Is Long-Term Potentiation (LTP) going out of fashion? And is Synaptic Plasticity now in?

We had some visitors to the lab last week from the UK. Did the usual lab things, showing off our various pieces of kit for neurophysiology, and spent a lot of time discussing experimental methodologies. One set-up looked a little forlorn in the lab – the one for doing long-term potentiation or LTP. It occurred to me that it was a while since I had read a pure LTP paper just for its own sake. It also left me wondering if LTP was going out of fashion, or if my lack of reading was simply our not doing anymore LTP experiments in the lab anymore – there not being any questions that we have recently wanted to understand by investigating LTP. Going back a few years, I well remember the early excitement regarding LTP: that it is the model of the biological processes that may be engaged by learning and memory, and that it is a good biological instantiation of the synaptic model of learning and memory developed by Donald Hebb in ‘The Organisation of Behavior‘.

Donald O. Hebb
Donald O. Hebb (Photo credit: Wikipedia)

The major findings regarding LTP are now in every textbook: it was first described in the hippocampus, a structure known to be vital for normal learning and memory. LTP involves a long-term enhancement of the strength of synaptic transmission; the induction of LTP involves the activation of NMDA receptors, metabotropic glutamate receptors and intracellular calcium stores. Blockade of NMDA receptors and/or mGluRs severely disrupts learning of a variety of tasks which depend on the integrity of the hippocampus. There are lots of other nuances too, but the foregoing is a reasonable summary.

Anyway, out of curiosity, I thought I would look at some research trends using Google Ngram and the Web of Science.

First, Ngram:

Google Ngram of LTP, synaptic plasticity and hippocampal place cells
Google Ngram of LTP, synaptic plasticity and hippocampal place cells

Here, I’ve compared the incidence of LTP, synaptic plasticity, and place cell. Synaptic plasticity switches places as the more frequent term found in books around about 2003 or so. And, if anything, the frequency of LTP dips around 2006 or so. Maybe a drop-off in LTP has been masked by a terminological switch. Interesting, too, that ‘synaptic plasticity’ appears in the 1960’s, and is then supplanted by LTP for about ten years, and then resumes its pole position.

Another way of looking at this is to do a ‘topic’ and ‘title’ searches for the phrases ‘long-term potentiation’ and ‘synaptic plasticity’ using the Web of Science to generate searches for these phrases in research papers, rather than books.

LTP and synaptic plasticity on the WoS
LTP and synaptic plasticity on the WoS

This graph seems to reflect the story above. The numbers of papers using the phrase ‘long-term potentiation’ in the title has been falling since somewhere around the turn of the century. Similarly, the number of papers featuring LTP as a topic turns down sharply around 2010 or so. ‘Synaptic plasticity’ by contrast has really taken off in both title and topic counts, passing LTP around about 2003 or so in title counts, and in topics around about the same time.

It’s hard to know whether or not to read something deeper into these trends or not. The science is pretty well settled (I don’t think there would be many dissents from the short summary above), and there may in fact not be too much left to discover – the big findings are already in. Instead, LTP might now be better studied as a proxy or biomarker for a more general case of synaptic plasticity induced by other methods, or as a useful readout for other conditions (in disease states, or cognitive enhancement, for example).

Hebb’s concept of the cell assembly* has not attracted the same experimental and theoretical attention as his ideas regarding synaptic plasticity. The critical advance for LTP was being able to reliably induce the phenomenon. Perhaps, in time, as appropriate high-density neurophysiological techniques become available, the cell assembly will attract a similar degree of attention as LTP and synaptic plasticity.

*(‘… a network of neurons that is … activated repeatedly during a certain mental process and in this way the excitatory synaptic connections among its members are being strengthened. In Hebb’s thinking the synaptic strengthening depends on the order of activation, and thus there is a time structure to the activation of cell assembly. Thus, the activity of a cell assembly is characterized by the spatiotemporal structure of the activity of its members. After being formed, activation of the first stage will revive the entire spatiotemporal signature of the cell assembly’).

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Author: Shane O'Mara