Distribution and regulation of ion channels in neurons: Quantitative studies of global ion channel transport and homeostatic synaptic scaling

A healthy neuron must continually produce millions of proteins and distribute them to function-specific regions of the cell. Among these proteins are ion channels that modulate neuronal excitability, allowing neurons to fulfill their primary role of information transfer. Neurons are unique among cells in their morphology, with projections that extend hundreds to thousands of microns. Neuron size and asymmetry pose a challenge for autoregulation of properties that require cargo transport across the cell. Homeostasis of ion channel localization has strong implications for neural excitability. This thesis concerns the intracellular distribution of ion channels in the context of longitudinal transport and global neuron regulation. The principal contributions are experimental measurements, data analysis, and modeling in the study of longitudinal neurite transport. Empirical investigations focus on the distribution and trafficking kinetics of ion channel Kv4.2, including quantitative measurements of both passive diffusion and active microtubule-based transport in both axons and dendrites (Chapters 3 and 5). Mass action models reveal that measured transport profiles corroborate discrepancies in Kv4.2 localization both between neurite types and along the somatodendritic axis (Chapter 4). Exchange between mobile and immobile fractions, inferred from analysis of repeated photobleaching, shapes intracellular distribution of Kv4.2 (Chapter 5). Further, the ensuing theoretical study surveys global regulation of ion channels, specifically for synaptic scaling, which requires cell-wide modulation of AMPA receptors for normalization of neural excitability. A unified model of synaptic potentiation, transport, and feedback reveals limitations imposed on synaptic scaling by neuron morphology. A neuron balances the stability, accuracy, and efficiency of synaptic scaling (Chapter 6)