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On the role of arachidonic acid in long-term potentiation

Richards, David Andrew; (1998) On the role of arachidonic acid in long-term potentiation. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Arachidonic acid (AA) is a putative retrograde messenger in hippocampal LTP. There are several enzymatic routes by which AA can be mobilised from membrane phospholipids; via secretory PLA2 (SPLA2), via cytoplasmic PLA2, and via the sequential actions of PLC and DAG lipase. Antagonists of sPLA2 have been shown to block the induction of LTP, but the role of AA mobilised via other routes has not been investigated. In this thesis, I present data suggesting a role for each of these pathways in the induction and/or expression of LTP in area CAl of the hippocampal slice. I have confirmed that perfusion with the SPLA2 antagonist BPB blocks the induction but not the expression of LTP. Inhibition of either CPLA2 by AACOCF3, or of DAG-lipase by RHC80267, results in a blockade of both the induction and the expression of LTP. D609, an inhibitor of phosphatidyl-choline-specific-PLC, also blocks the expression of LTP. D609 injected into CAl pyramidal cells blocked both the induction of LTP, and the expression of pre-existing LTP, suggesting that the source of AA required for both induction and expression of LTP is at least partly postsynaptic. The selectivity and efficacy of the drugs used were validated by measuring their effects on basal release of radiolabelled AA from hippocampal tissue. As AA was found to be required for the induction of LTP, I have investigated possible interaction between AA and glutamate receptors in cultured hippocampal neurones. AA was found to enhance the [Ca2+]i transient induced by iontophoretic application of NMDA, but not those induced by AMPA. To act as a retrograde messenger, AA must be capable of enhancing the release of neurotransmitter. To assess this, I have recorded the frequency of spontaneous mini-EPSCs and IPSCs in cultured hippocampal neurones. Mini-EPSCs show an increase in frequency following the application of AA, whereas the frequency of IPSCs is unchanged. The modal amplitude of mini-EPSCs is unchanged by AA. I propose a two-phase model for LTP, in which the sPLA2 pathway is utilised in the induction of LTP, possibly involving enhanced entry of calcium into the postsynaptic cell via the NMDA receptor. The maintenance of LTP requires the persistent mobilisation of AA from the CPLA2 and DAG pathways; it is during this later phase that AA may act as a retrograde messenger, by enhancing excitatory neurotransmitter release.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: On the role of arachidonic acid in long-term potentiation
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Arachidonic acid
URI: https://discovery.ucl.ac.uk/id/eprint/10103161
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