Diverse impact of acute and long-term extracellular proteolytic activity on plasticity of neuronal excitability

Abstract

Learning and memory require alteration in number and strength of existing synaptic connections. Extracellular proteolysis within the synapses has been shown to play a pivotal role in synaptic plasticity by determining synapse structure, function, and number. Although synaptic plasticity of excitatory synapses is generally acknowledged to play a crucial role in formation of memory traces, some components of neural plasticity are reflected by nonsynaptic changes. Since information in neural networks is ultimately conveyed with action potentials, scaling of neuronal excitability could significantly enhance or dampen the outcome of dendritic integration, boost neuronal information storage capacity and ultimately learning. However, the underlying mechanism is poorly understood. With this regard, several lines of evidence and our most recent study support a view that activity of extracellular proteases might affect information processing in neuronal networks by affecting targets beyond synapses. Here, we review the most recent studies addressing the impact of extracellular proteolysis on plasticity of neuronal excitability and discuss how enzymatic activity may alter input-output/transfer function of neurons, supporting cognitive processes. Interestingly, extracellular proteolysis may alter intrinsic neuronal excitability and excitation/inhibition balance both rapidly (time of minutes to hours) and in long-term window. Moreover, it appears that by cleavage of extracellular matrix (ECM) constituents, proteases may modulate function of ion channels or alter inhibitory drive and hence facilitate active participation of dendrites and axon initial segments (AISs) in adjusting neuronal input/output function. Altogether, a picture emerges whereby both rapid and long-term extracellular proteolysis may influence some aspects of information processing in neurons, such as initiation of action potential, spike frequency adaptation, properties of action potential and dendritic backpropagation.

The Effect of Acute Pharmacological Inhibition of Urokinase Plasminogen Activator and Neuropsin Extracellular Proteases on Neuronal Networks in vitro

“…We observed significant alterations in the collective emergent activity in vitro within just 1h following the application of the inhibitor, consistent with the rapid in vivo action of ECM proteases (i.e. over minutes to hours [33]). Our observations seem to point to both synaptic connectivity and to intrinsic single-cell excitability, in line with our current understanding of ECM proteases (see [33] for a review).…”

“…The ECM is a key player in the regulation of intrinsic excitability and structural synaptic connectivity, although the involvement of its different molecular constituents is largely unknown. Proteolytic regulation of ion channels is associated with the ECM [33] and the mechanisms underlying action potential generation (e.g. voltage-gated sodium channels) are also implicated in adhesion, migration, path finding, and transcription [34].…”

Matrix Metalloprotease 3 Activity Supports Hippocampal EPSP-to-Spike Plasticity Following Patterned Neuronal Activity via the Regulation of NMDAR Function and Calcium Flux

“…This may suggest that MMP-3 functions mainly in the perisynaptic space rather than in the somatic space (as shown for MMP-9; [49]). Alternatively, because PS potentiation relies on excitation/inhibition balance [10], local changes in GABAergic inhibition following HFS may have more of an impact on PS plasticity than on fEPSP plasticity. This issue will require further investigation.…”

“…Neurons can significantly enhance information storage capacity by scaling dendritic and somatic excitability and learning [7, 8]. A hallmark of such a phenomenon occurs during tetanically evoked synaptic LTP when the probability of firing an action potential in postsynaptic neurons increases beyond the probability that is predicted by an increase in synaptic input (excitatory postsynaptic potential (EPSP)-to-spike potentiation; E-S plasticity [9, 10]). Although synaptic and nonsynaptic plasticity differs in the mechanism of expression, these processes share the common requirements of NMDAR activation and rise in postsynaptic Ca 2+ .…”

“…More recent data showed that stromelysin MMP-3 was upregulated in the hippocampus following learning and supported hippocampal synaptic plasticity [14–16]. In addition to modulating synaptic plasticity, a recent study found that acute and long-term extracellular proteolysis affected long-term neuronal excitability [10]. We recently found that the activity of certain MMP subtypes may modulate long-term NMDAR function, and MMP-3 and MMP-2/9 inhibition differentially affected the time course of E-S potentiation [17].…”