Importance of astrocytes for potassium ion (K+) homeostasis in brain and glial effects of K+ and its transporters on learning

- Increased extracellular K+ is initially cleared by astrocytic Na+,K+-ATPase activity.
- Subsequent dispersion and Kir4.1 mediated release of K+ allow neuronal accumulation.
- The astrocytic NKCC1 creates the post-stimulatory K+ undershoot enhancing excitation.
- Transmitters regulate K+ channels and gap junctions with consequences for learning.
- Abnormal extracellular K+ concentrations or astrocytic Na+,K+-ATPase impair memory.

Initial clearance of extracellular K+ ([K+]o) following neuronal excitation occurs by astrocytic uptake, because elevated [K+]o activates astrocytic but not neuronal Na+,K+-ATPases. Subsequently, astrocytic K+ is re-released via Kir4.1 channels after distribution in the astrocytic functional syncytium via gap junctions. The dispersal ensures widespread release, preventing renewed [K+]o increase and allowing neuronal Na+,K+-ATPase-mediated re-uptake. Na+,K+-ATPase operation creates extracellular hypertonicity and cell shrinkage which is reversed by the astrocytic cotransporter NKCC1. Inhibition of Kir channels by activation of specific PKC isotypes may decrease syncytial distribution and enable physiologically occurring [K+]o increases to open L-channels for Ca2+, activating [K+]o-stimulated gliotransmitter release and regulating gap junctions. Learning is impaired when [K+]o is decreased to levels mainly affecting astrocytic membrane potential or Na+,K+-ATPase or by abnormalities in its α2 subunit. It is enhanced by NKCC1-mediated ion and water uptake during the undershoot, reversing neuronal inactivity, but impaired in migraine with aura in which [K+]o is highly increased. Vasopressin augments NKCC1 effects and facilitates learning. Enhanced myelination, facilitated by astrocytic-oligodendrocytic gap junctions also promotes learning.