Maintaining Activity Set-Points in the Hippocampus: From Long-Term Dynamics of Excitatory and Inhibitory Synapses to Functional Stability of CA1 Circuits.

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How neuronal circuits maintain the balance between stability and plasticity in a constantly changing environment remains a fundamental question in neuroscience. Empirical and theoretical studies suggest that homeostatic control systems stabilize neuronal activity at a specific set-point. In the hippocampus, the high levels of synaptic turnover and neuronal plasticity together with the constant generation of new neurons pose a challenge for homeostatic systems. Here, we propose to explore the relationship between structural and functional plasticity of hippocampal synapses and firing rate stability in hippocampal circuits in vivo by addressing three key open questions. First, is high turnover of synapses part of a homeostatic system, necessary to stabilize neuronal activity? Second, is invariance of population activity a function of the ability of single neurons to maintain stable firing properties or rather is an emerging property of a network of intrinsically unstable neurons? Third, how do molecular homeostatic mechanisms that stabilize neuronal activity affect hippocampal synaptic plasticity?To address these questions, we will use chronic optical imaging to track excitatory and inhibitory synapse dynamics and neuronal activity at the level of individual neurons and neuronal populations in the hippocampal CA1 area of live mice for extended periods of time. We will then investigate the relationship between synaptic plasticity, firing homeostasis and adaptive mechanisms by employing chemogenetic and electrical approaches to induce chronic hyperactivity in the CA3 area. Finally, we will explore the causal relationship between synapse loss and renormalization of activity upon temporary hyper activation by reducing synaptic loss by knockdown of AMPK signaling pathway and testing the effects of this manipulation on firing homeostasis in CA1. As aberrant network activity and impaired synaptic plasticity represent a hallmark of numerous brain disorders, including temporal lobe epilepsy and Alzheimer’s disease, our study will offer novel conceptual insights into the pathogenesis of these disorders.