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The Plasticity-Pathology Continuum: Defining a Role for the LTP

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The Plasticity-Pathology Continuum: Defining a Role for the LTP Journal of Neuroscience Research 58:42–61 (1999) The Plasticity–Pathology Continuum: Defining a Role for the LTP Phenomenon Jill C. McEachern1* and Christopher A. Shaw1,2 1Department of Physiology, University of British Columbia, Vancouver, Canada 2Departments of Ophthalmology and Neuroscience, University of British Columbia, Vancouver, Canada Long-term potentiation (LTP) is the most widely Key words: homeostasis; receptor regulation; kin- studied form of neuroplasticity and is believed by dling; age-dependence; neuroplasticity many in the field to be the substrate for learning and memory. For this reason, an understanding of the INTRODUCTION mechanisms underlying LTP is thought to be of fundamental importance to the neurosciences, but a Since its discovery by Bliss and Lomo (1973), the definitive linkage of LTP to learning or memory has phenomenon of long-term potentiation (LTP) has domi- not been achieved. Much of the correlational data nated the empirical and theoretical search for the synaptic/ used to support this claim is ambiguous and controver- cellular basis of learning and memory. Many thousands of sial, precluding any solid conclusion about the func- articles and chapters have been written about the diverse tional relevance of this often artificially induced form subtypes of the phenomenon and the myriad characteris- tics that describe it (for references, see McEachern and of neuroplasticity. In spite of this fact, the belief that Shaw, 1996a,b). Synaptic potentiations that appear to be LTP is a mechanism subserving learning and/or LTP-like have been identified in every imaginable neural memory has become so dominant in the field that the circuit and subpopulation of both vertebrates and inverte- investigation of other potential roles or actions of brates. And, whereas many of these experiments have LTP-like phenomena in the nervous system has been been phenomenological, often mundane, a large number seriously hindered. The multiple subtypes of the of experiments on LTP have been technological tours de phenomena and the myriad molecules apparently force that are models of intellectual precision and rigor. involved in these subtypes raise the possibility that Throughout it all, the underlying assumption, stated or observed forms of LTP may represent very different not, is that LTP is the synaptic basis of memory and that types of modification events, with vastly different when we understand the mechanisms behind it we will consequences for neural function and survival. A hold in our grasp the Holy Grail of the neurosciences. relationship between LTP and neuropathology is sug- Judging by a recent commentary (Stevens, 1998), many gested in part by the fact that many of the molecular neuroscientists not only accept that LTP or something processes involved in LTP induction or maintenance much like it is the basis of learning and memory, but, are the same as those activated during excitotoxic further, some think that the final elucidation of the events in neurons. In addition, some LTP subtypes are underlying mechanisms is within reach. To question clearly induced by pathological stimuli, e.g., anoxic either of these assumptions is to question the faith in the LTP. Such data raise the possibility that LTP is part of ‘‘LTP equals memory’’ orthodoxy that so clearly domi- a continuum of types of neural modification, some nates the field of neuroplasticity research. Until recently, leading to beneficial alterations such as may occur in relatively few investigators have chosen to query the learning and others that may be primarily pathologi- basic assumptions in the field, a rather astonishing fact cal in nature, as in kindling and excitotoxicity. In this given the amount of time and treasure invested in sorting article, we introduce a plasticity–pathology con- out the mechanisms of LTP. Indeed, it is our contention tinuum model that is designed to place the various that the field appears to be in stasis: new molecules are forms of neural modification into proper context. In vitro and kindling receptor regulation studies are used Contract grant sponsor: British Columbia Health Research Foundation; to provide a basis for evaluating the specific synaptic/ Contract grant sponsor: MITACS Centre of Excellence. cellular response modification along the continuum of *Correspondence to: Jill C. McEachern, 2177 Wesbrook Mall, Univer- events, from beneficial to detrimental, that will be sity of British Columbia, Vancouver, BC, Canada, V6T 1Z3. induced by a particular stimulus. J. Neurosci. Res. E-mail: [email protected] 58:42–61, 1999. ௠ 1999 Wiley-Liss, Inc. Received 10 May 1999; Accepted 17 May 1999 ௠ 1999 Wiley-Liss, Inc. LTP and the Plasticity–Pathology Continuum 43 constantly being tossed into the breach, but fundamental In the following sections we will briefly attempt to assumptions remain largely unquestioned. For example, deal with these issues. For a more comprehensive over- What if LTP has little or nothing to do with