The reconsolidation hypothesis posits that memories that have been reactivated can be either enhanced or disrupted by pharmacological manipulation. Synaptic plasticity is presumed to underlie the reconsolidation process.
Matrix metalloproteinases are
proteins that regulate the extracellular matrix involved in plasticity events, and these
proteins have recently been shown to influence learning and memory. However, all studies on the role of
matrix metalloproteinases in learning and memory have employed tasks that rely on contextual cues. The goal of this study was to determine the extent to which
FN-439 would disrupt the consolidation and/or reconsolidation of a fear memory associated with a conditioned stimulus that signaled tone-
shock pairings and that was independent of contextual cues. Male Sprague-Dawley rats were given infusions of
FN-439 (35 microg intracerebroventricular) 30 min prior to conditioning (tone-
shock paired association) or 30 min prior to a single reactivation session given 24h after conditioning. Administration of
FN-439 did not disrupt consolidation of the freezing response when the tone (conditioned stimulus) was presented. In contrast,
FN-439 infusion disrupted reconsolidation of the fear memory in a reactivation-dependent manner. The reduced freezing behavior was not due to a decrease in general anxiety levels, since
FN-439 had no effect on the percent of open-arm time or open-arm entries in an elevated-plus maze task. Thus, we demonstrated for the first time that
matrix metalloproteinase inhibition in the brain is capable of disrupting the reconsolidation of a tone-
shock association memory that does not depend on contextual cues. The finding that a fear response to a previously paired conditioned stimulus can be disrupted by treatment with an
MMP inhibitor during a single reactivation session suggests that this class of compounds may have therapeutic potential for
posttraumatic stress disorder and/or simple
phobias.