Molecular Mechanisms of Memory Storage

Hawkins, R.D., Kandel, E.R., & Bailey, C.H. (June 2006). Molecular Mechanisms of Memory Storage in Aplysia. Biological Bulletin, 210, 174-191.

This article reviews what molecular biology currently knows about the underlying nervous system mechanisms for memory. Memory comes in several forms. The short-term form, kicked off by brief and well-spaced stimulation pulses, lasts minutes and involves alterations in the effectiveness of existing synaptic connections. This can be accomplished via covalent modifications of pre-existing proteins by a variety of kinases, enhanced neurotransmitter release, and other means of short-term sensitization which increase the excitability of the neuron pair. The intermediate form, created by repeated and more prolonged exposure to stimulation, lasts hours and often requires translation-but-not-transcription-dependent processes. The final and most stable phase of long-term memory storage is characterized by the modulation of both function and structure of specific synaptic connections. This form, lasting days, weeks, or longer, requires full gene expression for synaptic remodeling and the growth of new synaptic connections. The mechanisms, though varied, together create a continuum between short- and long-term memory storage. (Other changes, such as increases in spine size, increases in the size and number of synaptic vesicles, or the clustering of such vesicles, can be seen along this spectrum.)

The paper also mentions the significance of synaptic tagging mechanisms discovered only recently. Given that many of these methods of potentiation kick off cell-wide processes, being able to identify the specific synapse whose activation originally triggered these processes is extremely important. (More here)

Finally, the article talks about potential memory longevity concerns. Since biological molecules have a short half-life (hours to days) compared to the duration of memory (up to years), researchers hoped to better understand the self-sustaining properties of memory. CPEB, which is a prion-like protein and is known to take two different conformational states, has an active state which has the ability to "awaken" dormant mRNAs to initiate translation at the local activated synapse. CPEB, in addition to being proposed as a synaptic marker, also seems to be a good candidate for sustained synapse-specific potentiation since it is also known to self-perpetuate once active. CPEB-3 has been found in mammal hippocampus and is induced by dopamine.