Neural Synaptic Circuit Changes During Alzheimer’s Disease Progression


Functional disruptions in Alzheimer’s disease (AD) have been well characterized. However, how AD affects the synaptic connectivity in neuronal networks leading to these functional disruptions has remained poorly understood. One major research direction in the principal investigator’s laboratory has been to investigate the synaptic mechanisms, in particular excitatory and inhibitory synaptic circuit mechanisms, underlying visual information processing in the mouse primary visual cortex (V1), by applying challenging electrophysiological techniques such as in vivo whole-cell voltage clamp recording and two-photon imaging guided patch recording in normal healthy mice. This project proposes to apply similar techniques to disease models related to AD. Malfunctioning of the blood-brain barrier (BBB) has been strongly implicated in contributing to the onset and progression of AD. Since the BBB is important for maintaining normal functioning of neural circuits in the brain, pericyte diseases that cause BBB malfunction may result in abnormal neural circuit computation and information processing even before neuronal degeneration, which is a hallmark of AD. Using awake mouse visual cortex as a model system, this project will test a central hypothesis that pericyte degeneration initiates disruption of cortical information processing by selectively injuring some specific types of cortical inhibitory neurons, resulting in alterations of the balance between excitatory (E) and inhibitory (I) synaptic circuits and weakening of coordinated control of brain activity prior to neurodegenerative changes. In collaboration with Dr. Berislav Zlokovic, a renowned scientist in the fields of pericyte biology, BBB and AD, the PI will test the hypothesis in two BBB deficiency mouse models: inducible pericyte-ablation model, and pericyte deficiency and rescue model. The group will examine functional spiking responses of excitatory and inhibitory neurons in V1 of these mouse models, as well as visually evoked excitatory and inhibitory synaptic inputs to individual cortical neurons, at different disease progression stages. Overall, the proposed studies will generate substantial understanding of how changes in the E/I balance contribute to the disruptions of neural circuit computation during AD disease progression.

Funding to Date



Studies of Alternative Neurodegenerative Pathways, Translational


Huizhong W. Tao, Ph.D.