Matrix metalloproteinase 9, hippocampus, and schizophrenia

Johanna Seitz-Holland, MD, PhD
Department of Psychiatry
Poster Overview

Schizophrenia is a severe disorder, with tremendous lifelong consequences for affected patients. While neuroimaging research has revolutionized our understanding of the biological factors that contribute to this disorder, the etiology of schizophrenia remains elusive. Evidence from various fields suggests an essential role of the hippocampus, a brain structure pivotal for memory performance, for the disorder’s pathology.

Here, we used a novel, multimodal approach to studying the role of a protein called Matrix metalloproteinases 9 (MMP-9) for the disorder’s pathophysiology.

We were able to demonstrate that patients with schizophrenia present with increased blood levels of MMP-9 and lower hippocampal volumes. Further, we showed an association between hippocampal volumes and MMP-9 levels.

Our findings might pave a new avenue towards neuroprotective treatments in schizophrenia. It has been suggested that MMP-9 inhibitors could reverse the adverse effects of schizophrenia on the brain and improve symptom severity. More extensive studies are needed to replicate our findings and to investigate the association between MMP9 and brain pathology along the schizophrenia spectrum.

Scientific Abstract

Matrix metalloproteinases 9 (MMP-9) is the most prevalent extracellularly acting protease in the central nervous system. It is involved in the regulation of hippocampal neuroplasticity and upregulated in individuals with schizophrenia. Here, we investigate the relation between hippocampal volumes and MMP-9 in 34 healthy and 30 individuals with schizophrenia.

All participants underwent a blood draw, T1-weighted magnetic resonance imaging, and clinical assessment. The FreeSurfer 6.0 hippocampal sub-field parcellation module was utilized to determine hippocampal volumes. We calculated ANCOVAs (corrected for age and sex) to compare MMP-9 levels and hippocampal volumes between groups. Pearson correlations were used to test for associations between MMP9 and hippocampal volumes. Last, we employed Spearman’s correlations to investigate the relationship between symptoms, medication, and MMP-9.

MMP-9 levels were significantly increased (F(1, 60) = 21.19, p<.0001), and hippocampal volumes were decreased in patients. The total hippocampal, CA1, and subiculum volume correlated negatively with MMP-9 levels. In patients, the MMP-9 levels correlated positively with negative symptoms (R = .39, p < .035).

Our findings suggest the association between MMP-9 and hippocampal structures and highlight the role of MMP-9 for the pathophysiology of schizophrenia. Future studies are needed to investigate if a therapeutic modulation of MMP9 promotes neuroprotective effects.

Clinical Implications
Our findings might pave a new avenue towards neuroprotective treatments in schizophrenia. It has been suggested that MMP-9 inhibitors could reverse the adverse effects of schizophrenia on the brain and improve symptom severity.
Research Areas
Authors
Johanna Seitz-Holland, Magdalena Seethaler , Nikos Makris , Jarrett Rushmore , Kang-Ik K. Cho , Elizabeth Rizzon, Mark Vangel , Olcay Senay Sahin , Carina Heller , Ofer Pasternak , Filip Szcezepankiewicz, Carl-Frederik Westin, Jan Losak, Libor Ustohal, Josef Tomandl, Lubomir Vojtisek , Petr Kudlicka Ing , Martin Jani , T. Wilson Woo , Tomas Kasparek , Zora Kikinis , Marek Kubicki
Principal Investigator
Marek Kubicki, MD, PhD

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