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bioRxiv · 10.1101/465112

Optogenetic activation of SST-positive interneurons restores hippocampal theta oscillation impairment induced by soluble amyloid beta oligomers in vivo

Chung, H.·Park, K.·Jang, H. J.·Kohl, M. M.·Kwag, J.
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Abstract

Abnormal accumulation of amyloid {beta} oligomers (A{beta}O) is a hallmark of Alzheimers 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 A{beta}O selectively impairs these SST+ and PV+ interneurons. To selectively manipulate SST+ or PV+ interneuron activity in mice with A{beta}O pathology in vivo, we co-injected A{beta}O 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 A{beta}O-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 A{beta}O-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 A{beta}O 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 A{beta}O-injected mice in vivo. Our findings identify SST+ interneurons as a target for restoring theta-frequency oscillations in early AD.

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Chung, H., Park, K., Jang, H. J., Kohl, M. M., Kwag, J.. 2018-11-07. Optogenetic activation of SST-positive interneurons restores hippocampal theta oscillation impairment induced by soluble amyloid beta oligomers in vivo. https://doi.org/10.1101/465112

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