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Title: Optogenetic manipulation of slow oscillations in an Alzheimer’s animal model

Ksenia Kastanenka

Massachusetts General Hospital/Harvard Medical School, USA

Biography

Dr. Ksenia Kastanenka is an independent investigator at Massachusetts General Hospital and Harvard Medical School in Boston, MA. Ksenia received her Doctorate of Philosophy in Neuroscience from Case Western Reserve University under the mentorship of Dr. Lynn Landmesser. During doctorate training, Ksenia has developed her expertise in optogenetic control of neuronal circuits by studying and manipulating motoneuron pathfinding during development. Subsequently, Ksenia has joined the laboratory of Drs. Brian Bacskai and Brad Hyman in the Neurology Department at Massachusetts General Hospital and Harvard Medical School to apply optogenetics and multiphoton microscopy in order to dissect the role neural activity plays in onset and development of Alzheimers disease (AD). Ksenia’s work has identified perturbations in neuronal activity stemming from overexcitation within cortical circuits. In an attempt to prevent and/or reverse the disorder, Ksenia has studied the effects and mechanisms of action of AD therapeutics, such as anti-Abeta immunotherapy, aducanumab, and the novel multimodal botanical extract DA-9803. Ksenia strongly believes that these translational studies are important for getting effective therapies to patients.

Abstract

Slow oscillations are important for consolidation of memory during sleep, and Alzheimer’s disease (AD) patients experience memory disturbances. Thus, we sought to examine slow wave activity using the voltage-sensitive dye RH1691 in an animal model of AD (APP mice). The power of slow oscillations at 0.6Hz was decreased starting at 3 months of age. Soluble amyloid-beta was sufficient to disrupt the slow waves. Cortical GABA levels were low in APP mice and application of exogenous GABA restored the slow oscillations, indicating that aberrant excitatory activity within the cortical circuit was responsible for slow oscillation dysfunction. Next we sought to manipulate slow waves in APP mice with optogenetics. Driving slow oscillations at normal frequency with light activation of channelrhodopsin-2 (ChR2) expressed in excitatory cortical neurons restored slow wave power by synchronizing neuronal activity. Using multiphoton microscopy, we performed longitudinal imaging of senile plaques and monitored intracellular calcium. Cytosolic calcium is a surrogate marker of neuronal activity and is normally tightly regulated. We had previously demonstrated that resting calcium levels measured with the genetically encoded calcium sensor YC3.6 were elevated in a subset of neurons in APP transgenics, and hypothesized that an effective treatment would restore calcium to control levels. Driving slow oscillation activity with optogenetics halted amyloid plaque deposition and prevented calcium overload associated with this pathology. On the other hand, driving slow oscillation activity at twice the normal frequency (1.2Hz) resulted in increased amyloid production, increased amyloid plaque deposition, disruptions in neuronal calcium homeostasis, and loss of synaptic spines. Therefore, while restoration of physiological circuit dynamics is sufficient to abrogate the progression of Alzheimer's disease pathology and should be considered an avenue for clinical treatment of patients with sleep disorders, pathophysiological stimulation of neuronal circuits leads to activity dependent acceleration of amyloid production, aggregation and downstream neuronal dysfunction.