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Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein

ABSTRACT: Octopamine is a well-established invertebrate neurotransmitter involved in fight-or-flight responses. In mammals, its function was replaced by norepinephrine. Nevertheless, it is present at trace amounts and can modulate the release of monoamine neurotransmitters by a yet unidentified mechanism. Here, through a multidisciplinary approach utilizing in vitro and in vivo models of a-synucleinopathy, we uncovered an unprecedented role for octopamine in driving the conversion from toxic to neuroprotective astrocytes in the cerebral cortex by fostering aerobic glycolysis. Neuron-derived octopamine acts on astrocytes via a TAAR1-Orai1-Ca2+-calcineurinmediated signaling pathway to stimulate lactate secretion. Lactate uptake in neurons via the MCT2-calcineurin-dependent pathway increases ATP and prevents neurodegeneration. Pathological increases of octopamine caused by a-synuclein halts lactate production in astrocytes and short-circuits the metabolic communication to neurons. Our work provides a novel function of octopamine as a modulator of astrocyte metabolism and hence neuroprotection with implications to a-synucleinopathies.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE213875 | GEO | 2023/04/01

REPOSITORIES: GEO

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Project description:Aubert2005 - Interaction between astrocytes and neurons on energy metabolism Enocded non-curated model. Issues: - Confusing equations A.41 and A.42 - Missing values for parameters Vv,0 and dHb,0 This model is described in the article: Interaction between astrocytes and neurons studied using a mathematical model of compartmentalized energy metabolism. Aubert A, Costalat R. J. Cereb. Blood Flow Metab. 2005 Nov; 25(11): 1476-1490 Abstract: Understanding cerebral energy metabolism in neurons and astrocytes is necessary for the interpretation of functional brain imaging data. It has been suggested that astrocytes can provide lactate as an energy fuel to neurons, a process referred to as astrocyte-neuron lactate shuttle (ANLS). Some authors challenged this hypothesis, defending the classical view that glucose is the major energy substrate of neurons, at rest as well as in response to a stimulation. To test the ANLS hypothesis from a theoretical point of view, we developed a mathematical model of compartmentalized energy metabolism between neurons and astrocytes, adopting hypotheses highly unfavorable to ANLS. Simulation results can be divided between two groups, depending on the relative neuron versus astrocyte stimulation. If this ratio is low, ANLS is observed during all the stimulus and poststimulus periods (continuous ANLS), but a high ratio induces ANLS only at the beginning of the stimulus and during the poststimulus period (triphasic behavior). Finally, our results show that current experimental data on lactate kinetics are compatible with the ANLS hypothesis, and that it is essential to assess the neuronal and astrocytic NADH/NAD+ ratio changes to test the ANLS hypothesis. This model is hosted on BioModels Database and identified by: MODEL1411210000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein

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