AUTHOR=Lana Daniele , Ugolini Filippo , Nosi Daniele , Wenk Gary L. , Giovannini Maria Grazia 

TITLE=The Emerging Role of the Interplay Among Astrocytes, Microglia, and Neurons in the Hippocampus in Health and Disease

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=Volume 13 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2021.651973

DOI=10.3389/fnagi.2021.651973

ISSN=1663-4365

ABSTRACT=For a long time, neurons were considered the basic functional units of the central nervous system while glia only elements of support. Activation of glia has been long regarded detrimental for neuron survival but more recently it appears that this is not always the case. In this review, we report and discuss the recent literature on the alterations of astrocytes and microglia during inflammaging, the low-grade, slow, chronic inflammatory response that characterizes normal brain aging, and in acute inflammation. By becoming reactive, astrocytes and microglia undergo transcriptional, functional, and morphological changes that transform them into cells with different properties and functions, such as A1 and A2 astrocytes, and M1 and M2 microglia. This classification of microglia and astrocytes in two different, all-or-none states seems too simplistic, not corresponding to the variety of phenotypes so far discovered in the brain. Different interactions occur among the many cell populations of the central nervous system in health and disease conditions. Such interactions give rise to a network of morphological and functional reciprocal reliance and dependency. Alterations affecting one cell population reasonably reverberate to the others either favoring or dysregulating their activities. In the last part of this review, we present the modifications of the interplay between neurons and glia in rat models of brain aging and acute inflammation, focusing on the differences between CA1 and CA3 areas of the hippocampus, one of the brain regions most susceptible to different insults. Using the method of the triple labelling fluorescent immunohistochemistry coupled to confocal microscopy (TIC), it is possible to evaluate and compare the quantitative and morpho-functional alterations of the components of the neuron-astrocyte-microglia triad. In the contiguous and interconnected regions of rat hippocampus, CA1 and CA3 Stratum Radiatum, astrocytes and microglia show a differential, finely regulated, and region-specific reactivity, demonstrating that glia responses are not uniform, but vary significantly from area to area. It will be of great interest to verify whether the differences of glia reactivity may explain the differential susceptibility of the hippocampal areas to aging or different insults, and particularly the higher sensitivity of CA1 pyramidal neurons to inflammatory stimuli.