Cellular and Network Substrates of Neuronal Excitability in Relation to Epileptic Seizures
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AbstractBrain function is, in part, maintained by an appropriate balance between excitatory and inhibitory elements. In relation to excitability, factors such as the complement and distribution of ion channels, properties and composition of synaptic proteins, and dynamics affecting network synchrony all interact to modulate neuronal firing and network activity. In this dissertation, I present a series of three focused studies at the level of ion channels (T-type calcium channels), synaptic transmission (prion protein), and network activity (high frequency oscillations) that affect neuronal excitability. With regards to Cav3.2 T-type voltage-gated calcium channels, I demonstrate that novel missense mutations, as identified in patients with idiopathic generalized epilepsies, can result in alteration of channel biophysical properties. The majority of mutants altered gating properties consistent with greater channel activity. However, most of these biophysical alterations were not large in magnitude suggesting that the role of these channels in relation to other cellular processes may be affected. At the level of synapses, I describe a novel interaction/modulation of NMDA receptor currents by the endogenous prion protein (PrP). Using PrP-null mice, I show that loss of PrP results in enhanced synaptic NMDA currents with greater amplitude and prolonged deactivation kinetics. These changes do not seem to be related to developmental effects and possibly involve an NMDA receptor subunit switch to functional receptors containing NR2D. At the network level, I show that high frequency oscillations in field recordings in vitro and in the EEG from patients with epilepsy are localized to the seizure onset zone and increase over time during the immediate pre-seizure period. This knowledge can be used to better localized seizures for surgical resection, thereby improving seizure control in intractable patients. These three topics and their relevance to hyperexcitable states are discussed in the context of epileptiform seizure activity and neurological disease.
Bibliography: p. 166-208