Cotransporters in Spreading Depolarization-Induced Neuronal Swelling
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Material below summarizes the article Chloride Cotransporters as a Molecular Mechanism Underlying Spreading Depolarization-Induced Dendritic Beading, published on September 2, 2015, in JNeurosci and authored by Annette B. Steffensen, Jeremy Sword, Deborah Croom, Sergei A. Kirov, and Nanna MacAulay.
Ischemic stroke and traumatic brain injury cause a loss of blood supply to the site of injury (the ischemic core) and reduced flow to the surrounding area (the ischemic penumbra). A rapid drop of ATP in the ischemic core leads to the failure of the ATP-dependent Na+/K+-pump and a resultant collapse of the ionic transmembrane gradients.
This ionic shift triggers recurrent waves of spreading depolarization which spreads across neurons and astrocytes as they actively propagate a collapse of ion gradients in cerebral gray matter. This results in dramatic neuronal and glial swelling. Neuronal cytotoxic edema induced by spreading depolarization involves swelling of soma and dendrites, which causes dendrites to resemble beads on a string. This focal dendritic swelling is therefore termed dendritic beading.
In the ischemic core, where blood flow is lost and thus energy deprivation persists, dendrites remain terminally beaded and injured by spreading depolarization. In contrast, in the ischemic penumbra where blood flow is reduced, waves of spreading depolarization result in rapidly reversible dendritic beading.
Once the energy demands for recovery of penumbral dendrites are no longer met by the diminishing blood flow, spreading waves of depolarization lead to terminally injured dendrites and lost spines. These features are indicative of acute damage to synaptic circuitry.
In normal cortex, spreading depolarization is the pathophysiological correlate of the migraine aura and it is relatively innocuous. Here, several rounds of spreading depolarization do not cause accumulating dendritic injury as all dendrites quickly recover from beading during repolarization. Yet, it is likely that beading during spreading depolarization occurs via a common molecular mechanism in both healthy and energy-compromised neocortex.
Why neurons suddenly swell when strongly depolarized during spreading depolarization was long unknown. Astrocytic plasma membranes contain water channels called aquaporins and are therefore highly water permeable. But pyramidal neurons do not express aquaporins and are thus largely water-impermeable under acute osmotic stress. Consequently, the structure and intrinsic electrophysiological properties of pyramidal neurons are stable during acute osmotic stress, even as the surrounding astrocytes swell.
Yet, under ischemic conditions evoking spreading depolarization, the same neurons rapidly swell, dendrites bead, and spines are lost with attendant synaptic failure and altered signal conduction along misshapen neuronal processes. These changes are responsible for the acute dysfunction that occurs within minutes of stroke onset and contribute to the progressive deterioration generated by recurrent spreading depolarization for several hours and days.
Real-time two-photon laser scanning microscopy allowed us to monitor the shape of fluorescent neuronal dendrites during a wave of spreading depolarization in mouse hippocampal slices and in anaesthetized mice. Spreading depolarization results in a net gain of excess electrolytes in the neuronal cytoplasm, but we confirmed that dendritic beading did not occur via simple osmotically obliged water fluxes after the ionic movements during depolarization.
We discovered that dendritic beading was not a result of cytoskeletal rearrangements such as unregulated actin polymerization triggered by a sharp ATP reduction during spreading depolarization or destabilization of microtubules caused by calcium influx. Rather, the chloride-coupled cotransporters localized in dendrites were activated by the massive channel-mediated shifts in the ion and proton gradients taking place during the spreading depolarization.
Under physiological conditions these cotransporters play a key role in regulation of intracellular Cl- and pH. They are bi-directional and can carry net ion and water influx or efflux, dictated by the transmembrane electrochemical gradients for the transported ions. In this regard, cotransport of ions and water must have a significant impact on the volume of neurons lacking aquaporins.
Therefore, via their established ability to cotransport water independently of the osmotic forces, activation of these cotransporters by altered ion gradients enacted a molecular mechanism underlying, at least in part, the dendritic beading observed during spreading depolarization.
These findings have clear clinical significance because they may point to a new class of pharmacological targets for prevention of neuronal swelling that consequently will serve as neuroprotective agents.
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Chloride Cotransporters as a Molecular Mechanism underlying Spreading Depolarization-Induced Dendritic Beading. Annette B. Steffensen, Jeremy Sword, Deborah Croom, Sergei A. Kirov, and Nanna MacAulay. JNeurosci Sept 2015, 35 (35). 12172-12187, DOI: 10.1523/JNEUROSCI.0400-15.2015