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 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 440813539

• Final Report Year: 2024

Final Report Abstract

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, in firing homeostasis had not been sufficiently explored. We propose in 2020 to explore how the homeostatic control of firing rate is implemented at the molecular level ex vivo and in vivo. We asked several key questions: 1) What are the key molecular pathways regulating the homeostatic recovery of firing in response to a perturbation in hippocampal networks? 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? Answering these questions entails establishing a causal link between firing rate homeostasis and ER/mitochondrial functions and dysfunctions. In our work, we established the following: 1) we found the molecular basis of the regulation of the mitochondria and Ca2+ involvement in the firing rate homeostasis; 2) we revealed new features of firing rate homeostasis, linked to mitochondria function, in behaving mice; 3) we described a neural circuit mechanism underlying the cognitive resilience to Alzheimer’s Disease (AD), in a mouse model; 4) we described novel mechanisms of homeostatic plasticity, linked to the dynamics of the extracellular matrix; 5) we obtained significant insight into the structural changes that accompany homeostatic plasticity in synapses; 6) we generated several technological advances. Our work has a dual impact. First, it should have a strong impact in basic science, since it provides 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.

Publications

• A large-scale nanoscopy and biochemistry analysis of postsynaptic dendritic spines. Nature Neuroscience, 24(8), 1151-1162.
  Helm, Martin S.; Dankovich, Tal M.; Mandad, Sunit; Rammner, Burkhard; Jähne, Sebastian; Salimi, Vanessa; Koerbs, Christina; Leibrandt, Richard; Urlaub, Henning; Schikorski, Thomas & Rizzoli, Silvio O.
  
• Extracellular matrix remodeling through endocytosis and resurfacing of Tenascin-R. Nature Communications, 12(1).
  Dankovich, Tal M.; Kaushik, Rahul; Olsthoorn, Linda H. M.; Petersen, Gabriel Cassinelli; Giro, Philipp Emanuel; Kluever, Verena; Agüi-Gonzalez, Paola; Grewe, Katharina; Bao, Guobin; Beuermann, Sabine; Hadi, Hannah Abdul; Doeren, Jose; Klöppner, Simon; Cooper, Benjamin H.; Dityatev, Alexander & Rizzoli, Silvio O.
  
• Presynaptic activity and protein turnover are correlated at the single-synapse level. Cell Reports, 34(11), 108841.
  Jähne, Sebastian; Mikulasch, Fabian; Heuer, Helge G.H.; Truckenbrodt, Sven; Agüi-Gonzalez, Paola; Grewe, Katharina; Vogts, Angela; Rizzoli, Silvio O. & Priesemann, Viola
  
• A Reliable Approach for Revealing Molecular Targets in Secondary Ion Mass Spectrometry. International Journal of Molecular Sciences, 23(9), 4615.
  Li, Fengxia; Fornasiero, Eugenio F.; Dankovich, Tal M.; Kluever, Verena & Rizzoli, Silvio O.
  
• An iodine-containing probe as a tool for molecular detection in secondary ion mass spectrometry. Chemical Communications, 58(54), 7558-7561.
  Kabatas, Glowacki Selda; Agüi-Gonzalez, Paola; Sograte-Idrissi, Shama; Jähne, Sebastian; Opazo, Felipe; Phan, Nhu T. N. & Rizzoli, Silvio O.
  
• Disrupted neural correlates of anesthesia and sleep reveal early circuit dysfunctions in Alzheimer models. Cell Reports, 38(3), 110268.
  Zarhin, Daniel; Atsmon, Refaela; Ruggiero, Antonella; Baeloha, Halit; Shoob, Shiri; Scharf, Oded; Heim, Leore R.; Buchbinder, Nadav; Shinikamin, Ortal; Shapira, Ilana; Styr, Boaz; Braun, Gabriella; Harel, Michal; Sheinin, Anton; Geva, Nitzan; Sela, Yaniv; Saito, Takashi; Saido, Takaomi; Geiger, Tamar ... & Slutsky, Inna
  
• IGF-1 receptor regulates upward firing rate homeostasis via the mitochondrial calcium uniporter. Proceedings of the National Academy of Sciences, 119(33).
  Katsenelson, Maxim; Shapira, Ilana; Abbas, Eman; Jevdokimenko, Kristina; Styr, Boaz; Ruggiero, Antonella; Aïd, Saba; Fornasiero, Eugenio F.; Holzenberger, Martin; Rizzoli, Silvio O. & Slutsky, Inna
  
• Measuring synaptic transmission and plasticity with fEPSP recordings in behaving mice. STAR Protocols, 3(1), 101115.
  Heim, Leore R.; Shoob, Shiri; de Marcas, Lior; Zarhin, Daniel & Slutsky, Inna
  
• Deep brain stimulation of thalamic nucleus reuniens promotes neuronal and cognitive resilience in an Alzheimer’s disease mouse model. Nature Communications, 14(1).
  Shoob, Shiri; Buchbinder, Nadav; Shinikamin, Ortal; Gold, Or; Baeloha, Halit; Langberg, Tomer; Zarhin, Daniel; Shapira, Ilana; Braun, Gabriella; Habib, Naomi & Slutsky, Inna