Figure 8.1. A microtubule segment from cryo-electron microscopy. [Credit: U.S. Department of Energy].

Microtubules are a major component of cytoskeleton responsible for intracellular transport of various cargos such as vesicles, organelles and neurotransmitter receptors. In Chapter 7, we have seen that the short-term memory is formed by inserting neurotransmitter receptors (e.g., AMPA receptors) into postsynaptic membranes at dendritic spines. However, the ultimate source of neurotransmitter receptors is protein synthesis at the cell body. Transport of neurotransmitter receptors from the cell body to spines requires microtubules (reference). Therefore, microtubules could be involved in memory formation and storage. This idea is supported by the following evidence:

1. Alzheimer's disease (loss of memory) is characterized by neurofibrillary tangles, resulting from damages to microtubules.
2. Microtubule-depolymerizing agents cause amnesia (reference).
3. Microtubules can enter dendritic spines and modulate spine morphology (reference 1; reference 2).
4. Many microtubules move from dendritic shafts to spines in hippocampal CA1 neurons after tetanic stimulation during long-term potentiation (reference).

A microtubule is a hollow cylinder with diameter about 25 nanometers. It consists of 13 protofilaments. Each protofilament is composed of tubulin dimers, with the α subunit of one dimer attached to the β subunit of the next dimer. Thus, a protofilament has one end (called "minus" end) with the α subunit exposed and another end (called "plus" end) with the β subunit exposed. Note that the definition of "+" and "-" on both ends does not imply that protofilaments are permanent dipoles. Under physiological conditions, protofilaments and the entire microtubule are highly negatively charged because the C-termini of both α and β subunits are rich in acidic (aspartate and glutamate) residues (reference).

Elongation of a microtubule is usually from the plus end. In the absence of microtubule-associated proteins (MAPs), a microtubule may shrink. MAPs also regulate the connection between a microtubule and neighboring microtubules or other cellular structures. In general, binding of MAPs to a microtubule makes it more stable and rigid. Their binding is determined by MAP phosphorylation, which in turn may be regulated by calcium ions (see Molecular Biology of the Cell). The tau protein involved in Alzheimer's disease belongs to MAPs. Its malfunction is due to hyperphosphorylation (review).

Kinesin and dynein are the major motor proteins mediating microtubular transport. These motor proteins can carry cargos and "walk" along a microtubule. Kinesin walks toward the plus end, but dynein walks toward the minus end (review 1; review 2). Neurotransmitter receptors are predominantly carried by kinesin which walks toward the plus end. As we shall see in the next chapter, the polarity and specific directional transport make microtubules a good binary system for memory encoding and storage.

Author: Frank Lee
First Published: September 4, 2009