title: Bidirectional Signaling of Neuregulin-2 Mediates Formation of GABAergic Synapses and Maturation of Glutamatergic Synapses in Newborn Granule Cells of Postnatal Hippocampus.
abstract: Expression of neuregulin-2 (NRG2) is intense in a few regions of the adult brain where neurogenesis persists; however, little is understood about its role in developments of newborn neurons. To study the role of NRG2 in synaptogenesis at different developmental stages, newborn granule cells in rat hippocampal slice cultures were labeled with retrovirus encoding tetracycline-inducible microRNA targeting NRG2 and treated with doxycycline (Dox) at the fourth or seventh postinfection day (dpi). The developmental increase of GABAergic postsynaptic currents (GPSCs) was suppressed by the early Dox treatment (4 dpi), but not by late treatment (7 dpi). The late Dox treatment was used to study the effect of NRG2 depletion specific to excitatory synaptogenesis. The Dox effect on EPSCs emerged 4 d after the impairment in dendritic outgrowth became evident (10 dpi). Notably, Dox treatment abolished the developmental increases of AMPA-receptor mediated EPSCs and the AMPA/NMDA ratio, indicating impaired maturation of glutamatergic synapses. In contrast to GPSCs, Dox effects on EPSCs and dendritic growth were independent of ErbB4 and rescued by concurrent overexpression of NRG2 intracellular domain. These results suggest that forward signaling of NRG2 mediates GABAergic synaptogenesis and its reverse signaling contributes to dendritic outgrowth and maturation of glutamatergic synapses.
  
  
  CONCLUSIONS
  The hippocampal dentate gyrus is one of special brain regions where neurogenesis persists throughout adulthood. Synaptogenesis is a critical step for newborn neurons to be integrated into preexisting neural network. Because neuregulin-2 (NRG2), a growth factor, is intensely expressed in these regions, we investigated whether it plays a role in synaptogenesis and dendritic growth. We found that NRG2 has dual roles in the development of newborn neurons. For GABAergic synaptogenesis, the extracellular domain of NRG2 acts as a ligand for a receptor on GABAergic neurons. In contrast, its intracellular domain was essential for dendritic outgrowth and glutamatergic synapse maturation. These results imply that NRG2 may play a critical role in network integration of newborn neurons.
authors.affiliation: Cell Physiology Laboratory Department of Physiology, bioMembrane Plasticity Research Center, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
authors.forename: Kyu-Hee
authors.identifier: http://orcid.org/0000-0001-7835-2645
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Cell Physiology Laboratory Department of Physiology, bioMembrane Plasticity Research Center, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
authors.forename: Hyunsu
authors.initials: H
authors.lastname: Lee
authors.affiliation: Cell Physiology Laboratory Department of Physiology, bioMembrane Plasticity Research Center, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
authors.forename: Che Ho
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Cell Physiology Laboratory Department of Physiology, bioMembrane Plasticity Research Center, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
authors.forename: Jeong-Soon
authors.initials: JS
authors.lastname: Ko
authors.affiliation: Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea.
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Park
authors.affiliation: Department of Anatomy and Neuroscience, College of Medicine, Eulji University, Daejeon 34824, Korea.
authors.forename: Ran-Sook
authors.initials: RS
authors.lastname: Woo
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul 02841, Korea, and.
authors.forename: Joo Yeon
authors.identifier: http://orcid.org/0000-0002-5563-4129
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul 02841, Korea, and.
authors.forename: Woong
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Life Sciences, POSTECH, Pohang 37673, Korea.
authors.forename: Joung-Hun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Cell Physiology Laboratory Department of Physiology, bioMembrane Plasticity Research Center, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
authors.forename: Won-Kyung
authors.initials: WK
authors.lastname: Ho
authors.affiliation: Cell Physiology Laboratory Department of Physiology, bioMembrane Plasticity Research Center, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea, leesukho@snu.ac.kr.
authors.forename: Suk-Ho
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003712:Dendrites / Q000187:drug effects; D004318:Doxycycline / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D005971:Glutamates / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology* / Q000254:growth & development / Q000502:physiology*; D008297:Male; D009414:Nerve Growth Factors / Q000235:genetics* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D066247:Receptor, ErbB-4 / Q000235:genetics / Q000378:metabolism; D018091:Receptors, AMPA / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013569:Synapses / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D005971:Glutamates; D009414:Nerve Growth Factors; C491452:Nrg2 protein, rat; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4; D004318:Doxycycline
keywords: ErbB4; dentate gyrus; neuregulin; neurogenesis; synaptogenesis