Date Published: January 23, 2017
Publisher: Public Library of Science
Author(s): Ksenia V. Kastanenka, Steven S. Hou, Naomi Shakerdge, Robert Logan, Danielle Feng, Susanne Wegmann, Vanita Chopra, Jonathan M. Hawkes, Xiqun Chen, Brian J. Bacskai, Stephen D Ginsberg.
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.
Spontaneous slow-wave thalamocortical activity, or slow oscillations, is characterized by oscillatory activity between cortex and thalamus at frequencies less than 1 Hz [1–3]. Slow waves alternate between depolarized (up state) and hyperpolarized (down state) membrane potentials. Cortical activity is solely responsible for transition of states . Pyramidal cells in cortical layer 5 generate waves through recurrent excitatory connections , 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 . Slow waves are responsible for a number of processes including consolidation of memories during sleep [8–10]. Since memory processes are perturbed in Alzheimer’s disease (AD), we set out to explore slow oscillatory activity in a mouse model of AD.
The current work identified alterations in slow cortical oscillations in APP mice before and after plaque deposition compared to wildtype controls. Because of the importance of slow oscillations in the consolidation of memories, this finding could have a large impact on the way the progression of Alzheimer’s disease is viewed. We found that slow oscillations were perturbed in APP mice starting at 3 months of age as imaged with the voltage sensitive dye, RH1691. This constitutes an early event in disease progression, since this is a time point prior to initiation of plaque deposition. Slow waves could be restored in these mice with the direct application of GABA or by synchronizing network activity with periodic stimulation of channelrhodopsin-2 expressing neurons. Mice whose cortical activity was driven continuously for 1 month with this approach showed a remarkable reduction in the rate of amyloid plaque deposition and the complete absence of neurons with elevated intracellular calcium. These results suggest first that amyloid pathology leads to altered neural network properties resulting from alterations in GABAergic neurotransmission, and second that modulation of inhibitory neurotransmission should be considered a therapeutic target for the treatment or prevention of Alzheimer’s disease.