memory? Or, view of the vast LTP literature, the reader is referred to What if it serves other processes as well? If LTP is not the the reviews cited in the article. basis for memory, what is? And, not least, If not memory, then what is LTP? We have previously (McEachern and Shaw, 1996a,b) LTP CHARACTERISTICS PERTINENT published two reviews on the LTP phenomena and laid TO A MODEL OF LEARNING OR MEMORY open to scrutiny the fundamental assumptions in the field. Permanence of LTP Since then, others have repeated these queries and Although with some induction methods LTP may be proposed alternatives (Shors and Matzel, 1997; for a long-lasting, it is not permanent (Jeffery et al., 1990; review, see also Cain, 1997). Moreover, whereas many Abraham et al., 1994, 1995). This fact argues against LTP investigators have responded in a positive way to the acting in itself as a lasting physical change underlying challenges to orthodoxy, others have taken refuge in the long-term memory. Impermanence is not necessarily a repetition of familiar litanies or in overt statements of fatal strike against LTP as a memory mechanism, how- faith (Abraham, 1997). ever. The problem can be circumvented in a variety of A fundamental goal of our reviews was to address ways, for example: (a) a relatively transient form of LTP selected sources of controversy in the LTP literature in an could, before decaying, trigger lasting alterations (e.g., effort to (1) assess the progress that had been made morphological) that then act as the substrate for memory; toward understanding the underlying mechanisms of LTP (b) the function of the hippocampus in memory may be and (2) sift compelling correlations to learning or memory most significant initially; subsequently its role may from vagaries of experimental technique. What we discov- diminish and that of other structures, possibly the cortex, ered as a result of our literature review was that LTP may become more important. Hippocampal LTP may be research, already a complex undertaking, was further sufficiently stable to reflect the time course of this type of complicated by the use of vastly different experimental relationship; however, studies of cortical LTP indicate techniques and preparations, often in disregard of vari- that it is not permanent either (Doyere et al., 1993); (c) ables that are absolutely crucial to experimental outcome. studies of human memory indicate that memories are Some of these practices included the failure to control for neither permanent nor invariant across the lifespan the effects of test stimulus intensity by measuring input/ (Bartlett, 1932), and mechanisms for reinvigorating mol- output curves, failure to account for age-dependent ecules involved in synaptic modifications have been variability, and lack of attention to nonspecific effects of proposed and may provide the basis for the longevity of drugs, gene deletion, temperature, and motor activity. certain memories (Kavanau, 1994). If LTP is periodically These factors, combined with the high level of contradic- refreshed or, alternatively, acts as a transient triggering tion in the field, left little room to draw firm conclusions mechanism for other changes, then it would be more about either the function or the underlying mechanisms of compatible with the durability of memory. LTP. In our view, the situation has not changed since that time, and to date the extent of homology between observed types of LTP, the site and nature of the Depotentiation/Reversal of LTP alteration, the temporal progression and duration of the The properties of LTP depotentiation/reversal are potentiation, and the relationship of LTP to learning and also pertinent to the questions of permanence and the memory all remain issues of contention. suitability of LTP as a memory mechanism. LTP induced Nevertheless, it is hard to circumvent the fact that in vitro and in vivo in the hippocampus (Dudek and Bear, changes in synaptic strength and/or number seem to be a 1993; Larson et al., 1993; Martin, 1998) and in vivo in the prerequisite for a memory model based on a non- afferent system to the prefrontal cortex (Burette et al., increasing population of neurons, despite the difficulty of 1997) can be reversed by various patterns of low- proving it. Certain attributes of LTP make it an attractive frequency stimulation and within time windows varying candidate as a memory mechanism: It can be relatively from only minutes to the longest experimental time point durable, has associative properties (but see Gallistel, measured (hours). In one of these experiments (Larson et 1995), can be induced by stimuli approximating endog- al., 1993), LTP reversal was possible with theta- enous activity patterns, and similar increases in synaptic frequency stimulation. The ability of the theta rhythm, a response may occur as a result of learning. However, a pattern of neural activity that accompanies certain forms model of learning or memory with LTP as its substrate of natural activity in the behaving animal, to both induce will need to account for a variety of other properties of the and reverse LTP suggests that if LTP is to serve in phenomenon.
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