Metalloproteinase-9 and depression: a study in an animal model and human postmortem brain, and its role in the mechanism of action of fast-acting antidepressant drugs

RESUMEN: El trastorno depresivo mayor es una enfermedad mental común, especialmente en mujeres. El cannabidiol, el mayor componente no psicomimético del Cannabis sativa, presenta un potencial efecto antidepresivo. Por otro lado, se han observado elevados niveles de la metaloproteinasa 9 (MMP-9) en modelos de estrés crónico y en pacientes deprimidos. En esta Tesis Doctoral, profundizamos en la implicación de la MMP-9 en la depresión. Observamos un efecto antidepresivo del tratamiento subcrónico con cannabidiol y la reversión del incremento en la actividad de la MMP-9 en un modelo de depresión inducido por la administración de corticosterona. La caracterización de ratones transgénicos MMP-9 mostraron que las alteraciones en MMP-9 tienen un impacto sexo-dependiente a nivel conductual, molecular y neuroquímico. Finalmente, detectamos una elevada actividad de MMP-9 en muestras cerebrales post-mortem de mujeres deprimidas que cometieron suicidio, pero no en hombres. Estos hallazgos refuerzan la implicación sexo-dependiente de MMP-9 en la etiopatología de la depresión.ABSTRACT: Major depression is a common mental illness, especially in women. Cannabidiol, the main non-psychomimetic component of Cannabis sativa, presents a potential antidepressant effect. On the other hand, high levels of metalloproteinase 9 (MMP-9) have been observed in models of chronic stress and depressed patients. In this Doctoral Thesis, we delve into the involvement of MMP-9 in depression. We observed an antidepressant-like effect of subchronic cannabidiol administration and the normalization of elevated MMP-9 activity in the corticosterone-induced model of depression. The characterisation of MMP-9 transgenic mice showed that alterations in MMP-9 have a sex-dependent impact at the behavioural, molecular, and neurochemical levels. Finally, we detected elevated MMP-9 activity in post-mortem brain samples from depressed women who committed suicide, but not in men. These findings reinforce the sex-dependent implication of MMP-9 in the etiopathology of depression.Para la realización de este trabajo, la doctoranda ha disfrutado de un contrato predoctoral de la “Convocatorias 2018 Proyectos de I+D de GENERACIÓN DE CONOCIMIENTO y Proyectos de I+D+i RETOS INVESTIGACIÓN”, del Centro de Investigación Biomédica en Red (CIBER). Este trabajo ha sido financiado por: - Ministerio de Ciencia, Innovación y Universidades (RTI2018-097534-B-I00). - Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III (CIBERSAM CB/07/09/0029 y CB/07/09/0008)

mTOR knockdown in the infralimbic cortex evokes a depressive-like state in mouse

Fast and sustained antidepressant effects of ketamine identified the mammalian target of rapamycin (mTOR) signaling pathway as the main modulator of its antidepressive effects. Thus, mTOR signaling has become integral for the preclinical evaluation of novel compounds to treat depression. However, causality between mTOR and depression has yet to be determined. To address this, we knocked down mTOR expression in mice using an acute intracerebral infusion of small interfering RNAs (siRNA) in the infralimbic (IL) or prelimbic (PrL) cortices of the medial prefrontal cortex (mPFC), and evaluated depressive- and anxious-like behaviors. mTOR knockdown in IL, but not PrL, cortex produced a robust depressive-like phenotype in mice, as assessed in the forced swimming test (FST) and the tail suspension test (TST). This phenotype was associated with significant reductions of mTOR mRNA and protein levels 48 h post-infusion. In parallel, decreased brain-derived neurotrophic factor (BDNF) expression was found bilaterally in both IL and PrL cortices along with a dysregulation of serotonin (5-HT) and glutamate (Glu) release in the dorsal raphe nucleus (DRN). Overall, our results demonstrate causality between mTOR expression in the IL cortex and depressive-like behaviors, but not in anxiety.Funding: This research was funded by grants of the Ministerio de Economía y Competitividad (SAF2011-25020 and SAF2015-67457-R MINECO); Ministerio de Ciencia, Innovación y Universidades (RTI2018-097534-B-I00); Ministerio de Ciencia e Innovación (PID2019-105136RB-100); and the European Regional Development Fund (ERDF), UE; Instituto de Salud Carlos III (PI19/00170), and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)

Brain matrix metalloproteinase-9 activity is altered in the corticosterone mouse model of depression

Major depressive disorder is a highly prevalent psychiatric condition. Metalloproteinase 9 (MMP-9), a gelatinase involved in synaptic plasticity, learning and memory processes, is elevated in both chronic stress animal models and human peripheral blood samples of depressed patients. In this study we have evaluated the MMP-9 activity and protein expression in brain areas relevant to depression using the chronic corticosterone mouse model of depression. These mice show a depressive- and anxious-like behaviour. The MMP-9 activity and protein levels are significantly elevated in both the hippocampus and the cortex, and nectin-3 levels are lower in these brain areas in this model. In particular, these mice display an increased gelatinase activity in the CA1 and CA3 subfields of the hippocampus and in the internal layer of the prefrontal cortex. Moreover, the immobility time in the tail suspension test presents a positive correlation with the cortical MMP-9 activity, and a negative correlation with nectin-3 levels. In conclusion, the chronic corticosterone model of depression leads to an increase in the protein expression and activity of MMP-9 and a reduction of its substrate nectin-3 in relevant areas implicated in this disease. The MMP-9 activity correlates with behavioural despair in this model of depression. All these findings support the role of MMP-9 in the pathophysiology of depression, and as a putative target to develop novel antidepressant drugs.This research was supported by the Ministerio de Ciencia, Innovación y Universidades (RTI2018-097534-B-I00) and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM).MMP-9Corticosterone modelDepressionCortexHippocampu