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Genetic Ablation of Dentate Hilar Somatostatin-Positive GABAergic Interneurons is Sufficient to Induce Cognitive Impairment

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Abstract

Aging is often associated with a decline in cognitive function. A reduction in the number of somatostatin-positive (SOM+) interneurons in the dentate gyrus (DG) has been described in cognitively impaired but not in unimpaired aged rodents. However, it remains unclear whether the reduction in SOM + interneurons in the DG hilus is causal for age-related cognitive dysfunction. We hypothesized that hilar SOM+ interneurons play an essential role in maintaining cognitive function and that a reduction in the number of hilar SOM + interneurons might be sufficient to induce cognitive dysfunction. Hilar SOM+ interneurons were ablated by expressing a diphtheria toxin transgene specifically in these interneurons, which resulted in a reduction in the number of SOM+ /GAD-67+ neurons and dendritic spine density in the DG. C-fos and Iba-1 immunostainings were increased in DG and CA3, but not CA1, and BDNF protein expression in the hippocampus was decreased. Behavioral testing showed a reduced recognition index in the novel object recognition test, decreased alternations in the Y maze test, and longer latencies and path lengths in the learning and reversal learning phases of the Morris water maze. Our results show that partial genetic ablation of SOM+ hilar interneurons is sufficient to increase activity in DG and CA3, as has been described to occur with aging and to induce an impairment of learning and memory functions. Thus, partial ablation of hilar SOM + interneurons may be a significant contributing factor to age-related cognitive dysfunction. These mice may also be useful as a cellularly defined model of hippocampal aging.

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Acknowledgements

The research reported in this study was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R01GM128183 to U.R. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Dr. CheMyong Ko for providing access to his microscopes.

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Authors and Affiliations

  1. Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Rajasekar Nagarajan, **rui Lyu, Maltesh Kambali, Muxiao Wang & Uwe Rudolph

  2. Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    **rui Lyu, Muxiao Wang, Connor D. Courtney, Catherine A. Christian-Hinman & Uwe Rudolph

  3. Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Catherine A. Christian-Hinman

  4. Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Catherine A. Christian-Hinman

  5. Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Uwe Rudolph

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Contributions

Conceptualization: UR; investigation: RN; analysis and interpretation: RN, JL, UR; methodology: RN, JL, MK, MW, CAC-H, CDC, UR; funding acquisition: UR; supervision: UR; writing – original draft: RN, UR; writing – review and editing: RN, JL, MK, MW, CDC, CAC-H, UR.

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Correspondence to Uwe Rudolph.

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Uwe Rudolph is a Scientific Advisor to Damona Pharmaceuticals. The other authors declare no competing interests.

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Nagarajan, R., Lyu, J., Kambali, M. et al. Genetic Ablation of Dentate Hilar Somatostatin-Positive GABAergic Interneurons is Sufficient to Induce Cognitive Impairment. Mol Neurobiol 61, 567–580 (2024). https://doi.org/10.1007/s12035-023-03586-3

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