Abstract
Excess neural activity in the CA3 region of the hippocampus has been linked to memory impairment in aged rats. We tested whether interventions aimed at reducing this excess activity would improve memory performance. Aged (24 to 28 months old) male Long–Evans rats were characterized in a spatial memory task known to depend on the functional integrity of the hippocampus, such that aged rats with identified memory impairment were used in a series of experiments. Overexpression of the inhibitory neuropeptide Y 13–36 in the CA3 via adeno-associated viral transduction was found to improve hippocampal-dependent long-term memory in aged rats, which had been characterized with impairment. Subsequent experiments with two commonly used antiepileptic agents, sodium valproate and levetiracetam, similarly produced dose-dependent memory improvement in such aged rats. Improved spatial memory with low doses of these agents was observed in both appetitve and aversive spatial tasks. The benefits of these different modalities of treatment are consistent with the concept that excess activity in the CA3 region of the hippocampus is a dysfunctional condition that may have a key role underlying age-related impairment in hippocampal-dependent memory processes. Because increased hippocampal activation occurs in age-related memory impairment in humans as observed in functional neuroimaging, the current findings also suggest that low doses of certain antiepileptic drugs in cognitively impaired elderly humans may have therapeutic potential and point to novel targets for this indication.
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Acknowledgements
This research was supported by National Institute of Neurological Disorders and Stroke Grant NS-35633 to Thomas J McCown and National Institute of Aging Grant P01-AG-09973 to Michela Gallagher.
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No pharmaceutical company or private entity provided support for the present research. The products and services described in this publication are licensed to and are being developed by AgeneBio. Dr Michela Gallagher is the founder and Chairman of AgeneBio. Dr Gallagher owns company stock, which is subject to certain restrictions under University policy. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. The authors (Koh, Haberman and Gallagher) are inventors on Johns Hopkins University intellectual property with patents pending that is under option to license to AgeneBio. Dr Gallagher serves as a member of the Board of Scientific Counselors to the National Institute on Aging and is also a member of the Scientific Advisory Board of the Stanley Center at the Broad Institute. Otherwise, she has had no consulting relationships with other public or private entities in the past 3 years and has no other financial holdings that could be perceived as constituting a potential conflict of interest. Drs. Ming Teng Koh, Rebecca Haberman, Stacey Foti, and Thomas J McCown have received, except for income received from their primary employer, no financial support or compensation from any individual or corporate entity over the past 3 years for research or professional services, and have no financial holdings that could be perceived as constituting a potential conflict of interest.
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Koh, M., Haberman, R., Foti, S. et al. Treatment Strategies Targeting Excess Hippocampal Activity Benefit Aged Rats with Cognitive Impairment. Neuropsychopharmacol 35, 1016–1025 (2010). https://doi.org/10.1038/npp.2009.207
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DOI: https://doi.org/10.1038/npp.2009.207
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