Tagging and capture hypothesis of synaptic plasticity: the roles of calmodulin kinases and the phenomenon of behavioural tagging.
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Date
2010Author
Redondo Pena, Roger Lluis
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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.