Ion Channel Function and Electrical Excitability in the Zona Glomerulosa: A Network Perspective on Aldosterone Regulation

Aldosterone excess is a pathogenic factor in many hypertensive disorders. The discovery of numerous somatic and germline mutations in ion channels in primary hyperaldosteronism underscores the importance of plasma membrane conductances in determining the activation-state of zona glomerulosa (zG) cells. Electrophysiological recordings describe an electrically quiescent behavior for dispersed zG cells. Yet, emerging data indicate that in native rosette structures in situ, zG cells are electrically excitable, generating slow periodic voltage spikes and coordinated bursts of Ca2+ oscillations. We revisit data to understand how a multitude of conductances may underlie voltage/Ca2+ oscillations, recognizing that zG layer self-renewal and cell heterogeneity may complicate this task. We review recent data to understand rosette architecture and apply maxims derived from computational network modeling to understand rosette function. The challenge going forward is to uncover how the rosette orchestrates the behavior of a functional network of conditional oscillators to control zG layer performance and aldosterone secretion. Expected final online publication date for the Annual Review of Physiology, Volume 83 is February 10, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Subthreshold Membrane Conductances Enhance Directional Selectivity in Vertebrate Sensory Neurons

Directional selectivity, in which neurons respond preferentially to one “preferred” direction of movement over the opposite “null” direction, is a critical computation that is found in the central nervous systems of many animals. Such responses are generated using two mechanisms: spatiotemporal convergence via pathways that differ in the timing of information from different locations on the receptor array and the nonlinear integration of this information. Previous studies have showed that various mechanisms may act as nonlinear integrators by suppressing the response in the null direction. Here we show, through a combination of mathematical modeling and in vivo intracellular recordings, that subthreshold membrane conductances can act as a nonlinear integrator by increasing the response in the preferred direction of motion only, thereby enhancing the directional bias. Such subthreshold conductances are ubiquitous in the CNS and therefore may be used in a wide array of computations that involve the enhancement of an existing bias arising from differential spatiotemporal filtering.

The High-Conductance State of Cortical Networks

We studied the dynamics of large networks of spiking neurons with conductance-based (nonlinear) synapses and compared them to networks with current-based (linear) synapses. For systems with sparse and inhibition-dominated recurrent connectivity, weak external inputs induced asynchronous irregular firing at low rates. Membrane potentials fluctuated a few millivolts below threshold, and membrane conductances were increased by a factor 2 to 5 with respect to the resting state. This combination of parameters characterizes the ongoing spiking activity typically recorded in the cortex in vivo. Many aspects of the asynchronous irregular state in conductance-based networks could be sufficiently well characterized with a simple numerical mean field approach. In particular, it correctly predicted an intriguing property of conductance-based networks that does not appear to be shared by current-based models: they exhibit states of low-rate asynchronous irregular activity that persist for some period of time even in the absence of external inputs and without cortical pacemakers. Simulations of larger networks (up to 350,000 neurons) demonstrated that the survival time of self-sustained activity increases exponentially with network size.