Neuregulin 1 in neural development, synaptic plasticity and schizophrenia

Abstract

Schizophrenia is a highly debilitating mental disorder that affects ∼1% of the general population, yet it continues to be poorly understood. The genes that encode neuregulin 1 (NRG1) and its receptor ErbB4 are both schizophrenia susceptibility genes. NRG1 is a trophic factor that contains an epidermal growth factor (EGF)-like domain, and its receptors are ErbB receptor tyrosine kinases. Pro-NRG1 is a transmembrane protein from which diffusible mature NRG1 is released by proteolytic cleavage. The expression and maturation of NRG1 are controlled by neuronal activity. NRG1 signalling is complex and can be bidirectional. In canonical forward signalling, NRG1 stimulates the Raf–MEK–ERK and PI3K–Akt–S6K pathways. In non-canonical forward signalling, ErbB4 undergoes proteolytic cleavage to release an intracellular domain that can travel to the nucleus to regulate gene expression. In backward signalling, ErbB4 or its diffusible extracellular domain can serve as a ligand for pro-NRG1. The intracellular domain of pro-NRG1 has been implicated in transcription regulation. NRG1–ErbB signalling has been implicated in the proliferation of neuronal progenitors and many other processes of neural development, including neuron migration and survival, axon guidance, glial development and myelination, and synapse formation. NRG1 is expressed in multiple regions in the adult brain and regulates neurotransmission and synaptic plasticity. ErbB4 is localized at the postsynaptic density (PSD) of glutamatergic synapses, presumably by interacting with the PSD protein PSD95. NRG1 suppresses the induction and expression of long-term potentiation in the hippocampus. In addition, ErbB4 is enriched in GABA (γ-aminobutyric acid)-ergic neurons and present at their presynaptic terminals. NRG1 enhances depolarization-dependent release of GABA. Mutations in NRG1 and ERBB4 have been associated with schizophrenia in multiple populations. Studies of Nrg1- and Erbb4-mutant mice have provided support for the potential role of loss-of-function mutations in these genes as risk factors for schizophrenia. Nrg1- and Erbb4-hypomorphic or conditional-knockout mice show 'schizophrenic-like' deficits and are generally hyperactive. Most genetic variants of NRG1 and ERBB4 are intronic or synonymous exonic substitutions or are located in 5′ or 3′ non-coding regions. It is believed that they might alter the expression of NRG1 and ErbB4 protein isoforms at the level of transcription and/or splicing. Expression of CYT-1 ErbB4 and Type I NRG1 and/or NRG1 signalling is enhanced in the hippocampus and prefrontal cortex of patients with schizophrenia.