UCSF

The hippocampus, critical for learning and memory, is one of the first brain regions impacted by Alzheimer’s disease (AD). Studies of the major genetic risk factor for AD, apolipoprotein E4 (apoE4), have implicated hilar GABAergic interneurons in the dentate gyrus of the hippocampus as a population particularly vulnerable to apoE4-induced damage. This thesis investigates the role of hilar GABAergic interneurons in learning and memory and characterizes apoE4-induced changes in hippocampal network activity that may underlie the development of learning and memory impairment. By using optogenetic techniques to inhibit hilar interneurons in a spatially and temporally restricted manner, we show that the loss of this population is sufficient to cause learning and memory impairment. This extends previous findings to suggest that the loss of hilar interneurons in apoE4 knock-in (KI) mice is a likely driver of learning and memory impairment. Furthermore, to investigate the network activity changes that result from interneuron loss and disrupt hippocampal learning and memory processes, we used chronic electrode arrays to record local field potentials from all major subregions of the hippocampus in freely behaving apoE3-KI and apoE4-KI mice. We found that hippocampal sharp-wave ripples (SWRs), a signature of memory replay critical for consolidation and retrieval processes, showed two major abnormalities in the apoE4-KI mice. First, they occurred less frequently than in apoE3-KI mice. Second, they showed reduced slow gamma activity during SWRs—a frequency component thought to be important for the organization and accuracy of replay. The removal of apoE4 from interneurons with a Cre-specific deletion has been shown to rescue learning and memory in apoE4-KI mice, and we show that this also causes selective rescue of the slow gamma impairment but not the reduced SWR abundance. This suggests that the slow gamma reduction during SWRs in apoE4-KI mice is driven by interneuron dysfunction and may critically contribute to the learning and memory deficits seen in apoE4-KI mice. Together, the optogenetic study and the local field potential recording study reveal critical roles for hilar GABAergic interneurons, and the dentate gyrus as a whole, in normal learning and memory as well as in AD.