title: Zif268/egr1 gene controls the selection, maturation and functional integration of adult hippocampal newborn neurons by learning.
abstract: New neurons are continuously added to the dentate gyrus of the adult mammalian brain. During the critical period of a few weeks after birth when newborn neurons progressively mature, a restricted fraction is competitively selected to survive in an experience-dependent manner, a condition for their contribution to memory processes. The mechanisms that control critical stages of experience-dependent functional incorporation of adult newborn neurons remain largely unknown. Here, we identify a unique transcriptional regulator of the functional integration of newborn neurons, the inducible immediate early gene zif268/egr1. We show that newborn neurons in zif268-KO mice undergo accelerated death during the critical period of 2-3 wk around their birth and exhibit deficient neurochemical and morphological maturation, including reduced GluR1 expression, increased NKCC1/KCC2b chloride cotransporter ratio, altered dendritic development, and marked spine growth defect. Investigating responsiveness of newborn neurons to activity-dependent expression of zif268 in learning, we demonstrate that in the absence of zif268, training in a spatial learning task during this critical period fails to recruit newborn neurons and promote their survival, leading to impaired long-term memory. This study reveals a previously unknown mechanism for the control of the selection, functional maturation, and experience-dependent recruitment of dentate gyrus newborn neurons that depends on the inducible immediate early gene zif268, processes that are critical for their contribution to hippocampal-dependent long-term memory.
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8195, F-91405 Orsay, France. alexandra.veyrac@u-psud.fr
authors.forename: Alexandra
authors.initials: A
authors.lastname: Veyrac
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gros
authors.forename: Elodie
authors.initials: E
authors.lastname: Bruel-Jungerman
authors.forename: Christelle
authors.initials: C
authors.lastname: Rochefort
authors.forename: Felix B
authors.initials: FB
authors.lastname: Kleine Borgmann
authors.forename: Sebastian
authors.initials: S
authors.lastname: Jessberger
authors.forename: Serge
authors.initials: S
authors.lastname: Laroche
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine; D018891:Dentate Gyrus / Q000737:chemistry / Q000254:growth & development*; D051766:Early Growth Response Protein 1 / Q000235:genetics* / Q000502:physiology; D007150:Immunohistochemistry; D018782:Maze Learning / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology*; D018091:Receptors, AMPA / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D000096922:K Cl- Cotransporters
chemical_list: D001973:Bromodeoxyuridine; D051766:Early Growth Response Protein 1; D018091:Receptors, AMPA; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D014157:Transcription Factors; D000096922:K Cl- Cotransporters; C486109:Egr1 protein, mouse; C578878:Slc12a2 protein, mouse