title: The glial phosphorylase of glycogen isoform is reduced in the dorsolateral prefrontal cortex in chronic schizophrenia.
abstract: 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.
authors.affiliation: Unitat de recerca, Parc Sanitari Sant Joan de Déu, Fundació Sant Joan de Déu, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM. Dr. Antoni Pujadas, 42, 08830, Sant Boi de Llobregat, Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Pinacho
authors.affiliation: Unitat de recerca, Parc Sanitari Sant Joan de Déu, Fundació Sant Joan de Déu, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM. Dr. Antoni Pujadas, 42, 08830, Sant Boi de Llobregat, Barcelona, Spain.
authors.forename: Elia
authors.initials: E
authors.lastname: Vila
authors.affiliation: Iproteos S.L., Baldiri I Reixac, 10, 08028 Barcelona, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Prades
authors.affiliation: Iproteos S.L., Baldiri I Reixac, 10, 08028 Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), Baldiri I Reixac, 10, 08028 Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Tarragó
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (Universidad de Cantabria, CSIC, SODERCAN), Departamento de Fisiología y Farmacología, Universidad de Cantabria, 39011, Santander, Spain, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Castro
authors.affiliation: Instituto de Neuropatología, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Centro de Investigación Biomédica en Red para enfermedades neurodegenerativas, CIBERNED, Feixa Llarga s/n, 08907 Hospitalet de LLobregat, Barcelona, Spain.
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: Unitat de recerca, Parc Sanitari Sant Joan de Déu, Fundació Sant Joan de Déu, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM. Dr. Antoni Pujadas, 42, 08830, Sant Boi de Llobregat, Barcelona, Spain. Electronic address: bramos@fsjd.org.
authors.forename: Belén
authors.initials: B
authors.lastname: Ramos
mesh_terms: D000368:Aged; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D002908:Chronic Disease; D015331:Cohort Studies; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D024981:Glycogen Phosphorylase / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes; D008297:Male; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000187:drug effects / Q000201:enzymology*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000201:enzymology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D007527:Isoenzymes; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D024981:Glycogen Phosphorylase; D020830:rac1 GTP-Binding Protein; D006220:Haloperidol
keywords: Energy metabolism; Glutamate; Glycogen phosphorylase, muscle form; Prefrontal cortex; RAC1 protein, human; Schizophrenia