Rapid Homeostatic Plasticity of Intrinsic Excitability in a Central Pattern Generator Network Stabilizes Functional Neural Network Output

Abstract

Neurons and networks undergo a process of homeostatic plasticity that stabilizes output by integrating activity levels with network and cellular properties to counter longer-term perturbations. Here we describe a rapid compensatory interaction among a pair of potassium currents, I A and I KCa , that stabilizes both intrinsic excitability and network function in the cardiac ganglion of the crab, Cancer borealis. We determined that mRNA levels in single identified neurons for the channels which encode I A and I KCa are positively correlated, yet the ionic currents themselves are negatively correlated, across a population of motor neurons. We then determined that these currents are functionally coupled; decreasing levels of either current within a neuron causes a rapid increase in the other. This functional interdependence results in homeostatic stabilization of both the individual neuronal and the network output. Furthermore, these compensatory increases are mechanistically independent, suggesting robustness in the maintenance of neural network output that is critical for survival. Together, we generate a complete model for homeostatic plasticity from mRNA to network output where rapid posttranslational compensatory mechanisms acting on a reservoir of channels proteins regulated at the level of gene expression provide homeostatic stabilization of both cellular and network activity.

Ionic Current Variability and Functional Stability in the Nervous System

“…Only a single exception has been reported showing a negative correlation between mRNA levels of two A-type K + currents (Bergquist et al 2010). Another case of negative correlation was reported between two K + currents (Ransdell et al 2012), which show positive correlations, however, at the mRNA level, which suggests posttranscriptional regulation of these correlations.…”

“…This is best exemplified in systems in which neurons are found with a single copy number. For example, in the stomatogastric and cardiac ganglia of the crab Cancer borealis identified neurons express highly variable conductance and mRNA levels of well-defined ionic currents (Liu et al 1998, Khorkova and Golowasch 2007, Schulz et al 2007, Ransdell et al 2012, Temporal et al 2012). However, what feature of activity each ionic current determines—or, inversely, which currents each activity trait in the system is determined by—is not clear for any system.…”

“…Other interesting results from these computational studies indicate a prominent place for correlations of Ca ++ conductances with other conductances and indicate negative correlations between conductance pairs in specifying constant activity features. Surprisingly, to date, nearly all experimental studies have revealed the existence of linear and positive correlations between mRNA levels that code for different ion channels (Schulz et al 2006, 2007, Tobin et al 2009, Ransdell et al 2012, Temporal et al 2012) and between maximal conductances or maximal currents of a number of ionic currents in different cell types (MacLean et al 2003, 2005, Schulz et al 2006, Khorkova and Golowasch 2007, Ransdell et al 2012, Temporal et al 2012). Only a single exception has been reported showing a negative correlation between mRNA levels of two A-type K + currents (Bergquist et al 2010).…”

“…However, the variability of ionic current or conductance levels between unambiguously identified neurons between individuals is being reported in a growing list of different preparations (Khorkova and Golowasch 2007, Olypher and Calabrese 2007, Schulz et al 2007, Leao et al 2012, Ransdell et al 2012, Temporal et al 2012, Unal et al 2012), including in genetically identical animals (Liss et al 2001, Swensen and Bean 2005, Etheredge et al 2007). This variability across individuals will here be referred to as population variability (box 1).…”

Kv7 channels regulate pairwise spiking covariability in health and disease

“…Indeed, persistent sodium current is implicated in some forms of epilepsy and is a target of some antiepileptic drugs (Stafstrom 2007). Likewise, homeostatic upregulation of other subthreshold-activated potassium conductances (Ping and Tsunoda 2012;Ransdell et al 2012) could perhaps partially compensate for loss of Kv7 conductance. Changes in the covariation of the activity of the two neurons could also affect synaptic currents through spike timing-dependent plasticity or could trigger changes in intrinsic excitability (Cudmore et al 2010).…”