Abstract
Matrix metalloproteases (MMPs) comprise a family of endopeptidases that are involved in remodeling the extracellular matrix and play a critical role in learning and memory. At least 24 different MMP subtypes have been identified in the human brain, but less is known about the subtype-specific actions of MMP on neuronal plasticity. The long-term potentiation (LTP) of excitatory synaptic transmission and scaling of dendritic and somatic neuronal excitability are considered substrates of memory storage. We previously found that MMP-3 and MMP-2/9 may be differentially involved in shaping the induction and expression of excitatory postsynaptic potential (EPSP)-to-spike (E-S) potentiation in hippocampal brain slices. MMP-3 and MMP-2/9 proteolysis was previously shown to affect the integrity or mobility of synaptic N-methyl-d-aspartate receptors (NMDARs) in vitro. However, the functional outcome of such MMP-NMDAR interactions remains largely unknown. The present study investigated the role of these MMP subtypes in E-S plasticity and NMDAR function in mouse hippocampal acute brain slices. The temporal requirement for MMP-3/NMDAR activity in E-S potentiation within the CA1 field largely overlapped, and MMP-3 but not MMP-2/9 activity was crucial for the gain-of-function of NMDARs following LTP induction. Functional changes in E-S plasticity following MMP-3 inhibition largely correlated with the expression of cFos protein, a marker of activity-related gene transcription. Recombinant MMP-3 promoted a gain in NMDAR-mediated field potentials and somatodendritic Ca2+ waves. These results suggest that long-term hippocampal E-S potentiation requires transient MMP-3 activity that promotes NMDAR-mediated postsynaptic Ca2+ entry that is vital for the activation of downstream signaling cascades and gene transcription.
Highlights
In the central nervous system, several forms of experiencedependent plasticity require the activity-dependent control of synaptic efficacy
We first studied the temporal requirement for N-methyl-D-aspartate receptors (NMDARs) activity in long-term E-S potentiation in the CA1 region of the NMDARs and Matrix metalloproteases (MMPs)-3 activity. a Recording scheme
We combined electrophysiology, immunocytochemistry, and Ca2+ imaging of hippocampal neurons to further investigate E-S plasticity’s temporal requirement for NMDARs and the extracellular activity of MMP-3 that was previously implicated as a potential modulator of NMDAR function
Summary
In the central nervous system, several forms of experiencedependent plasticity (i.e., substrates of learning and memory) require the activity-dependent control of synaptic efficacy. In a classic ( not unique) mechanism, N-methyl-D-aspartate receptors (NMDARs) gate Ca2+ influx following membrane depolarization during episodes of neuronal activity and determine the extent of synaptic long-term potentiation (LTP) or long-term depression (LTD) that subsequently develops [1]. Α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) mediate the majority of synaptic currents at excitatory synapses. In addition to synaptic plasticity, memory storage may involve multiple levels of longterm modifications of neuronal input-output properties through far more complex mechanisms than LTPLTDAMPA alone. Synaptic and nonsynaptic plasticity differs in the mechanism of expression, these processes share the common requirements of NMDAR activation and rise in postsynaptic Ca2+. The temporal requirement for NMDAR activity in synaptic LTPAMPA and E-S potentiation remains unknown
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