Glutamic acid (glutamate) is the primary excitatory neurotransmitter in the mammalian central nervous system — it is responsible for the vast majority of the excitatory synaptic transmission in the brain and spinal cord, and it is the primary mediator of the synaptic plasticity that underlies learning, memory, and cognitive function. Glutamate is synthesised in neurons from glucose via the TCA cycle and from glutamine (which is supplied by astrocytes and which is the primary precursor for glutamate synthesis in the brain), and it is packaged into synaptic vesicles by the vesicular glutamate transporters (VGLUTs). When an action potential reaches the presynaptic terminal, glutamate is released into the synaptic cleft and binds to one of three families of glutamate receptors — the ionotropic glutamate receptors (which are ligand-gated ion channels, including the NMDA receptor, the AMPA receptor, and the kainate receptor) and the metabotropic glutamate receptors (which are G-protein-coupled receptors). The activation of these glutamate receptors by synaptic glutamate produces the depolarisation of the postsynaptic neuron that is the basis of excitatory synaptic transmission and that is essential for virtually all higher cognitive functions.
Excitotoxicity and the NMDA Receptor
Excitotoxicity is the pathological process by which excessive glutamate receptor activation leads to neuronal death — it is one of the most important mechanisms of neuronal damage in acute brain injury (stroke, traumatic brain injury) and in chronic neurodegenerative disease (Alzheimer disease, Parkinson disease, Huntington disease, ALS). The mechanism of excitotoxicity involves the overactivation of the NMDA subtype of glutamate receptor, which is a calcium-permeable ion channel that is highly expressed on neurons. When glutamate levels are elevated (as occurs in stroke when the blood supply to a region of the brain is interrupted, depriving neurons of glucose and ATP and preventing the reuptake of glutamate from the synaptic cleft), the NMDA receptor is overactivated, excessive calcium ions flow into the neuron, and the intracellular calcium concentration rises to levels that activate the degradative enzymes — including the calpains, the caspases, and the phospholipases — that produce the membrane damage, the DNA fragmentation, and the mitochondrial dysfunction that characterise necrotic and apoptotic cell death.
The importance of excitotoxicity in acute brain injury is most clearly seen in the clinical management of stroke. The NMDA receptor antagonists (including memantine and ketamine, in various states of clinical development) have been studied as neuroprotective agents in stroke, but their clinical use has been limited by the побочные эффекты (side effects) that result from the widespread blockade of NMDA receptors throughout the brain — including hallucinations, sedation, and cognitive impairment. The current approach to neuroprotection in stroke is therefore focused on the upstream mechanisms that contribute to excitotoxic damage — including the maintenance of blood flow to the ischemic penumbra (the region of the brain that surrounds the core infarct and that is reversibly injured), the reduction of glutamate release from ischemic neurons, and the prevention of the calcium overload that is the primary trigger of the excitotoxic cascade.
Astrocytes and the Glutamate-Glutamine Cycle
Astrocytes are the cells that are primarily responsible for clearing glutamate from the synaptic cleft after glutamate release — they express the excitatory amino acid transporters (EAAT1 and EAAT2, also known as GLAST and GLT-1), which take up glutamate from the synaptic cleft and convert it to glutamine via the enzyme glutamine synthetase. The glutamine that is generated by astrocytes is then released back into the extracellular space and taken up by neurons, where it is converted back to glutamate by the enzyme phosphate-activated glutaminase (PAG). This glutamate-glutamine cycle between astrocytes and neurons is the primary mechanism by which the synaptic concentration of glutamate is cleared after each action potential, and its impairment (as occurs in chronic neurodegenerative disease, where astrocyte EAAT expression is downregulated) contributes to the extracellular glutamate accumulation and the excitotoxic neuronal damage that characterise these conditions. The glutamate-glutamine cycle is therefore a critical component of glutamatergic neurotransmission and of the maintenance of synaptic homeostasis in the CNS.
Practical Application
For general neurological support and for the prevention of excitotoxicity, the evidence-based approach is to ensure adequate magnesium status (magnesium blocks the NMDA receptor channel in a voltage-dependent manner, and magnesium deficiency lowers the threshold for NMDA receptor activation and for excitotoxic damage), to maintain stable blood glucose levels (hypoglycaemia is a powerful activator of excitotoxicity through the massive release of glutamate from neurons that are energy-deprived), and to avoid the excessive alcohol consumption that is associated with the downregulation of astrocyte EAAT expression and with the accumulation of extracellular glutamate in the brain. The supplement that has been most studied for its effects on excitotoxicity is magnesium (as magnesium L-threonate, which has better CNS penetration than other magnesium forms), at 200-400mg daily. For comprehensive neurological support, magnesium pairs well with the omega-3 fatty acids (which have membrane-stabilising effects that reduce the susceptibility of neurons to excitotoxic damage), with alpha-lipoic acid (which is a broad-spectrum antioxidant that protects neurons from the oxidative stress that is generated by excitotoxicity), with acetyl-L-carnitine (which supports mitochondrial function in neurons and which has been shown to be protective in excitotoxic models), and with the B-complex vitamins (which are required for the function of the enzymes of the glutamate-glutamine cycle and for the maintenance of normal neurotransmitter synthesis).
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