Role of adducins, actin-regulating proteins, in synaptic plasticity and learning

Changes at individual synapses are thought to underlie the cellular basis for learning and memory formation. Providing architectural support for both the pre- and postsynaptic terminals, the actin cytoskeleton is intricately linked to many proteins that are involved in mediating synaptic plasticity. Indeed, alterations in actin dynamics are essential for plastic changes to occur. Therefore, proteins that regulate the actin cytoskeleton may play an important role in synaptic plasticity and in learning and memory formation.; The adducin family of proteins interacts with the actin cytoskeleton and the plasma membrane in a calcium- and cAMP-dependent manner. Adducins cap actin filaments at the barbed end, bundle filaments together and also bind spectrin. Activity of adducins is regulated bi-directionally by several different kinase cascades. Although adducin function has been well characterized in a number of different cell types, very little is known about their function in neurons. We characterized the expression of alphaand beta-adducin mRNA and protein using in situ hybridization and SDS-PAGE, finding expression throughout the brain and that expression levels appear to correlate with cellular density. Demonstrating that the activity of adducins can be regulated in vivo, acute cocaine administration causes a marked increase in phosphorylation of adducins at the conserved PKC site in the MARCKS domain. Adducins are involved in normal neurotransmission, as basal responses in the SC-CA1 circuit are enhanced in acute hippocampal slices from mice lacking beta-adducin, although there are no differences in the presynaptic fiber volley to field excitatory postsynaptic potential ratio or in paired pulse facilitation. Tetanic long term potentiation decays rapidly to baseline in betaadducin knockout slices, further suggesting a role for adducins in synaptic plasticity. Analysis of spine morphology in naive animals by electron microscopy showed no difference in morphology or post-synaptic density number in knockouts and wild-types. Beta-adducin knockout mice are impaired in both the fear conditioning and water maze paradigms, and show enhanced locomotor sensitization to repeated cocaine administration. These results indicate that adducins may play an important role in the cellular mechanisms underlying activity-dependent synaptic plasticity associated with learning and memory and repeated exposure to drugs of abuse.