Amyloid Pathology Impairs Experience-Dependent Inhibitory Synaptic Plasticity

Alzheimer's disease patients and mouse models exhibit aberrant neuronal activity and altered excitatory-to-inhibitory synaptic ratio. Using multicolor two-photon microscopy, we test how amyloid pathology alters the structural dynamics of excitatory and inhibitory synapses and their adaptation to altered visual experience in vivo in the visual cortex. We show that the baseline dynamics of mature excitatory synapses and their adaptation to visual deprivation are not altered in amyloidosis. Likewise, the baseline dynamics of inhibitory synapses are not affected. In contrast, visual deprivation fails to induce inhibitory synapse loss in amyloidosis, a phenomenon observed in nonpathological conditions. Intriguingly, inhibitory synapse loss associated with visual deprivation in nonpathological mice is accompanied by subtle broadening of spontaneous but not visually evoked calcium transients. However, such broadening does not manifest in the context of amyloidosis. We also show that excitatory and inhibitory synapse loss is locally clustered under the nonpathological state. In contrast, a fraction of synapse loss is not locally clustered in amyloidosis, indicating an impairment in inhibitory synapse adaptation to changes in excitatory synaptic activity.