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Our explanation for the origin of mental fatigue at a cellular level

Deteriorated glutamate uptake and handling by astrocytes – our explanation for the origin of mental fatigue at a cellular level

Our hypothesis, which is a possible explanation for the origin of mental fatigue at a cellular level, originates from the fact that skull trauma or brain disease causes neuroinflammation, which impairs the function of the blood-brain barrier (BBB). It is well known from experimental studies that inflammatory activity with the concommittant production of proinflammatory cytokines impairs functions of the BBB and also reduces the glutamate uptake capacity by astrocytes. This indicates that inflammatory activity can be one important factor in impaired glutamate clearance of the extracellular space by astrocytes. When the extracellular level of glutamate is increased, neuronal signalling will be less specific. As glutamate signalling is important for information intake and information processing including concentration capacity and memory, it is of the utmost importance that the astrocyte glutamate uptake and handling is functioning optimally. Interestingly, the levels of other signalling substances, such as dopamine, noradrenalin and serotonin (5-HT), decline following damage to or disease of the CNS. The signalling substances are needed to support attention and concentration capacity.

Aspects on neuronal signalling following brain damage

Cognitive activities resulting in increased tiredness or fatigue have also been suggested to be related to compensatory activities when the brain works ineffectively. Magnetic Resonance Imaging (MRI) has demonstrated that larger regions are activated in the brain after mental effort in persons suffering from mental fatigue following brain damage, which may indicate that brain activity is altered following such damage.

The figure is a simplified illustration of neuronal networks which consist of the neurons A-G (red) under normal conditions (left in the figure). Cell A activates cell B, followed by C and later D. Surrounding astrocytes (blue) recognise, then interact with the neuronal activities.

Neuronal process endings will grow following brain damage (picture to the right), a phenomenon called sprouting. In the figure, the sprouting results in neuron C activating both D and E. By glutamate “spilling-over” and causing a slightly elevated extracellular glutamate level, neuron G will be activated as well. This in turn leads to neuron B being activated, resulting in the activation of greater neuronal networks. Subsequently, the astrocytes will swell, causing unspecific signalling in addition to the specific signalling, resulting in a higher level of noise. The astrocyte swelling further strengthens and retains these processes by limiting the extracellular space.

The astrocytes are central to glutamate signalling

Glutamate is the most widely used excitatory signalling substance within the brain. It is stored in vesicles in the presynaptic terminal and is released upon electrical activation of the neuronal process. Glutamate is released into the synaptic space where it affects the postsynaptic glutamate receptors and thereby triggers an electrical impulse in the new neuron. The astrocyte processes sense the signalling, and the astrocyte is affected metabolically. Furthermore, a Ca2 transient is created and such transients are propagated as Ca2 waves from cell to cell. In order for the transmission to be specific, it is important that the signalling substance is removed as soon as it has fulfilled its function. Thus, in the case of glutamate, this amino acid is taken up by the astrocytes and converted into glutamine, which can safely be transported back to the neuron where glutamine is converted back to glutamate.

The conclusion from many experimental studies is that astrocytes have the greatest capacity to remove gluatamate from the extracellular space. The astrocytes utilise well developed transport proteins for glutamate transport. The transport proteins take up glutamate from the synaptic region with high capacity and precision, and inside the astrocytes, glutamate is converted to glutamine by the enzyme glutamine synthetase.

Glutamine has no biological activity as a signalling substance and can therefore be safely transported back to the neuron, where it is converted to glutamate, which can again be used as a transmitter. It has been shown that the astrocytes release glutamine when high neuronal activity concerning glutamate transmission is registered. Through this arrangement, nature has secured effective glutamate signalling with high precision and endurance over time.

Astrocyte processes surround the synapse and the astrocytes form large cellular networks

Ordinary glutamate signalling with good capacity by the astrocytes to handle glutamate

The figure shows a synapse with a pre- (red, top) and a post synaptic terminal (red, bottom) surrounded by astrocyte processes (blue). Glutamate (green circles) is released from the pre synaptic terminal and affects the postsynaptic glutamate receptors, where a signal is transmitted to the next neuron. The surrounding astrocyte processes sense this signalling and when it is finished, these processes take up glutamate to allow further release. Due to osmotic effect, the astrocytes will slightly increase their volume. In normal conditions, the signalling system is highly effective and precise.

Heavy glutamate signalling with good capacity of the astrocytes to handle glutamate

With more intense glutamate signalling, the astrocytes surrounding single synapses may need help from closely situated astrocytes (blue). As a result, the astrocytes are coupled into larger cellular networks.


