TIMP-1 abolishes MMP-9-dependent long-lasting long-term potentiation in the prefrontal cortex.
BACKGROUND
Understanding of the molecular mechanisms of prefrontal cortex (PFC) plasticity is important for developing new treatment strategies for mental disorders such as depression and schizophrenia. Long-term potentiation (LTP) is a valid model for synaptic plasticity. The extracellular proteolytic system composed of matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) has recently been shown to play major role in the hippocampal plasticity.


METHODS
We tested whether induction of hippocampal-prefrontal LTP results in accumulation of tissue inhibitor of MMP-1, TIMP-1 mRNA, in the PFC of rats and whether adenovirally driven overexpression of TIMP-1 affects LTP. Additional study of slices was done with a specific MMP-9 inhibitor.


RESULTS
The TIMP-1 is induced in the rat medial PFC by stimuli evoking late LTP; its overexpression blocks the gelatinolytic activity of the MMP family; its overexpression before tetanization blocks late LTP in vivo; and MMP-9 inhibitor prevents late LTP in vitro.


CONCLUSIONS
We suggest a novel extracellular mechanism of late LTP in the PFC, engaging TIMP-1-controlled proteolysis as an element of information integration. Our results may also be meaningful to an understanding of mental diseases and development of new treatment strategies that are based on extracellular mechanisms of synaptic plasticity.
Okulski
Pawel
P
Department of Molecular and Cellular Neurobiology, Nencki Institute, Warsaw, Poland.
Jay
Therese M
TM
Jaworski
Jacek
J
Duniec
Kamila
K
Dzwonek
Joanna
J
Konopacki
Filip A
FA
Wilczynski
Grzegorz M
GM
Sánchez-Capelo
Amelia
A
Mallet
Jacques
J
Kaczmarek
Leszek
L
D000818:Animals; D006624:Hippocampus / Q000201:enzymology; D007150:Immunohistochemistry; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009434:Neural Pathways / Q000201:enzymology*; D017397:Prefrontal Cortex / Q000201:enzymology*; D011480:Protease Inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*
D011480:Protease Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9