Homeostasis of hippocampal circuits: From intracellular Ca2+ stores to firing stability

• Applicant: Professor Silvio-Olivier Rizzoli, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 440813539

How neurons and neural networks, which are composed from highly dynamic molecules with relatively short half-lives, maintain stable firing rates remains one of the most fundamental questions in neuroscience. A key element in this system is the Ca2+ homeostasis. While tremendous progress has been made during the last 50 years in our understanding of the coupling between action potential dynamics and intracellular Ca2+ dynamics, and their role in neurotransmitter release, the link between Ca2+ homeostasis and firing stability at long timescales remains obscure. In particular, the role of major intracellular Ca2+ stores, such as mitochondria and ER (mito-Ca2+ and ER-Ca2+), in firing homeostasis has not been sufficiently explored. We propose here to explore how the homeostatic control of firing rate is implemented at the molecular level ex vivo and in vivo. We will address several key questions, including the following. 1) What are the key molecular pathways regulating the homeostatic recovery of firing in response to a perturbation in hippocampal networks? We hypothesize, based on extensive preliminary data, that the Ca2+ regulation through ER and mitochondria plays a fundamental role in this process. 2) Do similar mechanisms operate in the hippocampus of behaving mice? 3) What are the structural and functional molecular mechanisms that underlie regulation of firing homeostasis by ER and mitochondria? Answering these questions entails establishing a causal link between firing rate homeostasis and ER/mitochondrial functions and dysfunctions. We will rely on an integrated experimental approach including electrophysiology, super-resolution microscopy and other advanced imaging tools, beyond the state-of-the-art. Our work will identify the machinery underlying homeostasis impairments, and will have a dual impact. First, it will have a strong impact in basic science, since it will provide new answers to a fundamental question in neuroscience: How do neural circuits maintain functional stability in a constantly changing environment? Second, it will have an equally strong impact on translational science, since identifying the mechanisms of firing homeostasis may provide new conceptual strategies for preventing the destabilization of activity patterns in numerous brain disorders. We are confident that this ambitious project can be achieved within the proposed time frame, especially as our collaboration has long been established, and has already resulted in an important publication (Gazit et al., Neuron, 2016).

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professorin Dr. Inna Slutsky