The intracellular interactions between CS and US signals are particularly relevant to understanding learning and memory because they can produce lasting changes in neurons when they occur. Research on associative learning has demonstrated the importance of second messenger systems in mediating changes at the synapse (box 3.2). These findings have linked many different second messenger systems and protein kinases to learning and memory across a phylogenetically diverse range of animals (Micheau and Riedel 1999). Studies
BOX 3.2 A Nobel Prize in the Molecular Basis of Memory
The 2000 Nobel Prize in Physiology or Medicine was awarded jointly to Arvid Carlsson, Paul Greengard, and Eric Kandel for their work on signal transduction in the nervous system. Carlsson received the prize for his discovery that dopamine is a neurotransmitter in the brain and for his research on the function of dopamine in the control of movement. Greengard received the prize for research on how neurotransmitters act on receptors and trigger second messenger cascades that lead to the phosphorylation of proteins and modification of ion channels. Kandel's award was for his work on the molecular mechanisms of memory.
Kandel's research on conditioning in the sea slug Aplysia revealed many of the basic intracellular processes of memory formation discussed in this chapter. Aplysia exhibit a gill withdrawal reflex when the gill is touched, and this reflex can be conditioned to stimulation elsewhere on the sea slug's body. Conditioning results from increases in the levels of second messenger molecules such as cAMP and PKA, leading to protein synthesis and changes in the shapes and properties of synaptic connections between cells. Kandel's recent work has explored comparable mechanisms such as long-term po-tentiation that may be responsible for memory formation in mammals and has described many similarities to the molecular mechanisms of memory discovered in invertebrates.
of learning in birds, mammals, and the sea slug Aplysia implicate protein kinase C (PKC), for example, in changes at the synapse, also known as synaptic plasticity (Micheau and Riedel 1999). Elevation of intracellular Ca2+ increases PKC activity. In the honeybee, PKC occurs in both the mushroom bodies and antennal lobes (Granbaum and Muller 1998; Hammer and Menzel 1995), but its role in conditioning of the proboscis extension response remains unclear. Repeated proboscis extension conditioning trials increase PKC in the antennal lobes, beginning 1 hour after conditioning and continuing for up to 3 days. Blocking PKC activation, however, does not affect initial acquisition of the PER (Grunbaum and Muller 1998). Elevation of intracellular Ca2+ may also act through other Ca2+-dependent kinases, such as Ca2+/calmodulin-dependent kinase IV (CaMKIV). Activation of this kinase by Ca2+ may be an important mechanism underlying long-term memory (see below).
As noted earlier, elevated cAMP levels in the honeybee mushroom bodies activate PKA. There are high levels of PKA in the mushroom bodies (Fiala et al. 1999; Muller 1997), and octopamine is able to activate PKA both in the antennal lobes (Hildebrandt and Muller 1995b) and in cultured Kenyon cells (Muller 1997; but see Menzel and Muller 1996). The activation of PKA by cAMP appears to be a necessary step in the sequence of events that leads to lasting change in mushroom body neurons. The importance ofPKA has been tested using antisense RNA. Inactivating PKA by injecting antisense RNA complementary to the mRNA sequence of a subunit of PKA impairs long-term memory measured 1 day after training (Fiala et al. 1999). Studies with Drosophila have also shown the importance of PKA. A variety of mutations have been identified in fruit flies that produce specific deficits in the flies' ability to form or retain simple associations, and many of these mutations affect the cAMP-PKA pathway (Dubnau and Tully 1998; Waddell and Quinn 2001). The Drosophila learning mutant dunce has a mutation of the gene for cAMP phosphodiesterase. Another learning mutant, rutabaga, has a mutation ofthe gene coding for adenylate cyclase. Both mutants have difficulty learning an association between odor and shock, and what learning they do exhibit decays very rapidly compared with that of wild-type fruit flies.
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