title: Neuregulin 1 promotes excitatory synapse development and function in GABAergic interneurons.
abstract: Neuregulin 1 (NRG1) and its receptor ErbB4 are both susceptibility genes of schizophrenia. However, little is known about the underlying mechanisms of their malfunction. Although ErbB4 is enriched in GABAergic interneurons, the role of NRG1 in excitatory synapse formation in these neurons remains poorly understood. We showed that NRG1 increased both the number and size of PSD-95 puncta and the frequency and amplitude of miniature EPSCs (mEPSCs) in GABAergic interneurons, indicating that NRG1 stimulates the formation of new synapses and strengthens existing synapses. In contrast, NRG1 treatment had no effect on either the number or size of excitatory synapses in glutamatergic neurons, suggesting its synaptogenic effect is specific to GABAergic interneurons. Ecto-ErbB4 treatment diminished both the number and size of excitatory synapses, suggesting that endogenous NRG1 may be critical for basal synapse formation. NRG1 could stimulate the stability of PSD-95 in the manner that requires tyrosine kinase activity of ErbB4. Finally, deletion of ErbB4 in parvalbumin-positive interneurons led to reduced frequency and amplitude of mEPSCs, providing in vivo evidence that ErbB4 is important in excitatory synaptogenesis in interneurons. Together, our findings suggested a novel synaptogenic role of NRG1 in excitatory synapse development, possibly via stabilizing PSD-95, and this effect is specific to GABAergic interneurons. In light of the association of the genes of both NRG1 and ErbB4 with schizophrenia and dysfunction of GABAergic system in this disorder, these results provide insight into its potential pathological mechanism.
authors.affiliation: Institute of Molecular Medicine and Genetics and Department of Neurology, Medical College of Georgia, Augusta, Georgia 30912, USA.
authors.forename: Annie K
authors.initials: AK
authors.lastname: Ting
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Wen
authors.forename: Dong-Min
authors.initials: DM
authors.lastname: Yin
authors.forename: Chengyong
authors.initials: C
authors.lastname: Shen
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Tao
authors.forename: Xihui
authors.initials: X
authors.lastname: Liu
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Xiong
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
mesh_terms: D000818:Animals; D001703:Biophysics; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003513:Cycloheximide / Q000494:pharmacology; D000076122:Disks Large Homolog 4 Protein; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D020890:Neuregulin-1 / Q000378:metabolism / Q000494:pharmacology*; D018408:Patch-Clamp Techniques / Q000379:methods; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D066247:Receptor, ErbB-4; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D014162:Transfection / Q000379:methods; D020032:Tyrphostins / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C081020:AG-879; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020890:Neuregulin-1; D011500:Protein Synthesis Inhibitors; D020032:Tyrphostins; D049452:Green Fluorescent Proteins; D005680:gamma-Aminobutyric Acid; D003513:Cycloheximide; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1