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bioRxiv · 10.1101/2022.11.01.514756

Genetic ablation of dentate hilar somatostatin-positive GABAergic interneurons is sufficient to induce cognitive impairment

Nagarajan, R.·Lyu, J.·Kambali, M.·Wang, M.·Courtney, C. D.·Christian-Hinman, C. A.·Rudolph, U.
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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 in CA1. Behavioral testing revealed a reduced recognition index in the novel object recognition test, a reduction in the percentage of correct alternations in the Y maze tests, and increased latencies and path lengths in the learning and the reversal learning phase 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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Nagarajan, R., Lyu, J., Kambali, M., Wang, M., Courtney, C. D., Christian-Hinman, C. A., Rudolph, U.. 2022-11-02. Genetic ablation of dentate hilar somatostatin-positive GABAergic interneurons is sufficient to induce cognitive impairment. https://doi.org/10.1101/2022.11.01.514756

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