Antibody-mediated stabilization of NRG1 induces behavioral and electrophysiological alterations in adult mice

Sara L Dominguez,Daniel Fleck,Jesse E Hanson,Siao Ping Tsai,Hai Ngu,Hong Xiang,Erica L Jackson,Martin Weber,C Andrew Boswell,Kimberly Scearce-Levie,Yan Wu,Danielle Mandikian,Ganapati V Hegde,Cecilia Chiu

doi:10.1038/s41598-018-26492-4

Sara L Dominguez, Daniel Fleck + Show 12 more

Open Access

https://doi.org/10.1038/s41598-018-26492-4

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Abstract

Neuregulin 1 (NRG1) is required for development of the central and peripheral nervous system and regulates neurotransmission in the adult. NRG1 and the gene encoding its receptor, ERBB4, are risk genes for schizophrenia, although how alterations in these genes disrupt their function has not been fully established. Studies of knockout and transgenic mice have yielded conflicting results, with both gain and loss of function resulting in similar behavioral and electrophysiological phenotypes. Here, we used high affinity antibodies to NRG1 and ErbB4 to perturb the function of the endogenous proteins in adult mice. Treatment with NRG1 antibodies that block receptor binding caused behavioral alterations associated with schizophrenia, including, hyper-locomotion and impaired pre-pulse inhibition of startle (PPI). Electrophysiological analysis of brain slices from anti-NRG1 treated mice revealed reduced synaptic transmission and enhanced paired-pulse facilitation. In contrast, mice treated with more potent ErbB4 function blocking antibodies did not display behavioral alterations, suggesting a receptor independent mechanism of the anti-NRG1-induced phenotypes. We demonstrate that anti-NRG1 causes accumulation of the full-length transmembrane protein and increases phospho-cofilin levels, which has previously been linked to impaired synaptic transmission, indicating enhancement of non-canonical NRG1 signaling could mediate the CNS effects.

Highlights

The NRG1 gene encodes numerous isoforms of the Neuregulin 1 (NRG1) protein due to extensive alternative promoter usage and alternative splicing
Abnormal cleavage of NRG1 could contribute to pathophysiology, as mice lacking NRG1 processing enzymes such as BACE1 and neuropsin show schizophrenia-like phenotypes[25,26] and one of the few schizophrenia-associated SNPs known to occur in the coding sequence impairs cleavage of NRG1 by γ-secretase[27,28]
To further explore whether the pre-pulse inhibition of startle (PPI) deficits observed in the anti-NRG1 treated mice are receptor independent, we evaluated PPI in animals treated with the anti-ErbB4/anti-ErbB3 combination

Summary

Introduction

The NRG1 gene encodes numerous isoforms of the Neuregulin 1 (NRG1) protein due to extensive alternative promoter usage and alternative splicing. Many of the risk-associated SNPs occur in noncoding regions of NRG1, and could alter expression levels[14], and both increases and decreases in NRG1/Erb4B levels and/or activity have been found in postmortem studies of schizophrenia patients[15,16,17,18,19] Both genetically increasing and decreasing the levels of specific NRG1 isoforms in mice result in schizophrenia-like behaviors[4,20,21,22,23]. We show that anti-NRG1 treatment increases p-cofilin by modulating receptor-independent signaling Our study both provides new insight into the role of NRG1 on synaptic function and behavior and provides a new approach for in vivo modeling of certain schizophrenia-like phenotypes

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