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Neuregulin 1 in neural development, synaptic plasticity and schizophrenia

Key Points

  • 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.

Abstract

Schizophrenia is a highly debilitating mental disorder that affects 1% of the general population, yet it continues to be poorly understood. Recent studies have identified variations in several genes that are associated with this disorder in diverse populations, including those that encode neuregulin 1 (NRG1) and its receptor ErbB4. The past few years have witnessed exciting progress in our knowledge of NRG1 and ErbB4 functions and the biological basis of the increased risk for schizophrenia that is potentially conferred by polymorphisms in the two genes. An improved understanding of the mechanisms by which altered function of NRG1 and ErbB4 contributes to schizophrenia might eventually lead to the development of more effective therapeutics.

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Figure 1: Different types of NRG1.
Figure 2: Canonical NRG1–ErbB signalling pathways.
Figure 3: Domain structures of four different ErbB4 isoforms.
Figure 4: Backward and non-canonical NRG1–ErbB4 signalling.
Figure 5: Roles of NRG1 in neural development.
Figure 6: NRG1 regulation of synaptic plasticity at excitatory and inhibitory synapses.
Figure 7: The structures of NRG1 and ERBB4 and their associated single nucleotide polymorphisms (SNPs).

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Acknowledgements

We thank C. Lai, M. Salter, B. Li, G. Pitcher and C. Bergson for critical reading of the Review, the anonymous reviewers for their comments and critiques, X. Liu, Y. Tao, X. Li and A. Ting for comments and suggestions, and X. Liu and X. Cao for figure preparation. The work of the authors' laboratories was supported in part by grants from the National Institute of Mental Health, the National Institute for Neurological Disorders and Stroke and the National Alliance for Research on Schizophrenia and Depression.

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Glossary

Antipsychotics

Drugs that are used to treat psychosis, often in people with schizophrenia.

Postsynaptic density

An electron-dense region of the postsynaptic membrane that is comprised of glutamate receptors, signalling and scaffolding proteins and cytoskeletal and cell-adhesion molecules.

Mesenchyme

Mesodermic embryonic undifferentiated tissue that will differentiate into blood, blood vessels, smooth muscle and connective tissue.

Radial migration

The migration of newly formed neurons from the ventricular zone, where they differentiate, to the neocortex, which they then laminate. The neurons are thought to migrate on tracks formed by radial glia.

Tangential migration

A mode of neuron migration that is non-radial. Most interneurons migrate tangentially.

Rostral migratory stream

(RMS). A pathway by which neuronal precursors formed in the subventricular zone migrate to the olfactory bulb.

Axon guidance

A process in which axons find their target cells.

Myelination

A process by which axons become ensheathed with myelin, which permits the rapid transmission of action potentials.

Long-term potentiation

(LTP). A persistent increase in synaptic strength following electrical or chemical stimulation. It is believed to be a cellular mechanism that underlies learning and memory.

Working memory

The ability to remember information over a short period of time. It is believed to be executed by the prefrontal cortex, the anterior cingulate cortex and parts of the basal ganglia.

Executive function

A set of cognitive abilities that connect past experiences with present actions, allowing the formation of concepts and abstract thought.

Inhibitory postsynaptic currents.

(IPSCs). Synaptic currents elicited by GABA or glycine (both of which are inhibitory neurotransmitters) that can inhibit the formation of action potentials.

Haplotype

A combination of genetically linked markers that are present on one chromosome and are transmitted together.

Single nucleotide polymorphism

(SNP). A DNA sequence variation in which a single nucleotide in the genome is altered. SNPs can occur in coding as well as non-coding regions of DNA.

Pre-pulse inhibition

(PPI). A reduction in the magnitude of the startle reflex that occurs when an organism is presented with a non-startling stimulus (a prepulse) before being presented with the startling stimulus. Deficits in PPI have been observed in patients with schizophrenia.

Schizotypal personality

A condition that is characterized by discomfort with close relationships and by eccentric beliefs and behaviours.

Anhedonia

The inability to experience pleasure from enjoyable life events. It is recognized as a key symptom of depression.

Open-field test

A behavioural analysis that measures locomotor activity, hyperactivity, exploratory behaviours and anxiety.

Glutamic acid decarboxylase

(GAD). An enzyme that is essential for GABA synthesis. It catalyses the decarboxylation of glutamate to produce GABA and CO2. In mammals there are two GAD isoforms: GAD67 and GAD65, which are encoded by GAD1 and GAD2, respectively.

Parvalbumin

A Ca2+-binding protein that is expressed in a subset of GABAergic interneurons (and fast-contracting muscles).

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Mei, L., Xiong, WC. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci 9, 437–452 (2008). https://doi.org/10.1038/nrn2392

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