Evidence of Energy Metabolism Alterations in Cultured Neonatal Astrocytes Derived from the Ts65Dn Mouse Model of Down Syndrome.

Bruna L Zampieri,Alberto C S Costa

doi:10.3390/brainsci12010083

Abstract

For many decades, neurons have been the central focus of studies on the mechanisms underlying the neurodevelopmental and neurodegenerative aspects of Down syndrome (DS). Astrocytes, which were once thought to have only a passive role, are now recognized as active participants of a variety of essential physiological processes in the brain. Alterations in their physiological function have, thus, been increasingly acknowledged as likely initiators of or contributors to the pathogenesis of many nervous system disorders and diseases. In this study, we carried out a series of real-time measurements of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in hippocampal astrocytes derived from neonatal Ts65Dn and euploid control mice using a Seahorse XFp Flux Analyzer. Our results revealed a significant basal OCR increase in neonatal Ts65Dn astrocytes compared with those from control mice, indicating increased oxidative phosphorylation. ECAR did not differ between the groups. Given the importance of astrocytes in brain metabolic function and the linkage between astrocytic and neuronal energy metabolism, these data provide evidence against a pure “neurocentric” vision of DS pathophysiology and support further investigations on the potential contribution of disturbances in astrocytic energy metabolism to cognitive deficits and neurodegeneration associated with DS.

Highlights

Down syndrome (DS), the genetic disorder typically resulting from the triplication of human chromosome 21, is the most prevalent genetically defined cause of intellectual disability [1,2]
Neonatal Ts65Dn astrocytes showed a 1.6-fold increase in basal oxygen consumption compared with neonatal wild-type control (WT) astrocytes
Under conditions in which basal respiration is significantly different between the experimental groups, it is important to consider the mitochondrial measurements as percentages of basal respiration

Summary

Introduction

Down syndrome (DS), the genetic disorder typically resulting from the triplication of human chromosome 21, is the most prevalent genetically defined cause of intellectual disability [1,2]. Astrocytes, once thought to have only a passive role, are acknowledged as active participants of a variety of essential physiological processes in the brain These cells control the extracellular homeostasis of ions and water, as well as axon and dendrite outgrowth, participate in the formation, maturation, and modulation of synapses, and regulate the clearance of neurotransmitters such as glutamate [8–10]. Glutamate released from active neurons activates astrocytic glycolysis, leading to production of lactate, which is subsequently shuttled to neurons as energy fuel [15]. This astrocytic–neuronal metabolic coupling is thought to play a central role in long-term neuronal plasticity and memory formation [16–18]. Considering the role of mitochondrial metabolism in proper astrocyte functioning [19], disturbances in astrocytic energy metabolism can potentially result in dysfunctional neuronal activity and in cognitive impairment

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