Thursday, January 21, 2010

Mechanisms, Experiments and Memories (Part 1): The LTP Mechanism

This post is part of my series on the work of the philosopher Carl Craver. The post deals with the nature of neuroscientific explanation. For an index, see here.

Over the next few posts, I will examine the following article:
Craver, C. "Interlevel Experiments and Multilevel Mechanisms in the Neuroscience of Memory" (2002) 69 Philosophy of Science 83-97.
This is one of my favourite of Craver's pieces. It offers a beautiful illustration of the methods and strengths of mechanistic explanations in neuroscience.

Craver's article has three aims:
  1. Offer a non-formal account of mechanistic theory structure in neuroscience.
  2. Develop a taxonomy of interlevel experiments that are used to explore proposed mechanisms.
  3. Use this experimental taxonomy to explore the integrative nature of neuroscientific theories.
As always, to help in achiveing his more abstract philosophical goals, Craver uses a concrete example as a reference point. On this occasion, the example used is that of spatial memory and LTP.

In this part, I will cover Craver's non-formal account of mechanistic theories.

Mechanistic Theories: A Sketch
For people who have been reading other entries in this series, the idea of a mechanism will be old hat. However, in this article Craver offers an excellent summary of the main points. It is worth repeating them here.

According to Craver, mechanisms are collections of entities and activities organised in the production of regular changes from start to finish. There are four important concepts concealed in this definition.

First, mechanisms consist of entities. In neuroscience, the relevant entities are ions, neurotransmitters, membranes, neurons, brain regions and whole animals (e.g. mice).

Second, mechanisms consist of activities. These are the processes or doings in which the entities participate. In neuroscience, relevant activities include: binding, phosphorylation, hydrolysis, firing, processing and so on.

Third, mechanisms are organised. That is: the entities and activities have a very specific spatial and temporal organisation. If they were not organised in this way the mechanism would not work.

Fourth, the mechanism does something: it carries out some task, produces some output or performs some function. We refer to this as the "role" of the mechanism.

A schematic diagram (based on one in Craver's article) is offered below. It illustrates all four features of a mechanism.

The Mechanism of LTP
Long-term potentiation (LTP) is a mechanism for strengthening the synaptic connections between neurons. Behavioural evidence suggests that it is crucial to the process of memory-consolidation. It is frequently studied in the hippocampal region of the mouse brain. The hippocampus has long been identified as a key brain region for memory formation. Many of the studies involve mice learning to navigate through mazes. Thus, spatial memory is the main type of memory being examined.

As with all things in science, there is no complete consensus on the mechanisms underlying LTP. Nonetheless, a great deal has been learned and there is a staggering amount of detail to current theories. If you would like to learn more, I suggest this lecture by Eric Kandel (lecture 4, 2008 is the relevant one). The following is merely a sketch.

LTP increases the effect of a presynaptic neuron on a post-synaptic neuron. Neurons that exhibit LTP use the neurotransmitter glutamate. This is released from the presynaptic neuron and binds to receptors on the postsynaptic neuron. One such receptor is the NMDA receptor. Glutamate changes the conformation (i.e. spatial orientation) of this receptor, thereby opening a pore in the membrane of the postsynaptic neuron.

Most of the time, this pore is blocked by magnesium ions (Mg2+), but when the postsynaptic neuron is depolarised it unblocks and calcium ions diffuse into the cell (Ca2+). These Ca2+ ions set off a cascade of biochemical reactions, which eventually result in new protein-synthesis by the DNA in the postsynaptic neuron. These proteins are used to make new dendritic buds (i.e. new locations at which the presynaptic neuron can exert an influence).

I will provide some diagrams of this process in the next part. For now, the words must paint the picture.

The LTP mechanism has the fourfold structure alluded to earlier:
  • It consists of entities: neurons, synapses, glutamate, NMDA, Ca2+, Mg2+ etc.
  • It consists of activities: binding, diffusing, changing conformation etc.
  • It is spatially and temporally organised: first binding, then changing conformation, then diffusing, then protein synthesis etc.
  • It has a role: it strengthens synaptic connections.
There is another crucial feature of the LTP mechanism, but I will discuss that in the next part.

1 comment:

  1. Just to let you know I am closely following this series on Carl's work. Keep it up.