Heavy glutamate signalling with impaired capacity of the astrocytes to handle glutamate

The glutamate signalling may experience problems if the signalling is intense, which may be the case with high mental activity and if the astrocyte capacity to handle glutamate is for some reason limited. The astrocytes will swell if they are not able to receive help from closely situated astrocytes (blue).

 A “deadlock” situation

Intense mental activity with high glutamate signalling can lead to astrocytes swelling, especially if their glutamate uptake capacity is impaired. This state, which is locked, may resemble the feeling of cramp in a muscle and the signalling takes a long time to be restored. This may explain the total exhaustion experienced by a person suffering from mental fatigue, when being too active and doing to many things.

Can we explain how mental fatigue arises at a cellular level?

It is well known that brain damage leads to impaired astrocyte capacity for glutamate uptake from the extracellular milieu. There may be down-regulation of the transport protein GLT-1 in the hippocampus and the cerebral cortex following traumatic brain injuries as well as at inflammatory and infectious states in the nervous system. Such impaired capacity to clear the extracellular space of the glutamate results in slightly increased extracellular levels of glutamate. High concentration of glutamate during longer time periods results in neuronal death by the promotion of Ca2 influx into the neurons,triggering the process of cell death. Here we concentrate upon effects on the neurotransmission when there is a slight or moderate increase in extracellular glutamate levels due to impaired uptake capacity by the astrocytes.

It is well known that the extracellular glutamate level has to be low, not exceeding a few µM, to allow for specific transmission with high precision. If there is a disturbance in the regulation of the extracellular glutamate level, the signalling noise level will be raised with the effect that the signalling precision will decline. It is then reasonable to believe that more signals will reach the cerebral cortex for processing and identification, simply due to the sensitising systems at lower levels not identifying the information and therefore not being able to recognise and determine its nature. As the information is always differing, it is interpreted as partially new, even when this is not so. Take the sound from a low-frequency fan as an example. During normal conditions, after a period of time we do not hear (experience) the sound, even if the fan is still on. Fortunately, the brain filters the pattern of the sound and does not allow it to reach our consciousness, as the brain would be overloaded if all information was allowed to pass to the cerebral cortex. However, the noise level would still be elevated, as it is impossible to shut out the fan sound. Hypothetically, disturbed regulation of the extracellular milieu could be one neurobiological explanation for the deficient filtering of information up to the adaptation centres of the brain following brain damage.

When more information reaches the brain cortex for processing, more and greater neuronal circuits will be activated. If there is a disturbance in the extracellular regulation of glutamate levels, these will increase. It must however, be emphasized that the extracellular increase in glutamate is very limited if there is no underlying brain damage. Under all circumstances, the mechanisms underlying mental fatigue can be due to slightly increased glutamate levels, however far below that inducing cell death. Slightly disturbed glutamate transmission may affect glutamate neurotransmission. When the volume of astrocytes increases, the extracellular volume will decrease, which in turn affects concentration and the transportation of neuro-active substances outside the neurons, thus affecting the extracellular signalling between the cells. Cell swelling also results in cell depolarisation. This in turn impairs the astrocyte glutamate uptake capacity, which is voltage dependent. Relative depolarisation also results in impaired astrocyte capacity to handle extracellular K , which is released during transmission. The result may be that the extracellular K levels increase somewhat, especially if the transmission is intensive. Even slightly increased extracellular K levels (8-10mM) have in experimental systems been shown to restrain neuronal capacity to release glutamate.

If the homeostasis of the extracellular milieu is disturbed, a microglial activation is likely. Such microglial activation results in production and release of pro-inflammatory cytokines, in the form of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). These cytokines have been found to further impair the astrocyte capacity of handling extracellular glutamate.

When the astrocyte glutamate uptake capacity is decreased, the amount of available glutamate within the cell is also decreased, which in turn reduces the formation of glutamine and consequently also glutamate formation. It is well known that glucose uptake is decreased leading to disturbed metabolism. Here we see many biomechanical mechanisms behind impaired transmission, which may constitute the cellular basis for mental fatigue.

The presented model can explain why the person is able to maintain cognitively exacting work for a short period, while stimulation for a longer time results in metabolic changes at a cellular level which require a long time to restore. It is important to remember that there are other theories as to the underlying mechanisms behind mental fatigue such as genetic, biochemical, immunological, neuro-endocrinological as well as autonomous reasons including sleep disturbances, which are of substantial importance.

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