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      Matrixmetalloproteinase-9 gene polymorphism (rs 17576) increases the risk of depressive symptoms in bipolar disorder

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          Abstract

          Objectives:

          Plasticity of neural synapses is known to be involved in the complications in bipolar disorder (BD) patients. Matrix metalloproteinases (MMPs) play a role in synaptic plasticity and memory. Even though elevated MMP-9 levels are reported in neuropsychiatric disorders, there is limited data about MMP-9 gene polymorphism in BD. The objectives of the study was to investigate genotype frequency and allele frequency of MMP-9 genetic variant (rs 17576) in BD and its association with disease severity.

          Materials and Methods:

          Eighty BD cases and 80 controls were recruited in the study. MMP-9 genotyping and allele frequency and plasma MMP-9 levels were analyzed in both the groups. Hamilton depression rating scale and Young’s Mania Rating Scale (YMRS) were used to evaluate severity of BD.

          Results:

          The genotype and minor allele (G allele) frequency were not significant between BD and controls. MMP-9 levels were significantly increased in BD patients with AG ( P < 0.001) and GG ( P = 0.022) genotypes compared to controls. BD patients with GG genotype ( P = 0.038, OR: 3.26 (1.16–9.09), and G (mutant) allele ( P = 0.013, OR 2.03(1.18–3.48) confer increased risk of depressive symptoms. MMP-9 was positively correlated with YMRS scale (r = 0.227, P = 0.043) in BD.

          Conclusion:

          MMP-9 gene polymorphism (rs 17576) is linked with depressive symptoms in BD.

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          Most cited references14

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          Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative.

          Kathleen R Merikangas, Robert Jin, Jian-Ping He … (2011)
          There is limited information on the prevalence and correlates of bipolar spectrum disorder in international population-based studies using common methods. To describe the prevalence, impact, patterns of comorbidity, and patterns of service utilization for bipolar spectrum disorder (BPS) in the World Health Organization World Mental Health Survey Initiative. Cross-sectional, face-to-face, household surveys of 61,392 community adults in 11 countries in the Americas, Europe, and Asia assessed with the World Mental Health version of the World Health Organization Composite International Diagnostic Interview, version 3.0, a fully structured, lay-administered psychiatric diagnostic interview. Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) disorders, severity, and treatment. The aggregate lifetime prevalences were 0.6% for bipolar type I disorder (BP-I), 0.4% for BP-II, 1.4% for subthreshold BP, and 2.4% for BPS. Twelve-month prevalences were 0.4% for BP-I, 0.3% for BP-II, 0.8% for subthreshold BP, and 1.5% for BPS. Severity of both manic and depressive symptoms as well as suicidal behavior increased monotonically from subthreshold BP to BP-I. By contrast, role impairment was similar across BP subtypes. Symptom severity was greater for depressive episodes than manic episodes, with approximately 74.0% of respondents with depression and 50.9% of respondents with mania reporting severe role impairment. Three-quarters of those with BPS met criteria for at least 1 other disorder, with anxiety disorders (particularly panic attacks) being the most common comorbid condition. Less than half of those with lifetime BPS received mental health treatment, particularly in low-income countries, where only 25.2% reported contact with the mental health system. Despite cross-site variation in the prevalence rates of BPS, the severity, impact, and patterns of comorbidity were remarkably similar internationally. The uniform increases in clinical correlates, suicidal behavior, and comorbidity across each diagnostic category provide evidence for the validity of the concept of BPS. Treatment needs for BPS are often unmet, particularly in low-income countries.
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            Biochemical and Biological Attributes of Matrix Metalloproteinases.

