Bradshaw, Karl David; (2001) An investigation of the processes underlying late-phase long-term potentiation. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

In this thesis I have investigated the role of RNA and protein synthesis, during the late-phase of hippocampal long-term potentiation (L-LTP). Additionally, the involvement of protein kinase C (PKC) in the induction of this late phase was addressed. Using protocols that allowed hippocampal slices to be maintained for long periods, L-LTP lasting 8 hours or more was successfully achieved. Field EPSPs were recorded from pyramidal cells in the CAl region of the stratum radiatum. Tetanically induced L-LTP was blocked by bath application of inhibitors of transcription (actinomycin-D) and translation (emetine), whilst L-LTP in slice preparations lacking presynaptic cells bodies was unaffected. In addition, bath application of bisindolylmaleimide I, a highly selective inhibitor of PKC, was found to block both E-LTP and L-LTP induction if applied within the first 15 minutes, after the tetanus. These results are consistent with a requirement for both protein synthesis and postsynaptic RNA synthesis during L-LTP induction, coupled with a requirement for a critical period of PKC activity. The locus of protein synthesis during L-LTP in CAl pyramidal cells was investigated by focally applying emetine to apical dendrites, while stimulating afferents to basal and apical dendrites. This significantly reduced L-LTP in the projection to apical dendrites, whilst leaving L-LTP unaffected in the projection to basal dendrites. Focal application of emetine to the cell bodies had no significant effect on L-LTP in either the apical or basal dendrites. Furthermore, preliminary data suggest that L-LTP in the basal dendrites is unaffected by focal emetine application. These experiments provide evidence that pyramidal cells in the CAl region of the hippocampus can support two different forms of L-LTP: type I, in the apical dendrites (stratum radiatum) that depends on protein synthesis, and a component of which relies on local dendritic protein synthesis and type II, in the basal dendrites (stratum oriens), that remains protein synthesis-independent for at least 8 hours.

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