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P3‐384: Impaired hippocampal adult neurogenesis in an animal model of Alzheimer's disease
Author(s) -
Halabisky Brian E.,
Sun Binggui,
Zhou Yungui,
Mueller-Steiner Sarah,
Wang Xin,
Yu Giuqiu,
Mucke Lennart,
Gan Li
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.1954
Subject(s) - dentate gyrus , neurogenesis , neuroscience , hippocampal formation , gabaergic , subgranular zone , biology , excitatory postsynaptic potential , neural stem cell , subventricular zone , stem cell , microbiology and biotechnology , inhibitory postsynaptic potential
Background: The hippocampal formation is severely affected by Alzheimer’s disease (AD). It contains the dentate gyrus (DG), which is among the few brain regions in adult rodents and humans in which new neurons are continually born and functionally integrated into the neural network. How A and AD affect the newborn neurons remains to be fully elucidated. Our objective was to assess the effect of amyloid(A ) on neurogenesis, determine underlying mechanisms, and develop strategies to counteract relevant pathogenic processes. Methods: We used human amyloid precursor protein (hAPP) transgenic mice from line J20 and nontransgenic controls at 3 weeks, 2-3 months or 6-7 months of age. Newborn neurons in the subgranular zone of their DG were labeled by stereotaxic injection of a GFP-expressing retroviral vector that only labels cycling progenitor cells. Neuronal dendrites and spines were quantitated by computer-assisted analysis of confocal microscopic images and electrophysiological responses by patch-clamp recordings. Results: At 2-3 weeks after the birth of adult-born neurons, when their response to GABAergic stimulation is still excitatory, adult-born granule cells in hAPP mice had more dendritic spines, received more GABAergic input, and showed stronger excitatory synaptic transmission than adult-born granule cells in controls. New granule cells in hAPP mice also exhibited an accelerated switch from a depolarizing to a hyperpolarizing chloride reversal potential. Thus, adult-born neurons in hAPP mice initially appear to undergo an abnormally accelerated development, which may relate to the excessive GABAergic sprouting in the dentate gyrus of hAPP mice (Neuron 55:697). By 4 weeks after the birth of adult-born neurons, when their response to GABAergic stimulation had switched from excitatory to inhibitory, adult-born granule cells in hAPP mice showed shorter dendrites, fewer dendritic spines, and poorer functional integration into the DG circuitry than controls. Importantly, nicotine treatment restored the normal dendritic and functional development of adult-born neurons in hAPP mice. Conclusions: hAPP/A first accelerates and then impairs the development of adult-born granule cells, possibly through increases in GABAergic input. Nicotine treatment blocks this process, possibly by improving the balance between excitatory and inhibitory activities. Supported by Whittier Foundation.