            Ning Cui, Min Hu, Raouf Khalil (2017)
            Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are involved in the degradation of various proteins in the extracellular matrix (ECM). Typically, MMPs have a propeptide sequence, a catalytic metalloproteinase domain with catalytic zinc, a hinge region or linker peptide, and a hemopexin domain. MMPs are commonly classified on the basis of their substrates and the organization of their structural domains into collagenases, gelatinases, stromelysins, matrilysins, membrane-type (MT)-MMPs, and other MMPs. MMPs are secreted by many cells including fibroblasts, vascular smooth muscle (VSM), and leukocytes. MMPs are regulated at the level of mRNA expression and by activation of their latent zymogen form. MMPs are often secreted as inactive pro-MMP form which is cleaved to the active form by various proteinases including other MMPs. MMPs cause degradation of ECM proteins such as collagen and elastin, but could influence endothelial cell function as well as VSM cell migration, proliferation, Ca2+ signaling, and contraction. MMPs play a role in tissue remodeling during various physiological processes such as angiogenesis, embryogenesis, morphogenesis, and wound repair, as well as in pathological conditions such as myocardial infarction, fibrotic disorders, osteoarthritis, and cancer. Increases in specific MMPs could play a role in arterial remodeling, aneurysm formation, venous dilation, and lower extremity venous disorders. MMPs also play a major role in leukocyte infiltration and tissue inflammation. MMPs have been detected in cancer, and elevated MMP levels have been associated with tumor progression and invasiveness. MMPs can be regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), and the MMP/TIMP ratio often determines the extent of ECM protein degradation and tissue remodeling. MMPs have been proposed as biomarkers for numerous pathological conditions and are being examined as potential therapeutic targets in various cardiovascular and musculoskeletal disorders as well as cancer.
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              Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory.

              Pawel Okulski, Ozlem Bozdagi-Gunal, Anna Matynia … (2006)
              Matrix metalloproteinases (MMPs) are extracellular proteases that have well recognized roles in cell signaling and remodeling in many tissues. In the brain, their activation and function are customarily associated with injury or pathology. Here, we demonstrate a novel role for MMP-9 in hippocampal synaptic physiology, plasticity, and memory. MMP-9 protein levels and proteolytic activity are rapidly increased by stimuli that induce late-phase long-term potentiation (L-LTP) in area CA1. Such regulation requires NMDA receptors and protein synthesis. Blockade of MMP-9 pharmacologically prevents induction of L-LTP selectively; MMP-9 plays no role in, nor is regulated during, other forms of short-term synaptic potentiation or long-lasting synaptic depression. Similarly, in slices from MMP-9 null-mutant mice, hippocampal LTP, but not long-term depression, is impaired in magnitude and duration; adding recombinant active MMP-9 to null-mutant slices restores the magnitude and duration of LTP to wild-type levels. Activated MMP-9 localizes in part to synapses and modulates hippocampal synaptic physiology through integrin receptors, because integrin function-blocking reagents prevent an MMP-9-mediated potentiation of synaptic signal strength. The fundamental importance of MMP-9 function in modulating hippocampal synaptic physiology and plasticity is underscored by behavioral impairments in hippocampal-dependent memory displayed by MMP-9 null-mutant mice. Together, these data reveal new functions for MMPs in synaptic and behavioral plasticity.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Neurosci Rural Pract
                Journal ID (iso-abbrev): J Neurosci Rural Pract
                Journal ID (publisher-id): JNRP
                Title: Journal of Neurosciences in Rural Practice
                Publisher: Scientific Scholar
                ISSN (Print): 0976-3147
                ISSN (Electronic): 0976-3155
                Publication date (Electronic preprint): 22 October 2022
                Publication date (Electronic): 16 December 2022
                Publication date (Print): Oct-Dec 2022
                Volume: 13
                Issue: 4
                Pages: 691-695
                Affiliations
                [1 ]Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research , Puducherry, India.
                [2 ]Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education and Research , Puducherry, India.
                [3 ]Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research , Puducherry, India.
                Author notes
                [* ] Corresponding author: Hanumanthappa Nandeesha, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India. nandijipmer@ 123456gmail.com
                Article
                Publisher ID: 10.25259/JNRP-2022-6-34
                DOI: 10.25259/JNRP-2022-6-34
                PMC ID: 9893938
                SO-VID: 11905265-e73e-4463-b125-a73fbf81dae6
                Copyright © © 2022 Published by Scientific Scholar on behalf of Journal of Neurosciences in Rural Practice
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

                History
                Date received : 12 September 2022
                Date accepted : 20 September 2022
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Neurosciences
                Keywords: bipolar disorder,matrix metalloproteinase,synaptic plasticity
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: bipolar disorder, matrix metalloproteinase, synaptic plasticity

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