To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Neurons maintain their electrical activity patterns despite channel turnover, cell growth, and variable extracellular conditions. A model is presented in which maximal conductances of ionic currents depend on the intracellular concentration of calcium ions and so, indirectly, on activity. Model neurons with activity-dependent maximal conductances modify their conductances to maintain a given behavior when perturbed. Moreover, neurons that are described by identical sets of equations can develop different properties in response to different patterns of presynaptic activity.

We study the electrical activity patterns and the expression of conductances in adult stomatogastric ganglion (STG) neurons as a function of time in primary cell culture. When first plated in culture, these neurons had few active properties. After 1 d in culture they produced small action potentials that rapidly inactivated during maintained depolarization. After 2 d in culture they fired large action potentials tonically when depolarized, and their properties resembled very closely the properties of STG neurons pharmacologically isolated in the ganglion. After 3–4 d in culture, however, their electrical properties changed and they fired in bursts when depolarized. We characterized the currents expressed by these neurons in culture. They included two TTX-sensitive sodium currents, a calcium current, a delayed-rectifier-like current, a calcium-dependent potassium current, and two A-type currents. The changes in firing properties with time in culture were accompanied by an increase in inward and decrease in outward current densities. A single-compartment conductance-based model of an STG neuron was constructed by fitting the currents measured in the biological neurons. When the current densities in the model neuron were matched to those measured for the biological neurons in each activity state, the model neuron closely reproduced each state, indicating that the changes in current densities are sufficient to account for the changes in intrinsic properties. These data indicate that STG neurons isolated in culture change their intrinsic electrical properties by selectively adjusting the magnitudes of their ionic conductances.

Exposure to HPV vaccines was not associated with an increased risk of ADs within the time period studied. Results were robust to case definitions and time windows of exposure. Continued active surveillance is needed to confirm this finding for individual ADs.

We analyze neuron models in which the maximal conductances of membrane currents are slowly varying dynamic variables regulated by the intracellular calcium concentration. These models allow us to study possible activity-dependent effects arising from processes that maintain and modify membrane channels in real neurons. Regulated model neurons maintain a constant average level of activity over a wide range of conditions by appropriately adjusting their conductances. The intracellular calcium concentration acts as a feedback element linking maximal conductances to electrical activity. The resulting plasticity of intrinsic characteristics has important implications for network behavior. We first study a simple two-conductance model, then introduce techniques that allow us to analyze dynamic regulation with an arbitrary number of conductances, and finally illustrate this method by studying a seven-conductance model. We conclude with an analysis of spontaneous differentiation of identical model neurons in a two-cell network.