Dentate gyrus network regulation by somatostatin- and parvalbumin-expressing interneurons differentially impacts hippocampal spatial memory processing

Abstract

GABAergic interneurons regulate circuit dynamics in hippocampal structures such as CA1 that appear to be essential for memory processing. The dentate gyrus (DG) is known to play a role in pattern recognition and spatial working memory. However, the role of the DG in different stages of long-term spatial memory is poorly understood. Moreover, the roles of the predominant interneuron subtypes within the DG - somatostatin-expressing (SST+) and parvalbumin-expressing (PV+) - in different stages of memory processing are unknown. We tested how chemogenetic manipulation of DG SST+ and PV+ interneurons in mice influences the encoding, consolidation, and retrieval of hippocampus-dependent object-location memory (OLM). We find that activation of DG SST+ interneurons impairs both OLM encoding and retrieval, dramatically suppresses DG granule cell cFos expression, and (in the case of encoding) suppresses downstream CA1 network activity. Among individual mice, the degree of DG granule cell suppression is proportional to the extent of SST+ interneuron activation, and predicts the extent of OLM deficits. In striking contrast, PV+ interneuron activation selectively disrupts encoding, but not retrieval, of OLM, and minimally impacts DG or downstream hippocampal network activity. These findings demonstrate that regulation of the DG network by SST+ and PV+ interneurons differentially contributes to the various stages of spatial memory processing, and suggest that distinct network mechanisms are engaged in the hippocampus during each processing stage. Significance statementNeuronal activity within the dentate gyrus (DG) of the hippocampus is regulated by multiple populations of inhibitory interneurons. To understand how inhibitory regulation contributes to spatial memory processing, we experimentally activated two major classes of DG inhibitory interneurons in mice - either during spatial learning, spatial memory storage, or memory recall. We find spatial learning is disrupted by activation of either SST+ or PV+ interneuron populations, although the two manipulations differentially affect hippocampal activity. Somewhat surprisingly, activation of neither inhibitory population affects spatial memory storage, only SST+ interneuron activation disrupts recall, and the hippocampal activity patterns affected by inhibition differ between learning and recall. These data provide a clearer understanding of the circuits engaged by different steps of spatial memory processing.