stefansson et al., 2002) (Wen et al., 1992, Yang et al., 2003) (Corfas et al., 2004, Dong et al., 1995, Marchionni et al., 1993, Plowman et al., 1993). NRG1 functions as a growth and differentiation factor and binds the erbB family of receptor tyrosine kinases, specifically erbB2, 3 and 4. Many isoforms of NRG1 are created by alternative splicing, but types 1, 2 and 3 constitute the major forms (Hashimoto et al., 2004). Several of these isoforms have been linked to aspects of neuronal development that are thought to contribute to the onset of schizophrenia. For instance, NRG1 type 1, also known as neu differentiation factor, modulates growth and differentiation of neural crest cells (Corfas et al., 1995, Goodearl et al., 1995). NRG1 type 2 promotes oligodendrocyte production and myelination in the CNS, while type 3 is involved in the development of Schwann cells (Edwards and Bottenstein, 2006, Marchionni et al., 1999, Meyer et al., 1997). NRG1 type 3 is thought to be the most abundant type of NRG1 found in the cortical regions of the brain. It has been shown to be important for normal sensory motor gating and memory functions as well as nicotine mediated hippocampal activity (Chen et al., 2008, Zhong et al., 2008). Of note, one line of Nrg1 transgenic mice were found to have decreased N-methyl-d-aspartic acid (NMDA) receptor binding when compared to their wild type littermates (Stefansson et al., 2002). Additionally, NRG1 binds preferentially to the ErbB4 receptor, which can modulate the function of glutamatergic receptors, further supporting its possible role in the pathophysiology of schizophrenia (Hahn et al., 2006, Huang et al., 2000, Kwon et al., 2005, Li et al., 2007).
Changes in NRG1 expression may profoundly effect the development and function of the brain through all of the previously discussed mechanisms and, therefore, may contribute to impairments seen in schizophrenia. Individuals with schizophrenia perform poorly across a range of cognitive, behavioral, and physiological measures. Problems with working memory and social interaction can contribute to an inability to function in society (Addington and Addington, 2000, Bowen et al., 1994, Cohen et al., 2006, Corrigan et al., 1994). Additionally, deficits in gating, mismatch negativity (MMN), and pre-pulse inhibition (PPI) of startle are well described endophenotypes of schizophrenia that may underlie some of the aforementioned problems (Boutros et al., 2004, Freedman et al., 1996, Grillon et al., 1992, Javitt et al., 1998, Light et al., 2000, Parwani et al., 2000, Umbricht and Krljes, 2005). Performing similar measures in mice has added a valuable tool for researchers to model schizophrenia. Fear conditioning and novel object recognition paradigms are used to determine if mice display deficits in memory (Crawley, 1999, Hashimoto et al., 2007, Powell et al., 2007). Gating, mismatch negativity, and PPI are evaluated in animals using tasks that are very similar to those used in the human population. Studies from our group as well as others have demonstrated such schizophrenia endophenotypes in rodent models using these tasks (Ehrlichman et al., 2008, Maxwell et al., 2006, Simosky et al., 2003, Swerdlow et al., 1998, Umbricht et al., 2005).
Several groups have reported increases in NRG1 in postmortem brain studies. This may suggest that mice that over-express Nrg1, rather than Nrg1+/−, may be a better model for schizophrenia. It is unknown, however, whether the modest increases in NRG1 previously observed are associated with enhanced NRG1–erbB4 signaling (Chong et al., 2008, Hashimoto et al., 2004, Law et al., 2006). Our group has reported a significant enhancement in erbB4 signaling, when postmortem brain tissues were stimulated with NRG1 (Hahn et al., 2006). In our Western analysis, we failed to detect significant differences in NRG1 expression between the schizophrenia and control groups (Hahn et al., 2006). Interestingly, Nrg1 induced activation of erbB4 in mice was found to have a trend for an increase in Nrg1+/− examined in this study (unpublished observation).
The purpose of this study is to examine the impact of Nrg1 on electrophysiological and social behaviors that have been implicated for schizophrenia. NRG1 has many isoforms and it is not entirely clear as to which isoforms are dysregulated in brains of patients with schizophrenia. Therefore, we chose to examine mice mutated for the activity of all isoforms among various mutant lines available. To accomplish this goal, we chose the mutants developed by (Meyer and Birchmeier, 1995) that contain mutations in EGF domain of all isoforms, which is critical for binding of Nrg1 to the receptors. In various lines of Nrg1+/− mice, recent studies showed deficits in physiology and behaviors (Chen et al., 2008, Duffy et al., 2008, O'Tuathaigh et al., 2008, Stefansson et al., 2002). We anticipated a reduction in gating of P20 and N40 event-related potentials (ERPs) and an attenuation of MMN in response to novel stimuli. In addition to those electrophysiological measures, we expected the Nrg1+/− mice in this study to display impairments in PPI, memory tasks including contextual fear conditioning and novel object recognition, social interaction and increased locomotor activity.
Section snippets
ERPs
A reduction in the amplitude of the second response (S2) referenced to the first (S1) was found across genotypes for both P20 and N40 ERPs (P20: F(1,26) = 38.729, p < 0.001, N40: F(1,26) = 26.34, p < 0.001). There was no main effect of genotype on either P20 or N40 response (p > 0.05 for both). There was no stimulus by gene interaction in P20 or N40 (p > 0.05 for both). These data do not support the hypothesis that Nrg1 signaling modulates gating of ERPs. Wild type mice displayed a MMN from 50–75 ms (p <
Expectations, summary of results
Multiple studies have identified NRG1 as a candidate susceptibility gene for schizophrenia (Harrison and Weinberger, 2005, Stefansson et al., 2003, Weinberger, 2005). We expected Nrg1+/− mice to exhibit behavior consistent with mouse models that have been shown to exhibit predictive or construct validity for positive and negative symptoms as well as cognitive and electrophysiological deficits in schizophrenia (Swerdlow and Geyer, 1998). Anticipated results included reduced amplitude and gating
Animals
Nrg1+/− mice were obtained from C. Birchmeier (Meyer and Birchmeier, 1995) and bred on a C57BL/6/129 hybrid background at the University of Pennsylvania. Briefly, exon 6 of the neuregulin gene is fused to beta-galactosidase, which results in partial deletion of the EGF like domains of all three major types of Nrg1. All protocols were performed in accordance with University Laboratory Animal Resources guidelines and were approved by the Institutional Animal Care and Use Committee. Mice were
Acknowledgments
The authors would like to thank Dr. Carmen Birchmeier for providing the mice used in this study and for her helpful input throughout the process. Funding was provided by NIMH P50 MH064045 (SJ Siegel Project PI, RE Gur Center PI), RO1MH075916 (C Hahn), R01MH080718 (ES Brodkin).
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