Aplysia californica is a curious beast indeed. The California sea hare is a species of sea slug; a hermaphroditic gastropod mollusc that feeds on seaweed and occasionally squirts ink if you piss it off. Charming little chap, really.
A. Californica has become the best friend of the neurobiologist. It is used extensively as a laboratory model in experiments looking to elucidate how learning occurs, and how responses decline as a result of repeated stimulation. What’s great about this animal is it elicits a gill/siphon withdrawal response- a reflex which can be induced simply by touching these parts of the animal’s body. This is brilliant for an experimenter- this is a measurable, predictable, behavioural response, which can be manipulated by different experimental conditions. Well done, California sea hare.
While this animal has been essential in a huge amount of neurobiological research, some of the most interesting hypotheses bourne-out of research on the sea hare implicate prion proteins in memory and learning. This is exciting, if a little controversial, because prions are often thought of negatively- they are notorious in neurological disease.
Prions are proteins which can take on at least two different conformations, one of which is self-replicating. The self-replicating conformation often results in protein aggregation and this can have unfortunate consequences when inappropriate, in that it facilitates the transmission of often fatal neural diseases such as Creutzfeldt-Jakob Disease (CJD). In CJD, a prion protein in the brain becomes problematic if it acquires the self replicating conformation. It begins to self replicate and aggregate, turning neural tissue in the brain into what is, effectively, mush. A further, and more grizzly example comes from ‘kuru’, a disease which blights the ‘Fore’ tribespeople of Papua New Guinea, and is transmitted by the practice of cultural cannibalism. Tribesmen eat the brain tissue of the dead as a mark of respect, and hence, ingest the self-replicating prion which causes neurological degeneration and contract the ‘kuru’ disease themselves.
Prions can self-replicate because the protein in the self-replicating conformation can act as a template to encourage other prions to take on its shape. In turn, these act as templates form more prions, and a chain reaction is triggered. The ability to self-replicate their conformation also allows prions to transmit information, meaning they may be important in cellular memory. Perhaps most controversially, prion-like proteins have been implicated with long term neuronal memory, and this is where our friend the sea slug comes in.
‘CPEBs’ are vital proteins which are conserved across species and bind specifically to short lengths of 3’ RNA. They are involved in activating mRNAs which are transcriptionally silent via polyadenylation / altering the cellular localization of the mRNA, and are hence referred to as ‘cytoplasmic polyadenylation elements’ (CPEs). ApCPEB is a specific type of the CPEB protein which carries an N-terminal domain that is rich in glutamine residues. These are uncharged, polar amino acids, so this domain promotes protein aggregation in a prion-like manner. A neuronal form of this protein is present in the sea slug Aplysia californica, and this regulates the transcription of genes important for synaptic growth and function. In fact, the translation of ApCPEB from mRNA in neurons is activated by the neurotransmitter serotonin.
Some studies suggest that this protein may be involved in neuronal memory, because when repressed, long-term facilitation is blocked in A. californica. In the wild type condition, if the gills are repeatedly touched, inducing the aforementioned withdrawal response, the animal will habituate. This means its withdrawal response will become less and less intense as the gills are touched more and more often. This indicates that the animal is becoming ‘used to’ the touch, is becoming familiar with the stimulation, and is perhaps ‘learning’ that no significant consequences come about from it. One study showed that the absence of functional ApCPEB in the animal lead to decreased habituation to repeated touching of the gills. Withdrawal response intensity did not decrease, suggesting the animal’s ability to learn and become familiar with the stimulation was inhibited. Specifically, it may be the prion-like conformation of ApCPEB that allows this associative memory, as it seems that the aggregated, prion-like form of ApCPEB is the one which is induced when synapses are stimulated.
What is intriguing about implicating prions in long-term memory is that they provide a solution for how information can be stored at a biochemical level despite the fact that proteins are continuously turning over. While transcriptional feedback loops provide an alternative explanation for possible mechanisms of ‘memory’, the prion explanation might be that these proteins store information despite being continuously made and degraded by forcing other prions into the self-replicating conformation, and so information is preserved.
While this is interesting, it is still controversial, and is far from being an established possibility. Undoubtedly, there are still many more questions to be answered about how we and other species are able to learn and remember, and perhaps the California sea hare will be of great aid in answering such questions in years to come.
Citation: Shorter, J&Lindquist, S; 'Prions as adaptive conduits of memory and inheritence'. Nature reviews genetics (2005).