title: Matrix metalloprotease activity shapes the magnitude of EPSPs and spike plasticity within the hippocampal CA3 network.
abstract: Matrix metalloproteases (MMP) play a pivotal role in long-term synaptic plasticity, learning, and memory. The roles of different MMP subtypes are emerging, but the proteolytic activity of certain MMPs was shown to support these processes through the structural and functional modification of hippocampal Schaeffer collateral and mossy fiber (MF) synapses. However, certain patterns of synaptic activity are additionally associated with non-synaptic changes, such as the scaling of neuronal excitability. However, the extent to which MMPs affect this process remains unknown. We determined whether MMP activity interferes with excitatory post-synaptic potential EPSP-to-spike (E-S) coupling under conditions of varying synaptic activity. We evoked short- and long-term synaptic plasticity at associational/commissural (A/C) synapses of CA3 pyramidal neurons and simultaneously recorded population spikes (PSs) and EPSPs in acute rat (P30-60) brain slices in the presence of various MMP inhibitors. We found that MMP inhibition significantly reduced E-S coupling and shortened the PS latency associated with 4× 100 Hz stimulation or paired burst activity of MF-CA3 and A/C synapses. Moreover, MMP inhibition interfered with the scaling of amplitude of measured signals during high-frequency trains, thus affecting the induction of long-term potentiation (LTP). The inhibition of L-type voltage-gated calcium channels with 20 µM nifedipine or GABA-A receptors with 1-30 µM picrotoxin did not occlude the effects of MMP inhibitors. However, MMP inhibition significantly reduced the LTP of NMDA receptor-mediated EPSPs. Finally, the analysis of LTP saturation with multiple single (1× 100 Hz) or packed (4× 100 Hz) trains indicated that MMPs support E-S coupling evoked by selected synaptic activity patterns and set the ceiling for tetanically evoked E-S LTP. In conclusion, the activity of MMPs, particularly MMP-3, regulated the magnitude of EPSPs and spike plasticity in the CA3 network and may affect information processing. Our data provide a novel link between MMP activity and neural excitability. Therefore, by limiting the number of firing neurons, MMP may functionally act beyond the synapse.
authors.affiliation: Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, Chalubinskiego 3, 50368, Wroclaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Wójtowicz
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Mozrzymas
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000528:radiation effects*; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D056654:CA3 Region, Hippocampal / Q000166:cytology*; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D010852:Picrotoxin / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D020782:Matrix Metalloproteinases; D010852:Picrotoxin; D011810:Quinoxalines; D014633:Valine; C056723:FG 9041; C056639:2-amino-5-phosphopentanoic acid
keywords: E-S coupling; EPSP-spike potentiation; inhibitor; matrix metalloprotease; synaptic plasticity