Schematic drawing of cellular regulation of extracellular glutamate concentrations ([Glu]ec) in normal brain function (left), and in the presence of the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 (right). Possible pathophysiology underlying mental fatigue at the cellular level is outlined below. To the left: Two neuronal cell bodies with processes (white) make contact with each other through a synapse (center). Astrocytic (pink) processes encapsulate the synapse and cover also the abluminal side of the blood vessel wall (right). The endothelial cells covering the luminal (blood) side of the vessel wall and the astrocytic processes make up the blood brain barrier (BBB). An oligodendroglial cell (bluish), with its myelin encapsulating the axon, and a microglial cell (yellow) are seen. The astrocytes, with their high-affinity glutamate transporters, are the main site for keeping [Glu]ec low. Even neurons express glutamate transporters, as do oligodendroglial cells, and endothelial cells at their abluminal side. To the right: TNF-α, IL-1β and IL-6 attenuate astroglial glutamate uptake transport and disintegrate the BBB, allowing glutamate from the blood to enter the brain. The overall result is slightly increased [Glu]ec. Tumor necrosis factor-alfa also decreases oligodendroglial cell glutamate uptake , while microglial glutamate uptake has been demonstrated to increase (Persson, M., Hansson, E., and Rönnbäck, L, to be published), though not to levels to compensate for the decreased astroglial glutamate uptake capacity. Due to increased [Glu]ec, astroglial swelling is shown. Below: Hypothetic cellular events underlying mental fatigue. Slightly increased [Glu]ec could make the glutamate neurotransmission less distinct (decrease the signal-to-noise ratio). At the cellular level, there would be astroglial swelling, which in turn would decrease the local extracellular (ec) volume and, as a consequence, lead to further increased [Glu]ec. Astroglial swelling also depolarizes the astroglial cell membrane, which further attenuates the electrogenic glutamate uptake and, in addition, the astroglial K+ uptake capacity. As a consequence, even [K+]ec may rise. The increased [K+]ec, together with decreased glutamine production and reduced glucose uptake concomitant with the decreased glutamate uptake, could lead to decreased presynaptic glutamate release and thereby decreased glutamate transmission, which, according to our hypothesis, is one cellular correlate to mental fatigue/exhaustion. Increased extracellular glutamate levels in the prefrontal region could lead to inhibition of the brain stem nuclei locus coeruleus (LC) and raphe nuclei and thereby inhibit noradrenaline (NA) and serotonin (5-HT) release in the cerebral cortex resulting in decreased astroglial metabolism and neuronal metabolic supply. Increased neuronal excitability may be part of the loudness and light sensitivity often accompanying the mental fatigue. In addition, the decrease in noradrenaline and serotonin release might be part of decreased attention and the appearance of depression often accompanying the mental fatigue.