The MILEDI project involves teams of computational and experimental neuroscientists from:
Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania (Project coordinator),
Institut de Pharmacologie Moléculaire et Cellulaire/ Centre national de la Recherche Scientifique, Valbonne, France,
Institute of Biophysics, National Research Council, Palermo, Italy
in collaboration with the Human Brain Project.
Start date: 1 April 2020
Project duration: 3 years
Neuron images for the title page provided courtesy of Dr. Christian Ebner (NeuroCure Cluster of Excellence, Charité–Universitätsmedizin Berlin, Germany)
Aim and objectives
The project aims at developing a new multi-scale (integrated molecular, cellular and network levels) data-driven in silico model of the hippocampal CA1 region under Alzheimer’s disease conditions.
The main project objectives:
Extend the experimental evidence of Amyloid beta (Aβ), Amyloid eta (Aη), Amyloid precursor protein C-terminal peptide (AICD)-related changes in the properties of hippocampal CA1 pyramidal neuron synaptic plasticity, synaptic signal integration and neuronal excitability.
Incorporate the dose-dependent effects of Alzheimer’s disease-related peptides into computational models of hippocampal synaptic plasticity, CA1 pyramidal neurons and CA1 network; determine and explain the molecular, synaptic, cellular, network-level mechanisms of altered hippocampal function that leads to impaired learning and progressive irreversible memory loss in Alzheimer’s disease.
Identify and assess experimentally and by computational modeling potential targets for innovative treatment of Alzheimer’s disease.
Alzheimer’s disease affects over 46 million people worldwide, estimated to triple by the year 2050. It has a long preclinical stage and, before any clinical symptoms appear, pathological processes are observed in the hippocampus and entorhinal cortex, key brain structures responsible for memory encoding and retrieval. AD cannot be prevented, halted or cured today, and new interdisciplinary ways are urgently needed for the understanding and treatment of this devastating disease. Recent experimental evidence supports the fundamental role of Alzheimer’s disease-related peptides early in the pathology: in particular the most widely studied Amyloid beta (Aβ), and the less investigated Amyloid eta (Aη) and Amyloid precursor protein (APP) C-terminal peptide (AICD).
Their differential effects on synaptic function and intrinsic excitability of hippocampal CA1 pyramidal neuron at a single cell level are currently being investigated. However, the dose-dependent impact and complex interaction effects of Aβ, Aη, AICD on hippocampal synaptic plasticity, CA1 network activity, memory encoding and retrieval capacity and dynamics remain largely unknown.
The interdisciplinary consortium will perform ex-vivo whole-cell patch clamp electrophysiology recordings (Dr. Helene Marie, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France), computational modeling of hippocampal synaptic plasticity (Prof. Ausra Saudargiene, Lithuanian University of Health Sciences, Lithuania), of neuronal excitability and of biologically realistic large-scale CA1 network (Prof. Michele Migliore, Institute of Biophysics, Palermo, Italy) under control and Alzheimer’s disease conditions. The consortium has a proven track-record of experimental, theoretical and computational expertise to successfully achieve these goals.
The project extends beyond the state-of-the-art by integrating ex-vivo experimental data into multi-scale in silico approaches to suggest potential targets for more effective treatments in the initial phase of Alzheimer’s disease. By including the models into the Brain Simulation Platform of the Human Brain Project, the project will provide to the community an essential multi-scale modelling tool for this devastating disease.
In this project, we gathered experimental data on the Aβ-, Aη- and AICD-induced alterations in synaptic plasticity, synaptic signal integration and intrinsic excitability of hippocampal CA1 pyramidal neurons. We built a new computational model of hippocampal synaptic plasticity in a mouse, based on NMDAR functioning, and optimized computational models of mouse CA1 pyramidal neurons under control and AD conditions. We showed that synaptic plasticity was impaired in CA1 pyramidal neurons, leading to perturbed memory storage and recall in CA1 networks. We demonstrated that partial blockade of Glu2NB-NMDAR led to normalization of hippocampal learning in AD conditions.
The project integrated experimental data with the computational modeling and enabled analysis of complex interactions at molecular, synaptic, cellular and network levels, leading to a deeper understanding of the mechanisms involved in AD. The suggested pharmacological manipulation of Glu2NB-NMDAR indicated the potential to restore cognitive functions in AD. The scientific results shed light on a complex AD pathophysiology and its possible treatment.
The activities organized within the project resulted in a productive and strong cooperation not only between the experimental and theoretical neuroscientists in Lithuania, France and Italy, but also with many leading groups external to the project and a major National Research Infrastructure. It also educated young scientists, increased the visibility of neuroscience in academic society and general audience through scientific seminars, summer schools, conferences and general outreach to the public.
