The Ubiquitin System Plays A Role In Synaptic Plasticity And Memory In Aplysia

by the enormous (relatively speaking) size of the neurons in Aplysia, allowing for easy microelectrode recording from specific, identified neurons in the animal's CNS.

A greatly simplified description of the circuitry underlying sensitization of the gill-and siphon-withdrawal reflex in Aplysia is as follows (we will cover this in more detail in Chapter 12). The touch to the gill and siphon complex stimulates siphon sensory neurons, which make direct and indirect connections (via interneurons) to gill motor neurons. The gill motor neurons stimulate muscles in the gill and siphon complex that mediate the defensive withdrawal reflex. The tail shock impinges upon this circuit by way of tail sensory neurons, which make direct contacts (and indirect contacts by way of interneurons) with the presynaptic terminals of the siphon sensory neurons.

It was soon realized that plasticity at the siphon sensory neuron/gill motor neuron synapse is one critical locus contributing to sensitization in the animal—one of the first demonstrations of the importance of synap-tic plasticity in learning and memory. A predominant component of plasticity at this synapse is increased neurotransmitter release from the siphon sensory neurons. Thus, tail shock and the attendant activity in tail sensory neurons and associated interneurons leads to release of modulatory neurotransmitters onto the siphon sensory neuron presynaptic terminal, increasing the release of neurotransmitter from these cells and augmenting the defensive withdrawal reflex. These observations highlighted the role of presynaptic facilitation of neurotransmitter release as a mechanism for memory in this system.

Although all of the modulatory neuro-transmitters involved in presynaptic facilitation in Aplysia sensory neurons are not yet identified, one important player is 5-Hydroxytryptamine (5HT, serotonin). Serotonin is released onto a subset of the siphon sensory neurons by a serotonergic tail sensory neuron stimulated by tail shock. In fact, serotonin application to siphon sensory neurons elicits the vast majority of the physiologic responses contributing to presynaptic facilitation of neurotransmitter release and sensitization in the animal.

As mentioned previously, sensitization in Aplysia exhibits both short-term and long-term forms. Similarly, in sensory neurons, serotonin application can lead to either short-term or long-term facilitation of neurotransmitter release. Single (5-minute) applications of serotonin give facilitation that lasts only a few minutes; repeated (5 x 5 minutes over the course of an hour) applications give facilitation lasting at least 24 hours.

What happens when the sensory neuron sees repeated applications of serotonin, which elicit long-lasting synaptic facilitation? Although many mechanistic details have not yet been worked out, several key steps resulting from 5HT application have been identified. The long-lasting elevation of cAMP leads to PKA activation and subsequent phosphorylation of CREB, and one of the genes whose activity CREB regulates controls an important pathway for the ubiquitination of specific proteins. The ubiquitin pathway is recruited to cause proteolytic degradation of one subunit of PKA, the PKA regulatory subunit (21, 22). Loss of regulatory subunits results in a

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