Matrix Metalloproteinase 9 in dendritic spine plasticity : PhD thesis

Legutko-Bijoch, Diana

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Matrix Metalloproteinase 9 in dendritic spine plasticity : PhD thesis

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Title: Matrix Metalloproteinase 9 in dendritic spine plasticity : PhD thesis

Abstract:

Neuronal plasticity, a process fundamental to memory formation manifests as changes in synaptic strength during encoding new information. Synapses undergo both structural and functional modifications, with dendritic spines—postsynaptic protrusions harbouring excitatory synapses—serving as primary sites for such remodelling. Long-term potentiation (LTP), a key form of plasticity, requires precise molecular coordination, consisting of well- characterized intracellular signalling cascades and less-understood extracellular events, particularly proteolysis. This study investigates the role of matrix metalloproteinase 9 (MMP-9) in structural LTP (sLTP) using hippocampal organotypic slices from wild-type and genetically modified mice. MMP-9 activity was modulated through chemical inhibitors and gene knockouts, while its interplay with neurotrophic factor signalling was assessed by measuring activation of tropomyosin receptor kinase B (TrkB, the receptor for Brain-Derived Neurotrophic Factor, BDNF) and Insulin-like Growth Factor 1 Receptor (IGF1R). Molecular biology techniques and bioinformatics approaches were employed to identify MMP-9 target proteins. My results demonstrate that MMP-9 is rapidly released upon stimulation and plays a pivotal role in spine growth and receptor activation. Inhibition or genetic knockout of MMP-9 significantly reduced sLTP-induced spine enlargement and impaired TrkB activation, indicating that MMP-9-mediated extracellular cleavage of proBDNF to mature BDNF is critical for sustained TrkB signalling. Furthermore, MMP-9 activity was shown to be essential for IGF1R activation, mediated through the cleavage of insulin-like growth factor-binding proteins (IGFBPs), with IGFBP2 identified as a likely target. Immunolabelling confirmed the localization of IGFBP2 in dendritic spines, implicating its involvement in this mechanism. In conclusion, this study identifies MMP-9 as a key regulator of synaptic plasticity, coordinating structural spine remodelling and functional signalling pathways through extracellular proteolysis. By facilitating BDNF/TrkB and IGF1/IGF1R signalling, MMP-9 bridges extracellular and intracellular mechanisms, shedding new light on the extracellular proteolysis modulating synaptic plasticity.