Contributions of matrix metalloproteinases to neural plasticity, habituation, associative learning and drug addiction

Abstract

The premise of this paper is that increased expression of matrix metalloproteinases (MMPs) permits the reconfiguration of synaptic connections (i.e., neural plasticity) by degrading cell adhesion molecules (CAMs) designed to provide stability to those extracellular matrix (ECM) proteins that form scaffolding supporting neurons and glia. It is presumed that while these ECM proteins are weakened, and/or detached, synaptic connections can form resulting in new neural pathways. Tissue inhibitors of metalloproteinases (TIMPs) are designed to deactivate MMPs permitting the reestablishment of CAMs, thus returning the system to a reasonably fixed state. This review considers available findings concerning the roles of MMPs and TIMPs in reorganizing ECM proteins thus facilitating the neural plasticity underlying long-term potentiation (LTP), habituation, and associative learning. We conclude with a consideration of the influence of these phenomena on drug addiction, given that these same processes may be instrumental in the formation of addiction and subsequent relapse. However, our knowledge concerning the precise spatial and temporal relationships among the mechanisms of neural plasticity, habituation, associative learning, and memory consolidation is far from complete and the possibility that these phenomena mediate drug addiction is a new direction of research.

Figure 1

Diagram describing the influences of PAI-1, tPA/uPA, plasminogen and plasmin upon the conversion of pro-MMPs to active MMPs. Many active MMPs function to degrade the ECM; while TIMPs are designed to deactivate the MMPs thus preserving ECM molecules and connections. Modified from Wright and Harding [29] (potential contributions in the areas of memory consolidation, reconsolidation, and retrieval).

Figure 2

Mean (± SEM) group changes in head-shake responses (HSR) per three-trial blocks during sessions I and II. These sessions were separated by 5 minutes, 2, 6, or 24 hours, respectively. There were no differences among these groups comparing the first trial blocks of Session I. Each group significantly differed from the others comparing the first trail blocks of Session II. Specifically, the 5 minute ISI group indicated very little spontaneous recovery suggesting excellent memory retention of the habituatory response. The 2 and 6 hours ISI groups showed increments in spontaneous recovery and thus some loss of memory retention, while the 24-hour ISI group revealed 95% spontaneous recovery suggesting nearly complete loss of memory retention for habituation of the HSR, *P < .05, modified from Wright et al. [115].

Figure 3

Mean (± SEM) group changes in number of HSR per 3-trial blocks during sessions I and II of habituation trials separated by a 24 hours ISI. (a) These independent groups of rats were bilaterally infused into the dorsal hippocampus with artificial cerebrospinal fluid (aCSF, 2.5 μL each side), a low dose of FN-439 of 25 μg (Low FN-439), or a high dose of FN-439 of 50 μg (High FN-439) at 5 and 60 minutes following the termination of session I. All groups received a contingent signaling tone immediately prior to the air stimulus on each trial. There were no differences among the groups concerning the pattern of habituation during session I. There were differences among the groups during the first trial block of session II with the high FN-439 group revealing a significantly higher level of spontaneous recovery (poorer memory retention) as compared with the other two groups that did not differ. (b) Members of these two groups were bilaterally infused with aCSF or MMP-3 inhibitor (MMP-3i, 50 μg in 2.5 μL aCSF) into the dorsal hippocampus at 5 and 60 minutes following the conclusion of session I. Members of both groups received contingent tone immediately pior to the application of the air stimulus on each trial. The two groups did not differ regarding pattern of habituation during session I; however, members of the MMP-3 inhibitor group revealed a significantly higher level of spontaneous recovery (poorer memory retention) as compared with the aCSF group during the first trial block of session II, *P < .0001, modified from Wiediger and Wright [136].