The Role And Mechanism Of Neuregulin 1 In Odor Discrimination

Schizophrenia is a serious psychiatric illness without definite pathogenesis.People with schizophrenia may experience a range of symptoms including abnormal sensory perception,learning and memory,thought processes,emotion,behaviors and discordance between mentation and environment.Olfactory dysfunctions are implicated in schizophrenia and at-risk youths.These disturbances include deficits in olfactory sensitivity,odor identification,odor discrimination and odor memory.These impairments usually occur at the onset of illness.Odor discrimination deficits are extensively found in schizophrenia,and considered to be a biomarker associated with the development of this psychosis.Thus,to explore the comprehensive mechanism of odor discrimination will be benefit for early diagnosis and treatment of schizophrenia.NRGs(Neuregulins)and their receptors ErbBs(Erythroblastic leukemia viral oncogene homologs)are susceptibility genes of schizophrenia.Postmortem studies on brain have shown that schizophrenia patients have abnormal expression of NRG 1 and ErbB4.Both NRG1 mutant and ErbB4 knock out mouse have neural developmental disorders and schizophrenia-like behaviors.Our previous data have also found that selective knock out ErbB4 in PV(parvalbumin-positive)interneurons caused odor discrimination deficit.These results indicate that NRG1/ErbB4 signaling and odor discrimination have close relationships in the onset and development of schizophrenia.However,their celluar and synaptic circuital mechanisms remain elusive.In this study,we explore the role and mechanism of NRG1/ErbB4 signaling in odor discrimination behavior,which will reveal the pathogenesis of odor discrimination in schizophrenia.Here we took advantage of Sprague Dawley rat and mice specifically knock out ErbB4 in PV-positive neurons(PV-ErbB4-/-mice),and used behavioral analysis,immunoblot and patch clamp electrophysiology techniques to evaluate the role of NRG1/ErbB4 signaling in odor discrimination behavior,ErbB4 expression,spike pattern and neurotransmission of mitral cell in olfactory bulb.Our results showed that:1)Odor discrimination was impaired in PV-ErbB4-/-mice;2)ErbB4 was mainly expressed in PV-positive interneurons in the olfactory bulb;3)NRG1 down-regulated mitral cell activity via ErbB4 in PV-positive interneurons;4)GABAA receptor activation was required for NRG1 down-regulation of mitral cell activity;5)NRG1 increased GABAergic but not glutamatergic neurotransmission via ErbB4 in PV interneurons;6)EPL(External Plexiform Layer)-lateral inhibition was dependent on ErbB4 in PV interneurons;7)NRG1 increased recurrent inhibition via ErbB4 in PV interneurons.In conclusion,selective knock out ErbB4 in PV interneurons leads to odor discrimination deficit,prevents NRG1 from stimulating GABA release and inhibiting mitral cell activity in olfactory bulb.The lateral and recurrent inhibition are also reduced in PV-ErbB4-/-mice.Together,our results indicate that NRG1/ErbB4 signaling regulates odor discrimination and olfactory bulb GABA circuitry development,providing a new perspective to odor processing and potential pathogenic mechanisms of schizophrenia with odor discrimination deficit.It will be also benefit for early diagnosis and treatment of schizophrenia,particularlly for patients with olfactory dysfunction.