Dynamic Gain Analysis Reveals Encoding Deficiencies in Cortical Neurons That Recover from Hypoxia-Induced Spreading Depolarizations

Abstract

Cortical regions that are damaged by insults, such as ischemia, hypoxia, and trauma, frequently generate spreading depolarization (SD). At the neuronal level, SDs entail complete breakdown of ionic gradients, persisting for seconds to minutes. It is unclear whether these transient events have a more lasting influence on neuronal function. Here, we describe electrophysiological changes in cortical neurons after recovery from hypoxia-induced SD. When examined with standard measures of neuronal excitability several hours after recovery from SD, layer 5 pyramidal neurons in brain slices from mice of either sex appear surprisingly normal. However, we here introduce an additional parameter, dynamic gain, which characterizes the bandwidth of action potential encoding by a neuron, and thereby reflects its potential efficiency in a multineuronal circuit. We find that the ability of neurons that recover from SD to track high-frequency inputs is markedly curtailed; exposure to hypoxia did not have this effect when SD was prevented pharmacologically. Staining for Ankyrin G revealed at least a fourfold decrease in the number of intact axon initial segments in post-SD slices. Since this effect, along with the effect on encoding, was blocked by an inhibitor of the Ca 2ϩ-dependent enzyme, calpain, we conclude that both effects were mediated by the SD-induced rise in intracellular Ca 2ϩ. Although effects of calpain activation were detected in the axon initial segment, changes in soma-dendritic compartments may also be involved. Whatever the precise molecular mechanism, our findings indicate that in the context of cortical circuit function, effectiveness of neurons that survive SD may be limited.

Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma model

“…Repeated episodes of cortical SD, hitherto unrecognized in brain tumor models, were captured; their potential proinflammatory effect adds a pathogenic mechanism that may play an amplifying role in progressive hyperexcitability. These pathological waves involve massive intracellular calcium influx mediated in part by NMDA receptor activation that transiently silences neuronal activity and briefly impairs the precise coding of high-frequency synaptic inputs in recovering neurons (55). SD appearance in brain tumors is of clinical relevance and may contribute to common transient neurological symptoms including confusional spells, motor deficits, and headache in glioma patients (56).…”

Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer’s Disease

“…The A152T-variant was also suggested to modulate the power of brain oscillations in the 0.5-6Hz frequency range, with suppression of hTau-A152T expression and levetiracetam treatment reported to reverse tau-dependent network dysfunction (Das et al, 2018), although, in this context, it is interesting to note that seizure-like low frequency activity may be naturally linked to cellular hypoactivity in the network, with a recent report of a similar effect resulting from hypoxia-induced spreading depolarization (Revah et al, 2019). Lastly, it is important to emphasize that two recent human studies have independently reported an association between measures of tau pathology and increased hippocampal activity during task-related fMRI in clinically normal older subjects (Berron et al, 2019;Huijbers et al, 2019).…”

“…Indeed, computational modeling work has revealed that emergent features of circuit dynamics are not simply related to cellular excitability thresholds or average synaptic strengths, but depend on subtle features of the neuronal populations' physiology, e.g. their speed and bandwidth (Brunel and Hakim, 1999;Geisler et al, 2005;Lazarov et al, 2018;Revah et al, 2019;Wei and Wolf, 2011), and critically on the speed of feedback inhibition Wolf, 2010, 2012;van Vreeswijk and Sompolinsky, 1996;Wolf et al, 2014). In addition, microcircuit models predict that relatively small differences in the overall strength of local circuit motifs can strongly affect computational function.…”

Transient Oxygen-Glucose Deprivation Causes Region- and Cell Type-Dependent Functional Deficits in the Mouse HippocampusIn Vitro

“…Increased firing may result from the reduction of inhibition (Elzoheiry et al, 2019), increased excitability (Fan et al, 2008), and ischemic long-term potentiation (Maggio et al, 2015). On the other hand, factors like the lack of energy-producing metabolites following hypoxia (Kass and Lipton, 1989), perturbed neuronal ion homeostasis (Müller and Somjen, 2000), and calciumtriggered disruption of the axon-initial segment morphology (Revah et al, 2019) may reduce neuronal activity following OGD and HSD.…”

“…This event results from the complete breakdown of the membrane potential due to insufficient ATP-driven pump activity and entails a dramatic shift of ions, including a massive influx of calcium. Interestingly, neurons recover their membrane potential and ability to fire action potentials upon timely re-oxygenation (Müller and Somjen, 2000;Hefter et al, 2016;Revah et al, 2019). It is suspected that HSD represents an additional insult, and it can be seen as a hallmark of HI-induced neuronal damage (Dreier, 2011).…”