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

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 Ca2+-dependent enzyme, calpain, we conclude that both effects were mediated by the SD-induced rise in intracellular Ca2+. 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. SIGNIFICANCE STATEMENT Spreading depolarization, which commonly accompanies cortical injury, entails transient massive breakdown of neuronal ionic gradients. The function of cortical neurons that recover from hypoxia-induced spreading depolarization is not obviously abnormal when tested for usual measures of neuronal excitability. However, we now demonstrate that they have a reduced bandwidth, reflecting a significant impairment of their ability to precisely encode high-frequency components of their synaptic input in output spike trains. Thus, neurons that recover from spreading depolarizations are less able to function normally as elements in the multineuronal cortical circuitry. These changes are correlated with activation of the calcium-dependent enzyme, calpain.