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

Abstract

AbstractAging is often associated with a decline in cognitive function. A reduction in the number of somatostatin-positive (SOM+) interneurons in the 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 diptheria toxin transgene specifically in these interneurons. An AAV-EF1α-mCherry-flex-dtA construct was stereotaxically injected (bilaterally) into the DG hilus of young adult Sst-IRES-Cre mice, which resulted in an approximately 50% reduction in the number of SOM+ neurons and also a reduction in the number of GAD-67+ neurons in the DG hilus. c-Fos staining was increased in DG and CA3 but not in CA1. Behavioral testing, which started 21 days after the stereotaxic injections, 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.