Schizophrenia (SZ) is a disabling mental disorder that affects ~ 1 % of the population worldwide and the seventh most costly illness in USA. It alters basic brain processes of perception, emotion, and judgment to cause hallucinations, delusions, thought disorder, anhedonia and cognitive deficits. Unlike neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, SZ lacks pathological hallmarks and thus remains one of the least understood brain disorders. SZ is considered a neurodevelopmental disorder, resulting from problems during neural development that lead to impaired neurotransmission and plasticity in adolescent and adult. Although hypofunction of glutamatergic and GABAergic pathways have been implicated, underlying molecular mechanisms are poorly understood. Recent identification of SZ susceptibility genes and studies of their functions have begun to shed light on its pathophysiology. Both neuregulin 1 (NRG1), a growth factor, and its receptor ErbB4 are SZ risk genes in diverse populations based on association studies. This notion is supported by recent meta-analysis, genome-wide association study, and genome-wide copy number analysis. Consistent with the neurodevelopmental hypothesis for SZ, NRG1 and ErbB4 have been implicated in various steps of neural development. In particular, ErbB4 is expressed specifically in interneurons and both in vitro and in vivo studies indicate that ErbB4 plays a critical role in the assembly of the GABAergic circuitry. On the other hand, NRG1 and ErbB4 are expressed in the adult brain; acute treatment with NRG1 increases GABA release in the cortex and hippocampus. Blocking NRG1/ErbB4 signaling reduces GABA release, increases the firing of pyramidal neurons, and enhances long term potentiation (LTP). ErbB4 mutant mice exhibit SZ-relevant behavioral deficits including impaired PPI and working memory. While these observations are exciting, several critical questions are raised. Despite NRG1 and ErbB4 are known to promote GABAergic transmission, a glaring gap in our understanding of their function in the brain is that little is known about exactly how NRG1 stimulates GABA release from interneurons. Are behavioral deficits observed in adult ErbB4 mutant mice due to abnormal neural development, or synaptic dysfunction in adulthood, or both? Can adult ErbB4 expression mitigate behavioral deficits and synaptic dysfunction? To address these questions, we 1) investigate mechanisms by which NRG1 promotes GABA release; 2) identify the critical time window for ErbB4 mutation to cause synaptic dysfunction and behavioral deficits; and 3) investigate the role of ErbB4 kinase activity in synaptic function and behavior by acute inhibition Results will provide proof-of-principle evidence that relevant SZ may be treatable by recovering or restoring ErbB4 expression or activity. Such information could be useful to studies of other SZ susceptibility genes and to development of novel therapeutic strategies of the devastating disorder.
The proposal is to investigate pathophysiological mechanisms of schizophrenia susceptibility genes neuregulin 1 and ErbB4. Results will provide proof-of-principle evidence that relevant schizophrenia may be treatable by recovering or restoring ErbB4 expression or activity and contribute to development of novel therapeutic strategies of the devastating disorder.
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