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. 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.Schizophrenia is a severe and disabling mental disorder that is characterized by chronic positive symptoms (hallucinations, delusions and thought disorders), negative symptoms (social withdrawal, apathy and emotional blunting) and cognitive deficits. Although schizophrenia is a highly prevalent CNS disorder, it continues to be one of the least understood, primarily owing to its lack of pathological hallmarks. Most, if not all, commonly prescribed antipsychotics are anti-dopaminergic, and their use has been based on the 'classical' dopamine hypothesis, which posits that it is the hyperactivity of dopaminergic transmission that causes positive symptoms 1 . However, current antipsychotics are only modestly effective treatments for the cognitive dysfunction and negative symptoms that are associated with schizophrenia. Moreover, studies on the mechanism of action of antipsychotics have not been particularly informative about the pathogenesis of the disease 2 .Recent genetic studies have provided insight into the possible aetiological mechanisms of this devastating disorder. Schizophrenia has a significant genetic component, and several genes have been associated with the disorder in diverse populations 3 . In particular, the identification of polymorphisms in the genes that encode neuregulin 1 (NRG1) and its receptor ErbB4 has provided a useful starting point from which to better dissect the pathogenic mechanisms of schizophrenia. The past few years have witnessed major progress in our understanding of NRG1 function in neurodevelopment, neurotransmission and synaptic plasticity and of the potential pathological basis of the increased risk that is conferred by polymorphisms in NRG1 and ERBB4. In this Review we briefly discuss the basic signalling machinery of NRG1, review recent findings on the roles of NRG1 and ErbB signalling during development and synaptic plasticity, and explore the implications for the pathophysiology of schizophrenia.Correspondence to: Lin Mei, Email: E-mail: lmei@mcg.edu. NIH Public Access Author ManuscriptNat Rev Neurosci. Author manuscript; available in PMC 2009 May 14. Published in final edited form as:Nat Rev Neurosci. 2008 June ; 9(6): 437-452. doi:10.1038/nrn2392. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript NRG1 an...

The response of neuregulin 1 mutant mice to acute restraint stress

“…The protein is involved in axon guidance, myelination, and synapse formation. Alternative promoter usage results in numerous splice variant types and more than 30 isoforms [11] and [21]. The isoform variants most commonly expressed in the brain contain a transmembrane domain [10], [11] and [35].…”

The relationship of anterior thalamic radiation integrity to psychosis risk associated neuregulin-1 variants

“…9 The ATR connects the dorsomedial and anterior thalamic nuclei with the prefrontal cortex. If psychosis-risk-related variants of NRG1 disrupt this connection, as we show here, this provides a possible explanation of the abnormal prefrontal function and connectivity often reported in psychosis, and a potential mechanistic link between variation in NRG1 genotype and risk for psychotic disorders.…”

Neuregulin-1 modulates the differentiation of neural stem cells in vitro trough an interaction with the Swi/Snf complex

“…In neurons, Nrg-1-encoded neuregulins induce neuronal migration, and selectively increase the expression of several neurotransmitter receptors (Loeb, 2003). They are also implicated in synaptic plasticity (Mei and Xiong, 2008).…”