The plasticity-pathology continuum: defining a role for the LTP phenomenon.

Long-term potentiation (LTP) is the most widely studied form of neuroplasticity and is believed by many in the field to be the substrate for learning and memory. For this reason, an understanding of the mechanisms underlying LTP is thought to be of fundamental importance to the neurosciences, but a definitive linkage of LTP to learning or memory has not been achieved. Much of the correlational data used to support this claim is ambiguous and controversial, precluding any solid conclusion about the functional relevance of this often artificially induced form of neuroplasticity. In spite of this fact, the belief that LTP is a mechanism subserving learning and/or memory has become so dominant in the field that the investigation of other potential roles or actions of LTP-like phenomena in the nervous system has been seriously hindered. The multiple subtypes of the phenomena and the myriad molecules apparently involved in these subtypes raise the possibility that observed forms of LTP may represent very different types of modification events, with vastly different consequences for neural function and survival. A relationship between LTP and neuropathology is suggested in part by the fact that many of the molecular processes involved in LTP induction or maintenance are the same as those activated during excitotoxic events in neurons. In addition, some LTP subtypes are clearly induced by pathological stimuli, e.g., anoxic LTP. Such data raise the possibility that LTP is part of a continuum of types of neural modification, some leading to beneficial alterations such as may occur in learning and others that may be primarily pathological in nature, as in kindling and excitotoxicity. In this article, we introduce a plasticity-pathology continuum model that is designed to place the various forms of neural modification into proper context. In vitro and kindling receptor regulation studies are used to provide a basis for evaluating the specific synaptic/cellular response modification along the continuum of events, from beneficial to detrimental, that will be induced by a particular stimulus.

Persistence of the interictal emotionality produced by long-term amygdala kindling in rats.

Long-term amygdala kindling in rats results in large and reliable increases in emotional behaviour that model the interictal emotionality often observed in temporal lobe epileptics [Kalynchuk L. E. et al. (1997) Biol. Psychiat. 41, 438-451; Pinel J. P. J. et al. (1977) Science 197, 1088-1089]. These experiments investigated the persistence of these kindling-induced increases in emotional behaviour after the cessation of the kindling stimulations. In Experiment 1, rats received 99 amygdala or sham stimulations. Then, they were tested on three tests of emotionality (i.e. activity in an unfamiliar open field, resistance to capture from the open field, and activity in an elevated-plus maze) either one day, one week, or one month after the final stimulation. The rats tested one day after the last stimulation displayed substantial decreases in open-field activity, increases in resistance to capture and increases in open-arm activity on the elevated-plus maze; these effects decreased, but not to control levels, in the rats tested one month after the final stimulation. In Experiment 2, rats received 99 amygdala or sham stimulations, and their resistance to capture was assessed one day later. Then, after a 60-day stimulation-free period, the rats received another zero, one, 10, or 30 amygdala stimulations and their resistance to capture was reassessed one day later. The high levels of resistance to capture observed in the rats tested one day after the 99 stimulations declined significantly during the 60-day stimulation-free period, but it remained significantly above control levels. However, the administration of 30 additional stimulations reinstated asymptotic levels of resistance to capture. These results provide the first systematic evidence that kindling-induced increases in emotional behaviour persist at significant levels for at least two months following the termination of kindling stimulations. Thus, they suggest that the neural changes underlying the genesis of interictal emotionality may be closely related to those mediating epileptogenesis itself.

An alternative to the LTP orthodoxy: a plasticity-pathology continuum model.

Long-term potentiation (LTP) is probably the most widely studied form of synaptic plasticity in the mammalian central nervous system. In the early descriptions, the term referred to a sustained increase in synaptic response following a brief high-frequency electrical tetanus. Apparently unique properties of the phenomenon triggered considerable excitement in the field: for many, LTP offered the promise of a potential substrate for learning and/or memory. In the more than 20 years since LTP was first discovered, investigators motivated by this promise have described a vast array of molecules and processes that may be involved in LTP induction and maintenance. And yet, the mechanisms by which LTP occurs have not been resolved. Instead, the compiled results have uncovered layer upon layer of intricacy, including multiple LTP forms and multiple molecular cascades involved in LTP expression. The generally stated thesis that LTP equates to learning and/or memory at a synaptic level has not faced a serious challenge despite the fact that workers in the field have not provided an unambiguous correlation of LTP with either. A number of investigators have now shifted their attention to a newer form of synaptic modification, long-term depression (LTP). Whatever studies of LTD reveal, it is clear that the fundamental questions about LTP remain unanswered: what is it really and what, if anything, is it used for? In this review, we summarize the data concerning putative LTP mechanisms and the evidence for LTP's role in learning and memory. We show that extant models are not sufficient to account for the various forms of LTP and that the experimental evidence does not justify the view that LTP equates to learning and memory. Instead, we suggest that LTP can be related to other forms of synaptic modification, e.g., LTD and kindling, in a neuroplasticity/pathology continuum of events. In particular, we suggest that neurotransmitter receptor regulation may be a key element leading to synaptic modification: in the adult nervous system, homeostatic receptor regulation normally compensates for alterations in synaptic input, while in the developing nervous system a form of 'homeodynamic' receptor regulation prevails. Our model proposes that homeodynamic receptor regulation leading to an LTP-like effect triggers, or acts in concert with, synaptogenesis to allow young neurons to modify response characteristics in response to altered input. In contrast, some forms of LTP in adult neurons may represent a 'failed' form of receptor regulation whose final outcome is neural death. The model suggests a series of experimentally verifiable hypotheses.