Transgenic inactivation of acetylcholinesterase impairs homeostasis in mouse hippocampal granule cells
| Autor: | Amir Dori, Naomi Melamed-Book, Jonathan Cohen, Gabriel Zimmerman, Hermona Soreq, Alon Friedman |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Cell Survival Cognitive Neuroscience Mice Inbred Strains Mice Transgenic Biology Hippocampal formation Gene Expression Regulation Enzymologic Food Preferences Mice chemistry.chemical_compound Conditioning Psychological medicine Animals Homeostasis Neurons Caspase 3 Dentate gyrus Neurogenesis Granule cell Acetylcholinesterase Alternative Splicing Phenotype medicine.anatomical_structure chemistry Dentate Gyrus Cholinergic Neuron Neuroscience Cell Division Acetylcholine medicine.drug |
| Zdroj: | Hippocampus. 18:182-192 |
| ISSN: | 1098-1063 1050-9631 |
| Popis: | In the adult murine hippocampus, dentate gyrus (DG), neurogenesis and neural cell death are thought to affect learning and memory in incompletely understood mechanism(s). Because cholinergic neurotransmission influences both of these functions, we hypothesized that cholinergic signaling, affected by acetylcholinesterase (AChE) activity, expression level, and alternative splicing, may provide a link between these processes. To challenge this hypothesis, we compared DG neurogenesis in transgenic mice overexpressing engineered “synaptic” AChE-S, incapable of acetylcholine (ACh) hydrolysis (TgSin) with strain-matched controls. In control mice, we observed increasing AChE gene expression with progressing neurogenesis. This involved dividing DG neurons expressing proliferating cell nuclear antigen (PCNA) and Tuj1-positive committed neurons compared with neighboring cells. However, TgSin hippocampi with lower hydrolytic AChE activity showed more PCNA-labeled cells than controls. In contrast, TgS mice overexpressing catalytically active AChE-S, with higher than control levels of AChE hydrolytic activity, presented elevated cell labeling by both bromodeoxyuridine and caspase-3, reflecting facilitated survival of newly born neurons as well as increased neural apoptosis. In comparison, overexpression of the stress-induced “readthrough” AChE-R variant in TgR mice resulted in higher hydrolytic activities but unchanged neurogenesis and apoptosis parameters, while all strains presented similar granule cell layer areas, cell density, and neuron numbers. Importantly, this homeostasis was maintained at a cognitive cost: in the hippocampal-dependent socially transmitted food preference task, TgS and TgSin mice showed impaired acquisition and retention, respectively. Our findings suggest that replacement of AChE-S with AChE-R serves to maintain DG homeostasis and associated cognitive tasks, highlighting the role of cholinergic signaling in adult hippocampal neurogenesis and functioning. © 2007 Wiley-Liss, Inc. |
| Databáze: | OpenAIRE |
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