Synaptic plasticity models under control and Alzheimer’s disease conditions
We built a phenomenological voltage-dependent NMDAR-based model of hippocampal synaptic plasticity at CA3-CA1 synapses and incorporated the effects of toxic AD peptides (Dainauskas et al, Front. Synapt. Neurosc., 2023; Dainauskas et al, Front. Comput. Neurosc., 2023). The model relies on the functioning of the GluN2A-NMDAR and GluN2B-NMDAR subunits as the separate mediators of LTD and LTP, respectively (Fig.1). It is assumed that LTP is mainly dependent on GluN2B-NMDAR, and GluN2A-NMDAR is the main mediator of LTD.
Computational modeling of AD-related peptide effects on the synaptic plasticity at CA3-CA1 synapses and the pharmacological treatment
We used the synaptic plasticity model, embedded into the multicompartmental model of a CA pyramidal neuron, to study how elevated concentrations of AICD, Aβ, and Aη influence synaptic changes at CA3–CA1 synapses in AD. In the presence of AD-related peptides, LTP was impaired (Dainauskas et al., Front. Comput. Neurosci., 2023), and LTD was slightly enhanced under AICD, Aβ, and Aη conditions, following the experimental data (Pousinha et al., Cell Reports 2017; Opazo et al., Cell Reports 2018).
We analyzed how synaptic plasticity was affected by a partial GluN2B-NMDAR blockade in the presence of increased concentrations of AICD, Aβ, and Aη, for high- and low-frequency stimulations. We successfully replicated the bell-shape effect of GluN2B-NMDAR downregulation in the presence of the elevated AICD concentration for high-frequency stimulation and LTP rescue by the optimal blockade of GluN2B-NMDAR (Pousinha et al., Cell Reports 2017). We qualitatively reproduced experimental findings that GluN2B-NMDAR downregulation restores LTP in oligomeric Aβ conditions. Increased AICD levels enhanced intracellular Ca2+ concentration via GluN2B-NMDAR and L-type Ca2+ channels, which activated the nearby Ca2+-dependent K+ channels and led to hypoexcitability of a CA1 pyramidal neuron. Oligomeric forms of Aβ caused synapse loss and prevented CaMKII activation via Glu2NB-NMDAR-dependent pathway. Optimal blockade of GluN2B-NMDAR normalized Ca2+-dependent K+ channel functioning, restored excitability and allowed CaMKII to be phosphorylated to induce LTP. Our modeling results show that LTP induction mechanisms at CA1 pyramidal neuron synapses can be restored by optimal partial blockade of synaptic NMDA GluN2B channel conductance in AICD, Aβ, and AICD & Aβ conditions (Fig. 2-3). Partial GluN2B-NMDAR blockade did not rescue LTP in Aη conditions.
Full-scale model of the hippocampus CA1 area under AD peptide conditions
We use a full-scale model of the hippocampus CA1 the Bianchi et al. 2014 network (Figure 4) integrating the synaptic plasticity models developed in for the CA3-CA1 synapses. The synapses undergo LTP resulting in a high quality recall, and in AD conditions, LTP is prevented, synaptic weight decreases and recall of the pattern is impaired.
Implementation of a full-scale model of the hippocampus CA1 area under control conditions
We have contributed to implementing the first scaffold model (soma positions and connectivity) of a human hippocampus CA1 area (Gandolfi et al, Nature Comput Sci., 2023a) under control conditions (Fig. 5).
Coordinator, Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania
The Computational Neuroscience group, headed by Prof. Ausra Saudargiene, focuses on computational modeling of synaptic plasticity in hippocampus and cortex in health and in neurodegenerative disorders. Prof. Ausra Saudargiene developed biophysical and molecular models of synaptic plasticity in hippocampus and cortex, analyzed memory encoding and retrieval in hippocampal CA1 microcircuit.
Saudargiene A, Graham BP. Factors affecting STDP learning rules in the ...
Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France
Dr Hélène Marie’s team is interested in understanding how physiological and pathological conditions shape neuronal plasticity. We have an integrated approach to delineate how molecular changes translate into behavioural outcomes. We have strong expertise in in vitro electrophysiology on brain slices (field and patch clamp recordings) and in behaviour. We use viral approaches for in vivo protein expression as well as transgenic lines to alter brain molecular mechanisms. We are also currently developing ...
Over the past 30 years the Computational Neuroscience Laboratory of CNR-IBF, headed by Prof. Michele Migliore, has been involved in the development and implementation of computational models of complex systems.
The broad long-term goal is to investigate, using realistic models and state of the art simulations techniques, the basic processes underlying the nervous system functions and dysfunctions. In close interdisciplinary collaboration with leading experimental laboratories, we investigate neuronal networks and single neurons at ...