Potassium Buffering in the Neurovascular Unit: Models and Sensitivity Analysis

Abstract

Astrocytes are critical regulators of neural and neurovascular network communication. Potassium transport is a central mechanism behind their many functions. Astrocytes encircle synapses with their distal processes, which express two potassium pumps (Na-K and NKCC) and an inward rectifying potassium channel (Kir), whereas the vessel-adjacent endfeet express Kir and BK potassium channels. We provide a detailed model of potassium flow throughout the neurovascular unit (synaptic region, astrocytes, and arteriole) for the cortex of the young brain. Our model reproduces several phenomena observed experimentally: functional hyperemia, in which neural activity triggers astrocytic potassium release at the perivascular endfoot, inducing arteriole dilation; K(+) undershoot in the synaptic space after periods of neural activity; neurally induced astrocyte hyperpolarization during Kir blockade. Our results suggest that the dynamics of the vascular response during functional hyperemia are governed by astrocytic Kir for the fast onset and astrocytic BK for maintaining dilation. The model supports the hypothesis that K(+) undershoot is caused by excessive astrocytic uptake through Na-K and NKCC pumps, whereas the effect is balanced by Kir. We address parametric uncertainty using high-dimensional stochastic sensitivity analysis and identify possible model limitations.

Vascular Inward Rectifier K+ Channels as External K+ Sensors in the Control of Cerebral Blood Flow

“…Further support for the involvement of this K + -to-K IR mechanism is demonstrated by the ability of Ba 2+ to inhibit vasodilation evoked by neuronal stimulation in brain slice preparations (by 50-70%) [26,68]. Notably, the salient features of this mechanism have been successfully recapitulated by computer models [131,132]. These studies suggest that K IR channel activity in response to endfoot-derived K + is indeed a vitally important mechanism for NVC, although the possibility that K + could act indirectly through Ba 2+ -sensitive K IR channels in another cell type, such as neurons or astrocytes (Table 1), cannot currently be discounted.…”

Downregulation of Astrocytic Kir4.1 Potassium Channels Is Associated with Hippocampal Neuronal Hyperexcitability in Type 2 Diabetic Mice

“…In addition, it has been shown that downregulation of Kir4.1 channels affects overall ion gradients and also impairs glutamate uptake by astrocytes [12,13]. There are numerous theoretical analyses supporting the spatial relationship between passive and active modulation of [K + ] o by astrocytes and the initiation or maintenance of epileptiform activity [54][55][56]. Furthermore, cell depolarization and impaired ion gradients inhibit glutamate transporter function and cause transporter reversal, thus glutamate release from the cell, which could further affect neuronal excitability [57,58].…”

Time-course of glial changes in the hyperhomocysteinemia model of vascular cognitive impairment and dementia (VCID)

“…In particular, they buffer potassium to regulate the excitability of the neurons (Newman et al, 1984, Simard and Nedergaard, 2004, Wallraff et al, 2006). This potassium buffering is also thought to contribute, at least in part, to the process of neurovascular coupling; i.e., the process of matching local cerebral blood flow to the local neuronal activity (Dunn and Nelson, 2010, Witthoft et al, 2013), however, the potassium buffering role in neurovascular coupling remains disputed (Metea et al, 2007). To perform the critical function of potassium buffering and osmotic homeostasis, astrocytes ensheath the cerebrovasculature with specialized processes called end-feet.…”