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Abnormal accumulation of amyloid β oligomers (AβO) is a hallmark of Alzheimer's disease (AD), which leads to learning and memory deficits. Hippocampal theta oscillations that are critical in spatial navigation, learning and memory are impaired in AD. Since GABAergic interneurons, such as somatostatin-positive (SST+) and parvalbumin-positive (PV+) interneurons, are believed to play key roles in the hippocampal oscillogenesis, we asked whether AβO selectively impairs these SST+ and PV+ interneurons. To selectively manipulate SST+ or PV+ interneuron activity in mice with AβO pathology in vivo , we co-injected AβO and adeno-associated virus (AAV) for expressing floxed channelrhodopsin-2 (ChR2) into the hippocampus of SST-Cre or PV-Cre mice. Local field potential (LFP) recordings in vivo in these AβO-injected mice showed a reduction in the peak power of theta oscillations and desynchronization of spikes from CA1 pyramidal neurons relative to theta oscillations compared to those in control mice. Optogenetic activation of SST+ but not PV+ interneurons in AβO-injected mice fully restored the peak power of theta oscillations and resynchronized the theta spike phases to a level observed in control mice. In vitro whole-cell voltage-clamp recordings in CA1 pyramidal neurons in hippocampal slices treated with AβO revealed that short-term plasticity of SST+ interneuron inhibitory inputs to CA1 pyramidal neurons at theta frequency were selectively disrupted while that of PV+ interneuron inputs were unaffected. Together, our results suggest that dysfunction in inputs from SST+ interneurons to CA1 pyramidal neurons may underlie the impairment of theta oscillations observed in AβO-injected mice in vivo . Our findings identify SST+ interneurons as a target for restoring theta-frequency oscillations in early AD.

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