Tagging and capture hypothesis of synaptic plasticity: the roles of calmodulin kinases and the phenomenon of behavioural tagging.

Abstract

The aims of this thesis were (1) to learn about the identities of the molecules involved in the maintenance of long-term potentiation (LTP), and (2) to develop and test a behavioural paradigm capable of elucidating the interaction between these molecular processes and the persistence of long-term memories. By improving the stability of field recordings in in vitro electrophysiology, it was possible to investigate the molecular processes that determine the long-term changes in synaptic efficacy. In these experiments, the interactions between two convergent inputs onto the same neuronal population in the CA1 region of the hippocampus were monitored for over ten hours. Analytically powerful three-pathway protocols using sequential strong and weak tetanization in varying orders, and test stimulation over long periods of time after LTP-induction, enabled a pharmacological dissociation of potentially distinct roles of the calmodulin kinase (CaMK) pathways in LTP. This places constraints on the mechanisms by which synaptic potentiation, and possibly memories, become stabilized. The experiments show that tag setting is blocked by the CaMK inhibitor KN-93 that, at low concentration primarily blocks CaMKII, whereas a CaMKK inhibitor, STO-609, selectively limits the synthesis or the availability of plasticity related proteins (PRPs). To test whether memories can be subject to modulation by independent experiences, behavioural studies tested the possibility of lengthening the persistence of a relatively weak memory by pairing its induction with an event capable of inducing the synthesis of the required PRPs. Corticosterone-dependent stressful events like a cold swim proved to interfere and weaken spatial memories. On the other hand, the exploration of a novel environment succeeded in rescuing the decay of a weak memory. The effect of the exploration of the novel environment was dependent on NMDA and dopamine receptor activation, as well as protein synthesis. These results are discussed in relation to the synaptic tagging and capture hypothesis and a novel model of the neuronal mechanisms underlying synaptic plasticity is developed from them.