Optogenetic Restoration of Disrupted Slow Oscillations Halts Amyloid Deposition and Restores Calcium Homeostasis in an Animal Model of Alzheimer's Disease.

Ksenia V Kastanenka,Jonathan M Hawkes,Steven S Hou,Xiqun Chen,Brian J Bacskai,Susanne Wegmann,Naomi Shakerdge,Vanita Chopra,Robert Logan,Danielle Feng

doi:10.1371/journal.pone.0170275

Ksenia V Kastanenka, Jonathan M Hawkes + Show 8 more

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https://doi.org/10.1371/journal.pone.0170275

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Abstract

Slow oscillations are important for consolidation of memory during sleep, and Alzheimer’s disease (AD) patients experience memory disturbances. Thus, we examined slow oscillation activity in an animal model of AD. APP mice exhibit aberrant slow oscillation activity. Aberrant inhibitory activity within the cortical circuit was responsible for slow oscillation dysfunction, since topical application of GABA restored slow oscillations in APP mice. In addition, light activation of channelrhodopsin-2 (ChR2) expressed in excitatory cortical neurons restored slow oscillations by synchronizing neuronal activity. Driving slow oscillation activity with ChR2 halted amyloid plaque deposition and prevented calcium overload associated with this pathology. Thus, targeting slow oscillatory activity in AD patients might prevent neurodegenerative phenotypes and slow disease progression.

Highlights

Spontaneous slow-wave thalamocortical activity, or slow oscillations, is characterized by oscillatory activity between cortex and thalamus at frequencies less than 1 Hz [1,2,3]
We found that slow oscillations were perturbed in APP mice starting at 3 months of age as imaged with the voltage sensitive dye, RH1691
Slow waves could be restored in these mice with the direct application of gamma-aminobutyric acid (GABA) or by synchronizing network activity with periodic stimulation of channelrhodopsin-2 expressing neurons

Summary

Introduction

Spontaneous slow-wave thalamocortical activity, or slow oscillations, is characterized by oscillatory activity between cortex and thalamus at frequencies less than 1 Hz [1,2,3]. Pyramidal cells in cortical layer 5 generate waves through recurrent excitatory connections [2], while inhibitory interneurons synchronize the activity [5,6]. Imaging with voltage-sensitive dyes (VSDs) in anesthetized and awake animals has allowed visualization of slow oscillations as waves propagating throughout the cortex [7]. Slow waves are responsible for a number of processes including consolidation of memories during sleep [8,9,10]. Since memory processes are perturbed in Alzheimer’s disease (AD), we set out to explore slow oscillatory activity in a mouse model of AD

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