Cortical Plasticity: LTP and LTD

In a literate introduction to Cortical Plasticity: LTP and LTD, Richard Morris characterizes the current state of the pre- versus postsynaptic LTP expression debate by quoting Francis Crick, that in research ‘the front line is almost always in a fog’1xCrick, F. What Mad Pursuit?. 1988; See all References. Today, most neuroscientists would agree that there are few simple answers to the induction, maintenance or expression of LTP, not to speak of its putative role in memory or other long-term plastic functions of the brain. Reflecting this general trend towards complexity, Cortical Plasticity is a collection of generous and unbiased reviews of the physiological, molecular and computational aspects of LTP and LTD, emphasizing the multiplicity of possible mechanisms. The book is a scholarly synopsis, ideal for a graduate student or scientist new to the area. The only problem is, having been introduced to complexity, controversy and paradox, why would any researcher enter the field?The short answer is that LTP, more than 20 years after its discovery, still passes the Crick Gossip Test1xCrick, F. What Mad Pursuit?. 1988; See all References: the most interesting areas of research are the ones you find yourself talking about. But in the past few years, while lunchtime talk still turns to the latest in LTP and LTD, the conversations often end with shrugs, as there is little agreement on results, and sometimes, even, on what is important.Given the current lack of consensus, the contributors to Cortical Plasticity have wisely chosen an inclusive approach. The physiology chapters include Anwyl on glutamate receptors, Collingridge and colleagues on post-translational modifications of these receptors, Segal and Auerbach on neuromodulators, and Bliss and Fazeli on LTP expression. The last is a model of equipoise, with every point of evidence for presynaptic expression balanced by a counterpoint for postsynaptic expression. The explosion of second messengers that follows a tetanus is neatly reviewed by Roberson, English and Sweatt, with nearly every model of LTP given its moment, from Ca2+–calmodulin kinase autoactivation to transitions from early LTP (E-LTP) to late LTP (L-LTP). By the time Thomas and Hunt describe the gene products that change at various stages during LTP, the potential mechanisms become layered, intricate, and, on the surface, unfathomably complex.While each chapter presents a coherent picture and is remarkably easy to read, the extent of the differences in perspective can be seen when these viewpoints are compared. For example, interpreting the same experiments with kinase inhibitors, which are among the most consistent in the field, Morris discerns that they do not prevent LTP induction, only limit its duration, while Sweatt perceives that they block induction of E-LTP, revealing shortterm potentiation. In general, most of the physiologists have little to say about how protein synthesis is involved with expression, while to the biochemists it has become canonical. No one at all has much to say about structural changes at the synapse, except they are a good way to close a chapter with a sense of finality. By suspending judgment on which molecular mechanisms are essential, the authors accurately describe the LTP field as it stands.Having finished Cortical Plasticity, I took the tip from Morris, and read as a chaser Crick's book, aptly entitled What Mad Pursuit? I recommend both books strongly to any researchers entering the LTP field. Here, in paraphrase, are some of Crick's guidelines for finding the way out of a research fog (my comments are in parentheses): (1) Do not confuse the mechanism itself with the completely separate mechanisms for controlling it (or do not confuse maintenance with the complexities of induction). (2) Do not believe too strongly in clever arguments (either yours or others), particularly if the arguments are negative. (Biochemists have often been told they cannot possibly observe molecular changes in LTP because the potentiated synapses would be so few. That turned out to be wrong.) (3) Evolution is a tinkerer, so try to see through Nature's clutter to the underlying mechanism. To do so the only reliable guide is not theory but experimental evidence. Corollary 1: some of the experimental evidence may be wrong. Corollary 2: widely-held, plausible assumptions may be wrong.As outlined in the chapter by Bear and Kirkwood, the symmetry and generality of LTP and LTD might be the bell toll of a unifying underlying mechanism out there. Of recent texts, Cortical Plasticity gives readers the best opportunity for surveying the field, and finding their own way. Researchers will come to LTP or LTD despite the fog – or because of it.