Remodeling of Intracellular Ca²⁺ Homeostasis in Rat Hippocampal Neurons Aged In Vitro

• Main Authors: Maria Calvo-Rodriguez, Elena Hernando-Pérez, Sara López-Vázquez, Javier Núñez, Carlos Villalobos, Lucía Núñez
• Format: Article
• Language: English
• Published: MDPI AG 2020-02-01
• Series: International Journal of Molecular Sciences
• Subjects: calcium; hippocampal neurons; aging; alzheimer’s disease; amyloid beta oligomers; endoplasmic reticulum; mitochondria
• Online Access: https://www.mdpi.com/1422-0067/21/4/1549

Aging is often associated with a cognitive decline and a susceptibility to neuronal damage. It is also the most important risk factor for neurodegenerative disorders, particularly Alzheimer’s disease (AD). AD is related to an excess of neurotoxic oligomers of amyloid β peptide (Aβo); however, the molecular mechanisms are still highly controversial. Intracellular Ca²⁺ homeostasis plays an important role in the control of neuronal activity, including neurotransmitter release, synaptic plasticity, and memory storage, as well as neuron cell death. Recent evidence indicates that long-term cultures of rat hippocampal neurons, resembling aged neurons, undergo cell death after treatment with Aβo, whereas short-term cultures, resembling young neurons, do not. These in vitro changes are associated with the remodeling of intracellular Ca²⁺ homeostasis with aging, thus providing a simplistic model for investigating Ca²⁺ remodeling in aging. In vitro aged neurons show increased resting cytosolic Ca²⁺ concentration, enhanced Ca²⁺ store content, and Ca²⁺ release from the endoplasmic reticulum (ER). Ca²⁺ transfer from the endoplasmic reticulum (ER) to mitochondria is also enhanced. Aged neurons also show decreased store-operated Ca²⁺ entry (SOCE), a Ca²⁺ entry pathway related to memory storage. At the molecular level, in vitro remodeling is associated with changes in the expression of Ca²⁺ channels resembling in vivo aging, including changes in N-methyl-D-aspartate NMDA receptor and inositol 1,4,5-trisphosphate (IP₃) receptor isoforms, increased expression of the mitochondrial calcium uniporter (MCU), and decreased expression of Orai1/Stim1, the molecular players involved in SOCE. Additionally, Aβo treatment exacerbates most of the changes observed in aged neurons and enhances susceptibility to cell death. Conversely, the solely effect of Aβo in young neurons is to increase ER−mitochondria colocalization and enhance Ca²⁺ transfer from ER to mitochondria without inducing neuronal damage. We propose that cultured rat hippocampal neurons may be a useful model to investigate Ca²⁺ remodeling in aging and in age-related neurodegenerative disorders.