PMID- 37085712 OWN - NLM STAT- MEDLINE DCOM- 20231101 LR - 20231212 IS - 1476-5578 (Electronic) IS - 1359-4184 (Print) IS - 1359-4184 (Linking) VI - 28 IP - 7 DP - 2023 Jul TI - Insulin effects on core neurotransmitter pathways involved in schizophrenia neurobiology: a meta-analysis of preclinical studies. Implications for the treatment. PG - 2811-2825 LID - 10.1038/s41380-023-02065-4 [doi] AB - Impairment of insulin action and metabolic dysregulation have traditionally been associated with schizophrenia, although the molecular basis of such association remains still elusive. The present meta-analysis aims to assess the impact of insulin action manipulations (i.e., hyperinsulinemia, hypoinsulinemia, systemic or brain insulin resistance) on glutamatergic, dopaminergic, gamma-aminobutyric acid (GABA)ergic, and serotonergic pathways in the central nervous system. More than one hundred outcomes, including transcript or protein levels, kinetic parameters, and other components of the neurotransmitter pathways, were collected from cultured cells, animals, or humans, and meta-analyzed by applying a random-effects model and adopting Hedges'g to compare means. Two hundred fifteen studies met the inclusion criteria, of which 180 entered the quantitative synthesis. Significant impairments in key regulators of synaptic plasticity processes were detected as the result of insulin handlings. Specifically, protein levels of N-methyl-D-aspartate receptor (NMDAR) subunits including type 2A (NR2A) (Hedges' g = -0.95, 95%C.I. = -1.50, -0.39; p = 0.001; I(2) = 47.46%) and 2B (NR2B) (Hedges'g = -0.69, 95%C.I. = -1.35, -0.02; p = 0.043; I(2) = 62.09%), and Postsynaptic density protein 95 (PSD-95) (Hedges'g = -0.91, 95%C.I. = -1.51, -0.32; p = 0.003; I(2) = 77.81%) were found reduced in insulin-resistant animal models. Moreover, insulin-resistant animals showed significantly impaired dopamine transporter activity, whereas the dopamine D2 receptor mRNA expression (Hedges'g = 3.259; 95%C.I. = 0.497, 6.020; p = 0.021; I(2) = 90.61%) increased under insulin deficiency conditions. Insulin action modulated glutamate and GABA release, as well as several enzymes involved in GABA and serotonin synthesis. These results suggest that brain neurotransmitter systems are susceptible to insulin signaling abnormalities, resembling the discrete psychotic disorders' neurobiology and possibly contributing to the development of neurobiological hallmarks of treatment-resistant schizophrenia. CI - (c) 2023. The Author(s). FAU - de Bartolomeis, Andrea AU - de Bartolomeis A AUID- ORCID: 0000-0002-3188-5652 AD - Section of Psychiatry, Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychiatric Disorders, Department of Neuroscience, Reproductive Sciences and Odontostomatology University of Naples "Federico II", School of Medicine, Via Pansini 5, 80131, Naples, Italy. adebarto@unina.it. FAU - De Simone, Giuseppe AU - De Simone G AUID- ORCID: 0000-0003-0422-3415 AD - Section of Psychiatry, Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychiatric Disorders, Department of Neuroscience, Reproductive Sciences and Odontostomatology University of Naples "Federico II", School of Medicine, Via Pansini 5, 80131, Naples, Italy. FAU - De Prisco, Michele AU - De Prisco M AUID- ORCID: 0000-0002-2032-1181 AD - Section of Psychiatry, Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychiatric Disorders, Department of Neuroscience, Reproductive Sciences and Odontostomatology University of Naples "Federico II", School of Medicine, Via Pansini 5, 80131, Naples, Italy. AD - Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel st, 12-0, 08036, Barcelona, Catalonia, Spain. FAU - Barone, Annarita AU - Barone A AD - Section of Psychiatry, Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychiatric Disorders, Department of Neuroscience, Reproductive Sciences and Odontostomatology University of Naples "Federico II", School of Medicine, Via Pansini 5, 80131, Naples, Italy. FAU - Napoli, Raffaele AU - Napoli R AD - Department of Translational Medical Sciences, University of Naples "Federico II", Via S. Pansini 5, 80131, Naples, Italy. AD - URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy. FAU - Beguinot, Francesco AU - Beguinot F AD - Department of Translational Medical Sciences, University of Naples "Federico II", Via S. Pansini 5, 80131, Naples, Italy. AD - URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy. FAU - Billeci, Martina AU - Billeci M AD - Section of Psychiatry, Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychiatric Disorders, Department of Neuroscience, Reproductive Sciences and Odontostomatology University of Naples "Federico II", School of Medicine, Via Pansini 5, 80131, Naples, Italy. FAU - Fornaro, Michele AU - Fornaro M AD - Section of Psychiatry, Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychiatric Disorders, Department of Neuroscience, Reproductive Sciences and Odontostomatology University of Naples "Federico II", School of Medicine, Via Pansini 5, 80131, Naples, Italy. LA - eng PT - Meta-Analysis PT - Systematic Review DEP - 20230421 PL - England TA - Mol Psychiatry JT - Molecular psychiatry JID - 9607835 RN - 0 (Insulin) RN - 0 (Disks Large Homolog 4 Protein) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - 0 (Neurotransmitter Agents) SB - IM MH - Humans MH - Animals MH - *Schizophrenia/metabolism MH - Insulin/metabolism MH - Neurobiology MH - Disks Large Homolog 4 Protein/metabolism MH - Receptors, N-Methyl-D-Aspartate MH - gamma-Aminobutyric Acid MH - Neurotransmitter Agents PMC - PMC10615753 COIS- The author declares no competing interests. The authors have no financial or non-financial interests to disclose with regard to the content and aims of the study therein presented. EDAT- 2023/04/22 10:42 MHDA- 2023/11/01 12:42 PMCR- 2023/04/21 CRDT- 2023/04/21 23:29 PHST- 2022/09/16 00:00 [received] PHST- 2023/03/31 00:00 [accepted] PHST- 2023/03/28 00:00 [revised] PHST- 2023/11/01 12:42 [medline] PHST- 2023/04/22 10:42 [pubmed] PHST- 2023/04/21 23:29 [entrez] PHST- 2023/04/21 00:00 [pmc-release] AID - 10.1038/s41380-023-02065-4 [pii] AID - 2065 [pii] AID - 10.1038/s41380-023-02065-4 [doi] PST - ppublish SO - Mol Psychiatry. 2023 Jul;28(7):2811-2825. doi: 10.1038/s41380-023-02065-4. Epub 2023 Apr 21.