Final Report Summary - ABATSYNAPSE (Evolution of Alzheimer’s Disease: From dynamics of single synapses to memory loss)
During recent years, the preclinical stage of Alzheimer's disease (AD) has become a major focus of research. Continued failures in clinical trials and the realization that early intervention may offer better therapeutic outcome triggered a conceptual shift from the late-stage AD pathology to the early-stage pathophysiology. While much effort has been directed to understand the factors initiating AD, little is known about the principle basis underlying the disease progression at its early stages. In this project, we explored the transition from ‘silent’ signatures of aberrant neural circuit activity to clinically evident memory impairments. Namely, we hypothesized that failure in firing homeostasis in hippocampal circuits represents the driving force of early disease progression. To test this hypothesis, we studied how firing homeostasis is maintained in hippocampal networks and what are the mechanisms that may cause the hyperactivity of hippocampal circuits associated with AD. Our results suggest that distributions of spontaneous population firing rates and synchrony are subject to accurate homeostatic control. Changes in firing rate trigger synaptic and intrinsic adaptive responses operating as global homeostatic mechanisms to maintain firing macro-stability, without achieving local homeostasis at the single-neuron level. Adaptive mechanisms, while stabilizing population firing properties, may reduce short-term facilitation essential for working memory function. These results suggest that invariant ongoing population dynamics emerge from intrinsically unstable activity patterns of individual neurons and synapses. The observed differences in the precision of homeostatic control at different spatial scales challenge cell-autonomous theory of network homeostasis and suggest existence of network-wide regulation rules. While neural network stability is maintained under normal, physiological conditions, our study suggest that some perturbations and experiences disrupt it under pathological conditions. For example, we found that sensory-deprivation and deficits in GABA(B)R-mediated inhibition disrupt neuronal homeostasis. Moreover, we uncovered aberrant IGF-1R signaling causes hippocampal hyperactivity in AD mouse model via misregulation of mitochondrial functions in energy production and calcium buffering. This project shed new light on the principal basis of neural circuits’ stability and uncovered new mechanisms underlying AD progression.