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 syna ptic response following a brief high-frequency electrical tetanus. App arently unique properties of the phenomenon triggered considerable exc itement 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 hav e described a vast array of molecules and processes that may be involv ed 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 genera lly stated thesis that LTP equates to learning and/or memory at a syna ptic level has not faced a serious challenge despite the fact that wor kers in the field have not provided an unambiguous correlation of LTP with either. A number of investigators have now shifted their attentio n to a newer form of synaptic modification, long-term depression (LTD) . Whatever studies of LTD reveal, it is clear that the fundamental que stions about LTP remain unanswered: what is it really and what, if any thing, is it used for? In this review, we summarize the data concernin g putative LTP mechanisms and the evidence for LTP's role in learning and memory. we show that extant models are not sufficient to account f or the various forms of LTP and that the experimental evidence does no t justify the view that LTP equates to learning and memory. Instead, w e suggest that LTP can be related to other forms of synaptic modificat ion, e.g., LTD and kindling, in a neuroplasticity/pathology continuum of events. In particular, we suggest that neurotransmitter receptor re gulation may be a key element leading to synaptic modification: in the adult nervous system, homeostatic receptor regulation normally compen sates for alterations in synaptic input, while in the developing nervo us system a form of 'homeodynamic' receptor regulation prevails. Our m odel 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 alter ed input. In contrast, some forms of LTP in adult neurons may represen t a 'failed' form of receptor regulation whose final outcome is neural death. The model suggests a series of experimentally verifiable hypot heses.