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Title: Modulation of calcium-activated potassium currents in hippocampal pyramidal cells
Author: Taylor, Ruth Doreen Theresa
ISNI:       0000 0004 2671 8133
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2008
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This thesis focuses on the modulation of two Ca++ activated K+ currents, IAHP and sIAHP that underlie part of the medium (mAHP) and the slow afterhyperpolarisation (sAHP) in cortical neurons. The afterhyperpolarisation is a transient hyperpolarisation of the membrane potential following a burst of action potentials. The aim of the first part of this study was to investigate whether neuronal SK channels, which are known to mediate IAHP in hippocampal neurons, are modulated by the newly characterised compound NS8593. I have characterised the effect of NS8593 on IAHP in mouse hippocampal slices, finding that NS8593 suppresses IAHP. The second part of my project focused on identifying the signal transduction cascade mediating the sIAHP suppression induced by application of pituitary adenylyl cyclase activating polypeptide (PACAP). PACAP acts via the activation of its own receptors (PAC-l-R) and of vasoactive intestinal peptide (VIP) receptors (V-PAC1, V-PAC2). Previous experiments have shown that the VIP-mediated reduction of sIAHP occurs via a protein kinase A (PKA) dependent mechanism. PACAP was found to suppress sIAHP in a PKA and p38 mitogen-activated protein kinase (MAPK)-dependent manner in rat CA1 pyramidal neurons. In part three, the involvement of the calcium stimulatable adenylyl cyclases (AC1/AC8), in the modulation of sIAHP/sAHP by the neuromodulators: isoproterenol, serotonin and dopamine was investigated. I found that different monoamines signalled through different adenylyl cyclases (AC) in order to suppress sIAHP/sAHP. Lastly, the modulation of sAHP by high frequency stimulation of the Schaffer-collateral pathway results in a transient inhibition of sAHP in CA1 pyramidal neurons by a pathway involving N-methyl-D-aspartate receptors (NMDAR) and PKA. My results showed that delivery of high frequency stimulation results in a transient sAHP suppression by a pathway that involves, besides NMDAR and PKA, the activation of AC1/AC8. Additionally, I found that when low frequency synaptic stimulation was paired with post-synaptic depolarisation, a transient sAHP suppression was elicited in an NMDAR and AC1/AC8 dependent manner.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available