Altered synaptic plasticity at hippocampal CA1-CA3 synapses in Alzheimer's disease: integration of amyloid precursor protein intracellular domain and amyloid beta effects into computational models

Justinas J Dainauskas; Paola Vitale; Sebastien Moreno; Hélène Marie; Michele Migliore; Ausra Saudargiene

doi:10.3389/fncom.2023.1305169

Altered synaptic plasticity at hippocampal CA1-CA3 synapses in Alzheimer's disease: integration of amyloid precursor protein intracellular domain and amyloid beta effects into computational models

Front Comput Neurosci. 2023 Dec 7:17:1305169. doi: 10.3389/fncom.2023.1305169. eCollection 2023.

Authors

Justinas J Dainauskas^{1

2}, Paola Vitale³, Sebastien Moreno⁴, Hélène Marie⁴, Michele Migliore³, Ausra Saudargiene^{1

2}

Affiliations

¹ Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania.
² Department of Informatics, Vytautas Magnus University, Kaunas, Lithuania.
³ Institute of Biophysics, National Research Council, Palermo, Italy.
⁴ Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Valbonne, France.

Abstract

Alzheimer's disease (AD) is a progressive memory loss and cognitive dysfunction brain disorder brought on by the dysfunctional amyloid precursor protein (APP) processing and clearance of APP peptides. Increased APP levels lead to the production of AD-related peptides including the amyloid APP intracellular domain (AICD) and amyloid beta (Aβ), and consequently modify the intrinsic excitability of the hippocampal CA1 pyramidal neurons, synaptic protein activity, and impair synaptic plasticity at hippocampal CA1-CA3 synapses. The goal of the present study is to build computational models that incorporate the effect of AD-related peptides on CA1 pyramidal neuron and hippocampal synaptic plasticity under the AD conditions and investigate the potential pharmacological treatments that could normalize hippocampal synaptic plasticity and learning in AD. We employ a phenomenological N-methyl-D-aspartate (NMDA) receptor-based voltage-dependent synaptic plasticity model that includes the separate receptor contributions on long-term potentiation (LTP) and long-term depression (LTD) and embed it into the a detailed compartmental model of CA1 pyramidal neuron. Modeling results show that partial blockade of Glu2NB-NMDAR-gated channel restores intrinsic excitability of a CA1 pyramidal neuron and rescues LTP in AICD and Aβ conditions. The model provides insight into the complex interactions in AD pathophysiology and suggests the conditions under which the synchronous activation of a cluster of synaptic inputs targeting the dendritic tree of CA1 pyramidal neuron leads to restored synaptic plasticity.

Keywords: Alzheimer's disease; CA1 pyramidal neuron; GluN2B-NMDA receptor subunit; NMDA receptor; Schaffer collateral synapses; amyloid beta; amyloid precursor protein intracellular domain; synaptic plasticity.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by the Research Council of Lithuania, Agence Nationale de la Recherche (France) (Flagship ERA-NET Joint Transnational Call JTC 2019 in synergy with the Human Brain Project, No. S-FLAG-ERA-20-1/2020-PRO-28), the EU Horizon 2020 Framework Program for Research and Innovation (Specific Grant 945539, Human Brain Project SGA3), the Fenix computing and storage resources was provided under Specific Grant Agreement No. 800858 (Human Brain Project ICEI), and a grant from the Swiss National Supercomputing Center (CSCS) under project ID ich011. MM also acknowledges administrative and technical assistance from Alessia Bonafede and a contribution from the Italian National Recovery and Resilience Plan (NRRP), M4C2 and funded by the European Union - NextGenerationEU (Project IR0000011, CUP B51E22000150006, EBRAINS-Italy).