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I.R.F. / Aging news / General / 05011201

Mental Fatigue and Glutamate Transport
Posted on: January 12, 2005

Hypothesis

Mental fatigue with reduced capacity for attention, concentration, and learning, as well as subsequent disturbance of short-term memory, is a common symptom in diseases with general or patchy neuroinflammation, such as multiple sclerosis (MS) and neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. The mental fatigue often appears prior to other more prominent mental, cognitive, or physical symptoms from the nervous system in these diseases. Mental fatigue is also common during the rehabilitation after meningitis or encephalitis (postinfectious mental fatigue), stroke or brain trauma (posttraumatic mental fatigue), being especially troublesome when major neurological symptoms have disappeared and the patient is on his way back to work. Mental fatigue is covered by the diagnoses "mild cognitive disorder" or "neurasthenia" and is included in the group of "mild neurocognitive disorders". According to the diagnostic classification by Lindqvist and Malmgren, mental fatigue is one of the symptoms of the "astheno-emotional syndrome".
Mental fatigue appears as a decreased ability to intake and process information over time. Mental exhaustion becomes pronounced when cognitive tasks have to be performed for longer periods with no breaks (cognitive loading). Often, the symptoms are absent or mild in a relaxed and stress-free environment. To explore the possible cellular neurobiology of mental fatigue, looking at some components important for information intake and processing within the central nervous system, namely glutamate neurotransmission, and at the clearance of extracellular glutamate ([Glu]ec) are of interest.

Glutamate neurotransmission is crucial in information intake and information processing within the brain. Glutamate transmission is also indispensable for long-term potential (LTP) formation, the cellular correlate to memory formation. In brain, the [Glu]ec has to be maintained at approximately 1-3 μM in order to assure a high precision (high signal-to-noise ratio) at normal glutamate neurotransmission and also, to avoid excitotoxic actions of glutamate on neurons. The clearance of glutamate from the extracellular space is achieved by high-affinity, sodium (Na+)-dependent electrogenic uptake transporters. The glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1) are most abundantly located on astrocytes surrounding synapses of glutamate-bearing neurons. In fact, GLAST and GLT-1 have different expression patterns. GLAST is the major transporter for glutamate uptake during development while expression of GLT-1 increases with the maturation of the nervous system. Glutamate transporter 1 expression seems to follow the formation and maturation of synapses and especially synaptic activity. Even more convincing for the role of astroglia in keeping the [Glu]ec low, it has been demonstrated with knockout techniques in rats that loss of GLT-1 or GLAST produces elevated [Glu]ec and neurodegeneration characteristic of excitotoxicity, while the loss of neuronal glutamate transporter does not elevate [Glu]ec.

It may be that mental fatigue is a stereotypical reaction to disturbance of "higher" brain functions. The brain, with its billions of specialized neurons and supporting glial cells, works as a "whole" organ. Every disturbance of brain homeostasis, no matter where the anatomical localization is, would therefore attenuate brain capacity for information processing and, as a consequence, information intake. One way to diminish information intake and processing at the cellular level would be to impair glutamate neurotransmission by attenuating the glial support and especially diminishing the astroglial capacity to clear [Glu]ec. The initial consequence would be slightly increased [Glu]ec, with less precision in glutamate transmission. This would disintegrate the "filter", which normally selects information and prevents it from reaching the cerebral cortex. We can take the sound from a low-frequency fan as an example. This sound is normally sorted out after hearing it for a while. If this sound is handled with less precision by auditory recognition systems, it will continually be recognized by brain centers as "new" information and be processed in the cerebral cortex as long as the sound is on. The "filter" that normally restrains already recognized information from reaching higher brain centers, has been "opened". From a physiological point of view, it seems appropriate that the individual, and not the brain at the synaptic level, should determine which information should reach, and be processed by, the cerebral cortex. The decreased attention, increased loudness and light sensitivity, and irritability could be physiological ways of avoiding overstimulation of higher cortical centers. In case the individuals cannot protect themselves from too much sensory stimulation, the filter's opening leads to overstimulation of the cerebral cortex. Here, the final shutdown of the glutamate transmission could be one mechanism underlying mental exhaustion (Figure 1).


