High Level Of NRG1 Impairs Development Of Dendritic Spine

Schizophrenia(SZ)is a disabling mental disorder that affects 1% of the population worldwide.However,it is still unclear about the pathogenesis of the disease.More and more evidences show that genetic factor play a significant role in the pathogenesis of SCZ.Recent genetic studies have provided insights into associations of more regions in human chromosomes and genes with SCZ.Among these genes,the genes encoding neuregulin1(NRG1)and its receptor ErbB4 have been identified as a SCZ susceptibility gene in different populations.Most single nucleotide polymorphisms(SNPs)in NRG1 gene which are associated with SCZ are located in the non-coding region,like promoter or introns.So how these SNPs lead to SCZ? One explanation is that these SNPs may alter the expression of NRG1.Moreover,both mRNA and protein levels of NRG1 are found to be increased in the prefrontal cortex(PFC)and hippocampus of SCZ patients.Likewise,NRG1/ErbB4 signaling was also increased in the forebrain of SCZ patients.Accordingly,transgenic mice with overexpression of NRG1 exhibit SCZ-relevant behavioral defects.However,it is not clear that how high level of NRG1 leads to SCZ.Therefore,our lab generate ctoNrg1 mice in which NRG1 is overexpress in forebrains including prefrontal cortex(PFC)and hippocampus,mimicking high levels of NRG1 in SCZ patients.Firstly,we recorded the miniature excitatory postsynaptic currents(mEPSCs)of pyramidal neurons in PFC and found that the frequency of mEPSCs was reduced in ctoNrg1 mice,which suggests impaired glutamate release or fewer functional synapses.SCZ is a neurodevelopmental disorder and density of dendritic spine is reduced in SCZ patients.We overexpressed NRG1 in primary hippocampal neurons and found the spine density is reduced.The reduction is in dose-dependent manner with NRG1 levels.The Golgi staining also showed that spine density has a significant decrease inPFC and hippocampus of ctoNrg1 mice.Nrg1 is localized to the PSDs.Previous researches have report that LIMK1 is involved in the development of dendritic spine.LIMK1 interacts with the intracellular domain of NRG1.Overexpression of NRG1 promotes the LIMK1/cofilin signaling.Moreover,the reduced spine density in NRG1 overexpressed primary hippocampal neurons can be rescued by adding DMN,a LIMK1 inhibitor.These results will identify a pathological mechanism that high level of NRG1 over activates LIMK1 and impairs the development of dendritic spine,thus leading to SCZ.