Williams, SL; (2017) AMPA receptors in the development and treatment of epilepsy. Doctoral thesis , UCL (University College London).

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Abstract

In this thesis I have determined the effects of seizures on AMPA receptors and examined the effects of AMPA receptor modulation, by medium chain triglycerides and derivatives, on seizures. AMPA receptors play a central role in synaptic transmission in the brain and are critical for the generation of seizure activity. Recent work has indicated that prolonged seizures alter AMPA receptor transmission. Here I determined whether these changes occur in an acute in vitro seizure model, to aid exploration of the underlying mechanisms of these alterations. I demonstrated that, as observed in vivo, seizure activity changes the kinetics of AMPA receptor-mediated currents by increasing the proportion of GluA2-lacking, calcium permeable AMPA receptors. I next showed that this subunit switch is dependent on the activation of NMDA receptors and calcineurin. In a separate set of experiments I determined the effects of a range of novel AMPA receptor antagonists on synaptic transmission and seizure activity. Decanoic acid, a key component of the medium chain triglyceride ketogenic diet used in refractory epilepsy, has recently been shown to act as a non-competitive AMPA receptor antagonist. Here I showed that a range of structurally related compounds which also act as AMPA receptor antagonists are effective in in vitro models of seizure-like activity. I have further explored the mechanisms underlying decanoic acid's action. Decanoic acid is synergistic with the AMPA receptor antagonist, perampanel, and is not use-dependent. Moreover, I have shown that decanoic acid has an action at voltage-gated sodium channels to decrease the intrinsic excitability of neurons. Decanoic acid reduces the persistent sodium current, without altering the transient sodium current. Surprisingly, decanoic acid has minimal effect on in vivo status epilepticus (prolonged seizure activity) possibly because of rapid and extensive metabolism by the liver. Lastly, I undertook preliminary experiments in human neurons. Decanoic acid effectively reduces induced seizure-like activity in slices from surgically-resected human neocortical tissue. It inhibits AMPA receptor-mediated currents but does not alter intrinsic excitability, as in rat CA1, possibly due to regional differences in neuronal properties. My findings indicate that seizure activity rapidly changes the AMPA receptors expressed in the synapse and identify a range of compounds that target AMPA receptors, which are effective against seizure activity.

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