Neuregulin-1 ( NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD)-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an “optimal” level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. Our data provide a potential pathomechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect.
Iscia Lopes-Cendes is a physician scientist, professor of Medical Genetics and head of the laboratory of Molecular Genetics at the department of Medical Genetics, School of Medical Sciences, University of Campinas (UNICAMP), Brazil. She obtained her M.D. Degree at UNICAMP, followed by a medical specialty training in pediatrics. The SGC-UNICAMP Protein Kinase Chemical Biology Center is looking for a motivated and proactive postdoc to run a project in mass spectrometry-based quantitative proteomics in collaboration with the Laboratory of Neuroproteomics (LNP), located at UNICAMP, Campinas, Brazil.
.Part of thebook series (MIMB, volume 1546) AbstractIn the case of major psychiatric disorders such as schizophrenia, shortcomings in the conversion of scientific discoveries into newer and safer treatment options has led to a loss of confidence and precipitated a crisis for large pharmaceutical companies. This chapter describes how incorporation of multiplex biomarker approaches into the clinical pipeline can lead to better patient characterization, delivery of novel treatment approaches and help to renew efforts in this important area. The development of specific biomarker test panels for disease prediction should facilitate early intervention strategies, which may help to slow disease development or progression.
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Furthermore, the development of such tests using lab-on-a-chip and smartphone platforms will help to shift diagnosis and treatment of this major disorder into a point-of-care setting for improved patient outcomes.