Antidepressant treatments regulate matrix metalloproteinases-2 and -9 (MMP-2/MMP-9) and tissue inhibitors of the metalloproteinases (TIMPS 1-4) in the adult rat hippocampus.
Antidepressants induce structural remodeling in the adult hippocampus, including changes in dendritic arbors, axonal sprouting, neurogenesis, and endothelial cell proliferation. Such forms of structural plasticity take place in the context of the extracellular matrix environment and are known to be regulated by matrix metalloproteinases (MMPs), in particular MMP-2/9, and their endogenous regulators, the tissue inhibitors of the metalloproteinases (TIMPs 1-4). Given the hippocampal structural remodeling associated with antidepressant treatments, we hypothesized that antidepressants may regulate the expression and activity of MMP-2/9 and TIMPs 1-4. The influence of distinct classes of antidepressants, namely, electroconvulsive seizure, fluoxetine, tranylcypromine, and desipramine, on the gene expression of MMP-2, MMP-9, and TIMPs 1-4 in the hippocampus was determined using radioactive in situ hybridization. In addition, zymography studies addressed the regulation of the gelatinase activity of MMP-2/9 following acute and chronic antidepressant administration. We observed that acute and chronic ECS differentially regulate the transcript levels of MMP-2/9 and TIMPs 1-4 and also increase gelatinase activity in the hippocampus. Acute and chronic pharmacological antidepressants on the other hand differentially alter the expression of the TIMPs without any observed effect on hippocampal MMP-2/9 expression or activity. These findings raise the possibility that extracellular matrix modifying enzymes and their endogenous regulators may serve as targets for antidepressant treatments and suggests the possibility that they may contribute to antidepressant-mediated structural plasticity in the hippocampus.
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
Madhurima
M
Benekareddy
Purvi
P
Mehrotra
Vaishali A
VA
Kulkarni
Parvathy
P
Ramakrishnan
Brian G
BG
Dias
Vidita A
VA
Vaidya
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology; D004334:Drug Administration Schedule; D004565:Electroconvulsive Therapy; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019714:Tissue Inhibitor of Metalloproteinases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014191:Tranylcypromine / Q000494:pharmacology
D000928:Antidepressive Agents; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D005473:Fluoxetine; D014191:Tranylcypromine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D003891:Desipramine