Hippocampal interneurons in novel memory formation in health and Alzheimer's disease

Remembering precise locations of importance is a key component of spatial memory. Over the past few decades, extensive prior work has shown that excitatory pyramidal cells in hippocampus code for various spatially relevant cues. Hippocampal inhibitory interneurons have been ascribed important roles in generating oscillations and maintaining optimal levels of excitatory activity, but their role in spatial memory formation is unclear. Understanding the role of interneurons in memory formation processes is crucial because several studies have revealed deficits in inhibition due to Alzheimer’s disease (AD) pathology such as elevated amyloid beta. Among other types of inhibitory interneurons, parvalbumin-positive (PV) interneurons are especially susceptible to AD pathology and directly inhibit excitatory cells. Spatial navigation deficits and hippocampal dysfunction occur early in AD but exactly how hippocampal PV inhibitory deficits contribute to impaired memory remains uncertain. Thus, there is an urgent unmet need to understand the role of hippocampal inhibitory interneurons in forming representations of new experiences and to determine how this process fails due to AD pathology. Elucidating the role of PV inhibition in memory formation requires causal manipulations to record and stimulate PV activity in a cell-type specific and temporally precise manner. Accordingly, these studies will record the electrical activity of many inhibitory and excitatory neurons simultaneously and selectively stimulate PV interneurons in mice acquiring novel spatial memory. The proposed research will use closed-loop optogenetic stimulation to specifically abolish or generate particular patterns of PV activity in healthy mice and in mouse models of Aβ pathology. With these approaches, the planned studies will test the hypothesis that intact inhibitory activity is necessary for normal memory formation and altered inhibitory activity disrupts memory formation in mouse models of Aβ pathology. This research will show how vulnerability of PV interneurons to AD pathology leads to impaired spatial learning and memory formation. These findings will lead to new stimulation and pharmacological treatments for AD based on restoring PV function.