TY - JOUR
T1 - Genetic Ablation of Dentate Hilar Somatostatin-Positive GABAergic Interneurons is Sufficient to Induce Cognitive Impairment
AU - Nagarajan, Rajasekar
AU - Lyu, Jinrui
AU - Kambali, Maltesh
AU - Wang, Muxiao
AU - Courtney, Connor D.
AU - Christian-Hinman, Catherine A.
AU - Rudolph, Uwe
N1 - 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.
PY - 2024/2
Y1 - 2024/2
N2 - 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.
AB - 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.
KW - Aging
KW - Diphtheria toxin
KW - GABAergic interneurons
KW - Microglia
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U2 - 10.1007/s12035-023-03586-3
DO - 10.1007/s12035-023-03586-3
M3 - Article
C2 - 37642935
AN - SCOPUS:85168867562
SN - 0893-7648
VL - 61
SP - 567
EP - 580
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 2
ER -