What Is Spreading Depolarization?

Spreading depolarization refers to a phenomenon observed in the gray matter of the central nervous system, characterized by the swelling of neurons, distortion of dendritic spines, and significant alterations in the slow electrical potential. This process leads to a silencing of electrical activity in the brain, commonly known as spreading depression.

Mechanisms of Spreading Depolarization

Spreading depolarization involves a cascade of physiological and biochemical events that result in a breakdown of neuronal homeostasis. Neurons and their proximal dendrites are the central players in spreading depolarization, which begins with the disruption of ion gradients critical for neuronal function.

Neuronal Electrochemical Energy

Neurons function like batteries, using ion gradients (mainly sodium, potassium, and chloride) across their membranes to generate electrical signals (action potentials). The energy required for action potentials comes primarily from sodium pumps, which maintain ion gradients, consuming about half of the brain's resting metabolic energy.

Breakdown of Ion Gradients

During spreading depolarization, there is near-complete disruption of these ion gradients. This results in sustained depolarization of neurons, loss of electrical activity, a drastic reduction in membrane resistance, and cellular swelling. The neurons can no longer generate action potentials due to the inactivation of membrane channels responsible for action potentials.

Electrophysiological and Morphological Changes

Spreading depolarization is characterized by the complete loss of electrical activity (spreading depression), with a pronounced negative shift in the slow potential in the extracellular space. This slow potential change is likely due to the longitudinal depolarization along neurons and large influxes of small cations like sodium and calcium.

Propagation and Mechanisms

While spreading depolarization can occur in individual neurons, it typically spreads at a rate of 2-6 mm/min. This propagation can occur through gap junctions, allowing synchronized activity between neurons. Interestingly, propagation can happen without neuronal firing or astrocyte involvement.

Genetic Factors

Gene mutations, such as those in the CACNA1A gene (which encodes the P/Q-type calcium channel) or the ATP1A2 gene (encoding the astrocytic sodium pump), can lower the threshold for spreading depolarization. These mutations often lead to increased glutamatergic neurotransmission.

Neurotransmitter Release

During spreading depolarization, high levels of neurotransmitters (e.g., glutamate, acetylcholine, and GABA) are released. Specifically, glutamate induces a cation influx through glutamate-gated ion channels, further contributing to the sustained depolarization and propagation of spreading depolarization.

Fig. 1 Mechanisms of spreading depolarization in the neuron. (Dreier, et al., 2011)

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Spreading Depolarization in Stroke

Spreading depolarization is a pathophysiological phenomenon observed in the brain, characterized by a wave of sustained depolarization that propagates across neuronal tissue. These depolarizations typically occur in response to conditions of metabolic stress, such as ischemia or lack of oxygen (hypoxia), and are believed to be a significant contributor to neuronal injury and death. Spreading depolarization has now been demonstrated in the human brain in patients with aneurismal subarachnoid hemorrhage, delayed ischemic stroke after subarachnoid hemorrhage, and malignant hemispheric stroke.

Spreading Depolarization-Induced Cytotoxic Edema in Stroke

The influx of water during spreading depolarization leads to neuronal swelling, a phenomenon that has been widely observed in both in vitro and in vivo studies. When spreading depolarization occurs, it triggers a cascade of ionic imbalances, including influx of Na⁺ and Ca²⁺ ions, as well as efflux of K⁺. This ion imbalance disrupts cellular homeostasis and results in osmotic changes that lead to water influx.

The water influx causes the swelling of neuronal somata and can also induce dendritic beading. Dendritic beading refers to the formation of swellings along the dendrites, which is thought to be associated with dysfunction of the cytoskeletal elements and loss of normal structural integrity in the neuron. This damage is particularly concerning in the context of ischemic injury or traumatic brain injury, where spreading depolarization may exacerbate tissue damage and contribute to neuronal loss.

Fig. 2 Spreading depolarization (SD) in the human cortex of a patient with aneurysmal subarachnoid hemorrhage (aSAH). (Dreier, et al., 2018)

The Hemodynamic Response to Spreading Depolarization in Stroke

Spreading depolarization can trigger significant hemodynamic changes, including both hyperemia and ischemia, depending on the tissue's pre-existing conditions. In healthy tissue, the hyperemic response to spreading depolarization supports metabolic demands, while in ischemic tissue or conditions with disturbed neurovascular coupling, spreading depolarization can lead to spreading ischemia with potentially severe consequences, including extended ischemic injury and delayed recovery. The interaction between potassium accumulation, NO depletion, and calcium dysregulation plays a crucial role in these pathological responses.

Fig. 3 The neurovascular unit acutely mediates the rCBF response to spreading depolarization. (Dreier, et al., 2018)

Vasogenic Edema Response to Spreading Depolarization in Stroke

Vasogenic edema develops slowly over hours to days after ischemic events and is linked to BBB dysfunction. Spreading depolarization causes early ionic changes that disrupt osmotic gradients, which eventually lead to water influx and vasogenic edema.

The relationship between spreading depolarization and vasogenic edema is complex, involving both damaging and potentially adaptive roles depending on the context. The vasogenic edema formation process is multifactorial and involves changes in BBB permeability, osmotic gradients, and solute fluxes across the neurovascular unit.

Spreading Depolarization As a Target for Stroke Treatment

The therapeutic goal of targeting spreading depolarization in neurological conditions, particularly after ischemic events like stroke, is to protect neurons by conserving their intracellular environment during periods of ATP depletion. One potential strategy is to slow down the initial phase of spreading depolarization, which involves fast ion shifts. This could be done by inhibiting specific ion channels responsible for the rapid depolarization. The hemodynamic response to spreading depolarization, particularly spreading ischemia, is thought to play a crucial role in lesion progression by recruiting additional tissue into ischemia and subsequent necrosis. Targeting this hemodynamic response, particularly preventing the vasoconstriction associated with spreading ischemia, may present a more feasible and modest therapeutic target compared to directly blocking the spreading depolarization process.

1. Dreier, J. P. (2011). The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nature medicine, 17(4), 439-447.
2. Dreier, J. P., et al. (2018). Spreading depolarization is not an epiphenomenon but the principal mechanism of the cytotoxic edema in various gray matter structures of the brain during stroke. Neuropharmacology, 134, 189-207.