Genetic inactivation of synaptosomal‐associated protein 25 (SNAP‐25) in adult hippocampal neural progenitors impairs pattern discrimination learning but not survival or structural maturation of newborn dentate granule cells

• Published in: Hippocampus 2018-10, Vol.28 (10), p.735-744
• Main Authors: Gustus, Kymberly C., Li, Lu, Chander, Praveen, Weick, Jason P., Wilson, Michael C., Cunningham, Lee Anna
• Format: Article
• Language: English
• Subjects: Action potential; Adult hippocampal neurogenesis; Animals; Animals, Newborn; Cells, Cultured; Cognition; contextual fear discrimination; Dendritic branching; Discrimination learning; Discrimination Learning - drug effects; Discrimination Learning - physiology; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - genetics; Fear - physiology; Glutamic Acid - pharmacology; Granule cells; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Hippocampus; Hippocampus - cytology; Hippocampus - growth & development; Learning Disabilities - genetics; Learning Disabilities - pathology; memory; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nestin - genetics; Nestin - metabolism; Neural stem cells; Neurogenesis; Neurogenesis - physiology; Neurons - drug effects; Neurons - physiology; Neurotransmitter release; Phosphopyruvate Hydratase - metabolism; RNA, Messenger - metabolism; Statistical analysis; synaptic neurotransmission; Synaptic transmission; Synaptosomal-Associated Protein 25 - deficiency; Synaptosomal-Associated Protein 25 - genetics; Tamoxifen; time; Transfection; Transgenic mice
• ISSN: 1050-9631; 1098-1063
• DOI: 10.1002/hipo.23008

Adult neurogenesis is necessary for proper cognition and behavior, however, the mechanisms that underlie the integration and maturation of newborn neurons into the pre‐existing hippocampal circuit are not entirely known. In this study, we sought to determine the role of action potential (AP)‐dependent synaptic transmission by adult‐generated dentate granule cells (DGCs) in their survival and function within the existing circuitry. We used a triple transgenic mouse (NestinCreERT2:Snap25fl/fl: tdTomato) to inducibly inactivate AP‐dependent synaptic transmission within adult hippocampal progenitors and their progeny. Behavioral testing in a hippocampal‐dependent A/B contextual fear‐discrimination task revealed impaired discrimination learning in mice harboring SNAP‐25‐deficient adult‐generated dentate granule cells (DGCs). Despite poor performance on this neurogenesis‐dependent task, the production and survival of newborn DGCs was quantitatively unaltered in tamoxifen‐treated NestinCreERT2:Snap25fl/fl: tdTomato SNAP compared to tamoxifen‐treated NestinCreERT2:Snap25wt/wt: tdTomato control mice. Although SNAP‐25‐deficient adult DGCs displayed a small but statistically significant enhancement in proximal dendritic branching, their overall dendritic length and distal branching complexity was unchanged. SNAP‐25‐deficient newborn DGCs also displayed robust efferent mossy fiber output to CA3, with normal linear density of large mossy fiber terminals (LMTs). These studies suggest that AP‐dependent neurotransmitter release by newborn DGCs is not essential for their survival or rudimentary structural maturation within the adult hippocampus.