Figure 1

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 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-α also decreases oligodendroglial cell glutamate uptake, while microglial glutamate uptake has been demonstrated to increase, 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.

In line with these theoretical proposals, increased [Glu]ec has in fact been demonstrated in MS, meningitis, and encephalitis, Alzheimer's disease, ischemia and traumatic brain injury. Furthermore, it has been shown in experimental studies that even extracellular K+ is involved in the post-traumatic hyperexcitability, and a recent study has proposed that the larger extracellular K+ increase evoked by neuronal activity is a consequence rather than the primary mechanism underlying post-traumatic hyperexcitability.
The theory also involves the possibility of a disturbed noradrenaline/serotonin turnover in the cerebral cortex due to a slight hyperexcitability in the frontal cortex. Interestingly, increased [Glu]ec in the prefrontal cortex has been reported in asymptomatic simian immunodeficiency virus (SIV)mac251-infected macaques without major brain involvement, being consistent with theory at least in this set of animal experiments. If valid even in humans, a disturbed noradrenaline/serotonin turnover in the cerebral cortex could be coupled to the disturbed attention and depression often occurring in addition to the mental fatigue.

It is not possible at present to ultimately prove whether the altered neuronal-glial interactions in glutamatergic transmission induced by proinflammatory cytokines could serve as a model to explain cellular mechanisms underlying mental fatigue. Brain imaging techniques able to determine and follow [Glu]ec and [K+]ec over time would be important to use in humans suffering from mental fatigue. Today, this is not possible for technical reasons. Instead, we must use experimental systems to learn about glial cell biology and neuron-glia-neuron signaling and interactions, and thus test specific parts of the hypothesis. Neuroactive substances produced by, or altered conditions related to, the production of proinflammatory cytokines could be evaluated with regard to their effects on astroglial support of glutamate transmission, and especially glutamate transport capacity. The role of the intact astroglial network in higher brain functions (cognition and behavior) could be studied in animal models. Effects of astroglial dysfunction with regard to glutamate transport capacity would be of special interest. Even clinical studies with different treatment strategies could be important in casting some light on the accuracy of the hypothesis. Of utmost importance in all such studies would be test batteries making it possible to objectify and even quantify the degree of mental fatigue.

Providing information about mental fatigue, its cause and the prognosis, is of utmost importance for breaking the vicious circle, which comes with the risk for secondary anxiety and depression. Furthermore, it is important for the patient to imagine and learn how much sensory stimulation they can tolerate prior to feeling too exhausted. Due to recent results on changes in cell signaling and neuronal plasticity, it may be important to identify the symptoms and treat them as early as possible to avoid formation of new and functionally disturbing neuronal circuits due to overstimulation of neuronal-glial units. If hypothesis is correct, it may be possible to further improve the symptoms by suppressing the production of proinflammatory cytokines and, thereby, restoring the normal astroglial glutamate uptake. In this context, xanthine derivatives may be of use. Another substance, worth considering, may be minocycline, a synthetic tetracycline derivative that has been shown to attenuate microglial activation and, consequently, the production of proinflammatory cytokines. During recent years substances, which enhances glutamate uptake have been identified. Nicergoline, different growth factors including pituitary adenylate cyclase-activating polypeptide (PACAP), some low molecular weight factors as well as metabotropic glutamate agonists have all been able to stimulate glutamate transport in experimental systems and could be of interest in the pharmacotherapy of mental fatigue. Interestingly, even AMPA receptor modulators have been demonstrated as cognitive enhancers.

Source: Lars Ronnback and Elisabeth Hansson; Hypothesis on the potential role of glutamate transport in mental fatigue; Journal of Neuroinflammation 2004, 1:22-31 doi:10.1186/1742-2094-1-22
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