Lectures and seminars Fysiologföreningen presents: Professor Pierre J. Magistretti

Abstract

A tight metabolic coupling between astrocytes and neurons is a central feature of brain energy metabolism (Magistretti and Allaman, Neuron 2015; Nat Rev Neurosci 2018; Bolaños and Magistretti, Nat Metab 2025). Over the years my lab has identifed and molecularly characterized two key mechanisms of neurometabolic coupling: neuromudulator (VIP, adenosine and noradrenaline)-induced glycogenolysis in astrocytes (Magistretti et al., PNAS 1981; Magistretti et al, J. Neurosci 1986) and glutamate-stimulated aerobic glycolysis (Pellerin and Magistretti, PNAS 1994). Both processes lead to the release of lactate from astrocytes, which serves as an energy substrate for neurons as defined by the Astrocyte Neuron Lactate Shuttle (ANLS) model.

Subsequent work in my lab showed that lactate also acts as a signaling molecule, enhancing NMDA receptor activity, promoting long-term memory, and activating gene expression programs linked to synaptic plasticity (Suzuki et al., Cell 2011; Yang et al., PNAS 2014; Margineanu et al., Front Neurosci 2018; Vezzoli et al., Cereb Cortex 2019). Electrophysiological and behavioral studies further demonstrated that astrocytic lactate supply is activity-dependent and scales with computational demand (Dembitskaya et al., PNAS 2022). Recent data indicate that lactate potentiates NMDAR currents via monocarboxylate transporter (MCT)-dependent neuronal uptake, conversion to pyruvate, increased NADH, and redox-sensitive modulation of GluN2B subunits, involving CaMKII signaling (Fiumelli et al., J Physiol, in press 2026).

Recent preclinical studies in conditions show that pharmacological stimulation of the ANLS restores behavioral deficits present in hypometabolic conditions such as Glut1 deficiency syndrome (de Vivo disease) and Alzheimer’s disease supporting the strategy of targeting astrocytes to overcome brain hypometabolism (Beard et al., Front Physiol 2022; Lengacher et al., Pharmaceuticals 2026). In preclinical models of depression, lactate was shown to exert antidepressant effects that depend on neurogenesis (Carrard et al., Mol Psychiatry 2018, 2021). Together, these findings establish lactate as a metabolic–signaling nexus linking astrocyte function to neuronal computation, plasticity, and behavior, and open new therapeutic perspectives for neurodegenerative, mood, and metabolic brain disorders.