Two-photon imaging of neural networks in a mouse model of Alzheimer's disease

In humans, Alzheimer's disease (AD) develops over many years. It comprises a chain of subtle yet irreversible alterations in brain function, finally leading to impairment of memory and cognition. Presymptomatic and thus invisible in humans, these alterations can be studied in the animal models of AD. Mouse models of the disease expressing AD-related proteins with familial mutations reproduce several pathological hallmarks of AD. Although the models do not recapitulate the abundant neuronal loss seen in humans, they offer a unique opportunity to learn more about synaptic and cellular mechanisms underlying the disease (both in their essence and in their temporal sequence) through in vivo analyses of brain function. This, however, requires in vivo monitoring of brain function in aged living animals at both a single-cell and network level. Tools developed over the last several decades can be used to selectively mark and to visualize in vivo many important elements of the diseased brain parenchyma, such as amyloid plaques, individual neurons, and glial and microglial cells. Here we describe a method in which cell-type-specific labeling of neurons and glia is combined with in vivo two-photon calcium imaging and fluorescent labeling of amyloid plaques to study functional properties of cortical circuits in a mouse model of AD.