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Reduced glutamatergic activity and energy metabolism in the dorsolateral prefrontal cortex (DLPFC) have been described in schizophrenia. Glycogenolysis in astrocytes is responsible for providing neurons with lactate as a transient energy supply helping to couple glutamatergic neurotransmission and glucose utilization in the brain. This mechanism could be disrupted in schizophrenia. The aim of this study was to explore whether the protein levels of the astrocyte isoform of glycogen phosphorylase (PYGM), key enzyme of glycogenolysis, and the isoform A of Ras-related C3 botulinum toxin substrate 1 (RAC1), a kinase that regulates PYGM activity, are altered in the postmortem DLPFC of chronic schizophrenia patients (n=23) and matched controls (n=23). We also aimed to test NMDAR blockade effect on these proteins in the mouse cortex and cortical astrocytes and antipsychotic treatments in rats. Here we report a reduction in PYGM and RAC1 protein levels in the DLPFC in schizophrenia. We found that treatment with the NMDAR antagonist dizocilpine in mice as a model of psychosis increased PYGM and reduced RAC1 protein levels. The same result was observed in rat cortical astroglial-enriched cultures. 21-day haloperidol treatment increased PYGM levels in rats. These results show that PYGM and RAC1 are altered in the DLPFC in chronic schizophrenia and are controlled by NMDA signalling in the rodent cortex and cortical astrocytes suggesting an altered NMDA-dependent glycogenolysis in astrocytes in schizophrenia. Together, this study provides evidence of a NMDA-dependent transient local energy deficit in neuron-glia crosstalk in schizophrenia, contributing to energy deficits of the disorder.

Original publication




Journal article


Schizophr Res

Publication Date





37 - 43


Energy metabolism, Glutamate, Glycogen phosphorylase, muscle form, Prefrontal cortex, RAC1 protein, human, Schizophrenia, Aged, Animals, Antipsychotic Agents, Astrocytes, Cells, Cultured, Chronic Disease, Cohort Studies, Dizocilpine Maleate, Excitatory Amino Acid Antagonists, Female, Glycogen Phosphorylase, Haloperidol, Humans, Isoenzymes, Male, Mice, Inbred C57BL, Prefrontal Cortex, Random Allocation, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate, Schizophrenia, rac1 GTP-Binding Protein