Neuregulins and Neuronal Plasticity: Their Possible Relevance in Schizophrenia Polymorphisms in the Neuregulin-1 (NRG-1) and ErbB-4 receptor genes have been genetically associated in numerous cohort and family studies with schizophrenia, a prevalent developmental psychiatric disorder that afflicts over 1% of the population worldwide. Importantly, a NRG-1 polymorphism is associated with poor cognitive function and increased risk of psychosis, two characteristics associated with schizophrenia. Moreover, biochemical analyses of synaptic proteins in membranes isolated from postmortem brains of afflicted individuals indicate that the NRG-ErbB signaling pathway is altered in schizophrenia.
Neuregulins are a family of trophic and differentiation factors that signal via the ErbB receptor tyrosine kinase family; ErbB-4 is the major receptor expressed in neurons. We, and others, have shown that NRG/ErbB signaling during development and in the adult regulates the expression of neurotransmitter receptors for glutamate, GABA and acetylcholine), myelination, and neuronal migration. Our recent work indicates the NRG signaling regulates plasticity at glutamatergic synapses, an intriguing finding given the importance of these functions for memory and cognition, and because of the proposed deficits in glutamate neurotransmission associated with schizophrenia. Interestingly, the activation of ErbB-4 receptors in the hippocampus reverses long-term potentiation at glutamatergic synapses by selectively promoting the internalization of GluR1-containing AMPA receptors. Interestingly, genetically altered mice that express lower levels of NRG-1 and ErbB-4 exhibit a series of alte! red behaviors that are similar to other animal models of schizophrenia, and treatment of these mutants with antipsychotics ameliorates their symptoms. The continued focus of our laboratory will be to use animal models to elucidate how imbalances in the NRG/ErbB signaling pathway regulate neuronal function and behavior, with the ultimate goal of understanding how this pathway can contribute to normal brain function and alterations associated psychiatric disorders.
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