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.

Autor:	Dainauskas JJ; Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania.; Department of Informatics, Vytautas Magnus University, Kaunas, Lithuania., Vitale P; Institute of Biophysics, National Research Council, Palermo, Italy., Moreno S; Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Valbonne, France., Marie H; Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Valbonne, France., Migliore M; Institute of Biophysics, National Research Council, Palermo, Italy., Saudargiene A; Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania.; Department of Informatics, Vytautas Magnus University, Kaunas, Lithuania.
Jazyk:	angličtina
Zdroj:	Frontiers in computational neuroscience [Front Comput Neurosci] 2023 Dec 07; Vol. 17, pp. 1305169. Date of Electronic Publication: 2023 Dec 07 (Print Publication: 2023).
DOI:	10.3389/fncom.2023.1305169
Abstrakt:	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 (A β ), 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 A β 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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Dainauskas, Vitale, Moreno, Marie, Migliore and Saudargiene.)
Databáze:	MEDLINE
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