Gating of homeostatic regulation of intrinsic excitability produces cryptic long-term storage of prior perturbations

Abstract

Neurons and neuronal circuits must maintain their function throughout the life of the organism despite changing environments. Previous theoretical and experimental work suggests that neurons monitor their activity using intracellular calcium concentrations to regulate their intrinsic excitability. Models with multiple sensors can distinguish among different patterns of activity, but previous work using models with multiple sensors produced instabilities that lead the models’ conductances to oscillate and then to grow without bound and diverge. We now introduce a nonlinear degradation term that explicitly prevents the maximal conductances to grow beyond a bound. We combine the sensors’ signals into a master feedback signal that can be used to modulate the timescale of conductance evolution. Effectively, this means that the negative feedback can be gated on and off according to how far the neuron is from its target. The modified model recovers from multiple perturbations. Interestingly, depolarizing the models to the same membrane potential with current injection or with simulated high extracellular K + produces different changes in conductances, arguing that caution must be used in interpreting manipulations that serve as a proxy for increased neuronal activity. Finally, these models accrue traces of prior perturbations that are not visible in their control activity after perturbation but that shape their responses to subsequent perturbations. These cryptic or hidden changes may provide insight into disorders such as posttraumatic stress disorder that only become visible in response to specific perturbations.

Targeted Stimulation of the Sensory Afferents Improves Motoneuron Function in Humans With a Degenerative Motoneuron Disease

“…Our finding is consistent with the hypothesis that people living with SMA have a set of surviving motoneurons, some or most of which have reduced firing capabilities that can be rescued by targeted neurostimulation. This suggests that targeted electrical stimulation can alleviate motor deficits by reversing the maladaptive homeostatic processes 27 triggered by spinal circuit dysfunction. Importantly, evidence of improved motoneuron function was consistent across all three participants, irrespectively of their state of disease progression, age and importantly of them being or not under SMN inducing therapies (SMA01 was not taking any therapy up until the end of our study).…”

“…Importantly, excitatory synaptic input to spinal motoneurons coming from primary proprioceptive afferents is significantly lower in SMA 5,6 . In turn, this excitatory synaptic deficiency causes SMA-affected motoneurons to undergo homeostatic compensation for loss of excitatory input that alter membrane ion-channels densities 27,28 . Unfortunately, these maladaptive homeostatic changes in membrane properties lead to hyperexcitable motoneurons that are paradoxically incapable of producing sustained action potential firing and in consequence normal muscle contraction 5,29 ( Fig.…”

A possible path to persistent re-entry waves at the outlet of the left pulmonary vein

“…Dynamics of the ion channel density of the I CaL -current We will use a recently developed mathematical model to demonstrate a possible progressive path to sustained re-entry. In a series of papers, a theory on the regulation of the density of ion channels has been developed, see [21,22,23,24,25,26,27,32]. For the regulation of the calcium current, the essence of this theory is that the density of ion channels is governed by the intracellular calcium concentration.…”

Do calcium channel blockers applied to cardiomyocytes cause increased channel expression resulting in reduced efficacy?

“…How is the expression of ion channels controlled to preserve the electrical properties essential for physiological functions? This pressing question has been the subject of extensive investigation by Marder and colleagues, among others, over several years; see, e.g., [1,2,3,4,5,6,7].…”