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. memory consolidation | neurogenesis | plasticity | hippocampus | transcription factor N ew neurons are continuously generated in adult life in discrete regions of the mammalian brain, including in the dentate gyrus (DG) of the hippocampus (1). After birth, the majority of newborn dentate granule cells (DGCs) follow a 2-mo race of development to become fully mature and integrate into existing circuits (2-4), a condition for their contribution to hippocampal functions, in particular to hippocampal-dependent learning and memory and spatial pattern discrimination (5). The cells' involvement as part of neuronal networks supporting learning and memory is believed to be timelocked to a critical stage of maturation (6). From the second week after birth, axons of newborn DGCs elongate (3) and contact hilar and CA3 pyramidal cells (7), then dendrites extend in the molecular layer and spines start to appear (2, 3). Newborn DGCs are initially tonically activated by ambient depolarizing GABA and then hyperpolarized after the gradual conversion of Cl − cotransporter expression (8), along with expression of glutamate receptors and their progressive responsiveness to glutamatergic inputs (8, 9). At this stage, they are hyperexcitable, display properties of enhanced synaptic plasticity, and are prone to integrate the existing hippocampal neurocircuitry (10-12). As their functional maturation progresses, however, newborn DGCs compete to survive, ...

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