Abstract
Long-term synaptic plasticity is shaped by the controlled reorganization of the synaptic proteome. A key component of this process is local proteolysis performed by the family of extracellular matrix metalloproteinases (MMPs). In recent years, considerable progress was achieved in identifying extracellular proteases involved in neuroplasticity phenomena and their protein substrates. Perisynaptic metalloproteinases regulate plastic changes at synapses through the processing of extracellular and membrane proteins. MMP9 was found to play a crucial role in excitatory synapses by controlling the NMDA-dependent LTP component. In addition, MMP3 regulates the L-type calcium channel-dependent form of LTP as well as the plasticity of neuronal excitability. Both MMP9 and MMP3 were implicated in memory and learning. Moreover, altered expression or mutations of different MMPs are associated with learning deficits and psychiatric disorders, including schizophrenia, addiction, or stress response. Contrary to excitatory drive, the investigation into the role of extracellular proteolysis in inhibitory synapses is only just beginning. Herein, we review the principal mechanisms of MMP involvement in the plasticity of excitatory transmission and the recently discovered role of proteolysis in inhibitory synapses. We discuss how different matrix metalloproteinases shape dynamics and turnover of synaptic adhesome and signal transduction pathways in neurons. Finally, we discuss future challenges in exploring synapse- and plasticity-specific functions of different metalloproteinases.
Highlights
Neuroplasticity is often defined as the ability of neural networks in the brain to change through various growth, reorganization, or other modulatory processes to adapt to an organism’s variable environment and change with experience
matrix metalloproteinases (MMPs) have been implicated in synaptic plasticity at excitatory synapses for many years, it is only recently that it has been appreciated that metalloproteinases play significant roles in inhibitory synapses
This unique role of MMP3 underscores the intricate relationship between extracellular proteolysis and activity-dependent changes in the pool of synaptic receptors, which is critical for almost all forms of postsynaptic plasticity
Summary
Neuroplasticity is often defined as the ability of neural networks in the brain to change through various growth, reorganization, or other modulatory processes to adapt to an organism’s variable environment and change with experience. In the follow-up study, the same group reported increased extracellular proteolytic processing of amyloid-beta precursor protein (APP) and neural cell adhesion molecule (NCAM) after LTP [23] These results, together with the discovery of the role of tissue plasminogen activator (tPA) [24] and TIMP1 in LTP [25], provided the first direct evidence that elevated extracellular proteolysis can be a hallmark of long-term synaptic plasticity. Future studies are needed to describe this process precisely, as was the case, for instance, with BDNF [44,45] At this point, it is important to note that MMP9-deficient mice show normal long-term depression (LTD) at excitatory synapses in the hippocampal CA1 field [32], suggesting that the frequency of synaptic stimulation or the timing of postsynaptic action potentials determines whether MMP9 is involved in a given type of long-term synaptic plasticity. The mechanisms underlying this selectivity are not clear: proMMP9 could be released selectively at small synapses prone to structural plasticity, or big spines could lack specific receptors for MMP9 that would concentrate it, enabling the protease to trigger the plasticity mechanisms
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