Glutamic acid (glutamate) is the most abundant excitatory neurotransmitter in the human brain and is the direct precursor of GABA (gamma-aminobutyric acid) — the most abundant inhibitory neurotransmitter in the brain. The glutamate-GABA cycle is one of the most important regulatory mechanisms in the brain: glutamate is released from excitatory synapses, activates the NMDA and AMPA receptors on postsynaptic neurons, and is then cleared by the astrocytes (via the GLT-1 glutamate transporter) and converted to glutamine (by the astrocyte-specific enzyme glutamine synthetase); the glutamine is released by astrocytes and taken up by neurons, where it is converted back to glutamate (by the neuron-specific enzyme phosphate-activated glutaminase) and to GABA (by the GABA transaminase enzyme, GABA-T). This glutamate-GABA cycle is the primary mechanism by which the balance between excitation and inhibition in the brain is maintained — and disruption of this balance is the primary mechanism underlying seizure disorders, anxiety disorders, and many forms of chronic pain.
Glutamate and Synaptic Plasticity
Glutamate is the primary mediator of the excitatory neurotransmission that underlies synaptic plasticity — the process by which the strength of synaptic connections is modified in response to activity. The NMDA receptor is the primary mediator of the calcium influx that triggers the long-term changes in synaptic strength that constitute LTP and LTD. When glutamate binds to the NMDA receptor, calcium ions flow into the postsynaptic neuron, activating CaMKII (calcium/calmodulin-dependent protein kinase II), which phosphorylates and activates the transcription factor CREB (cAMP response element-binding protein). CREB activation drives the transcription of the genes that are required for the growth of new synaptic connections and for the strengthening of existing synapses — including the neurotrophic factors BDNF and NT-3, the scaffolding proteins PSD-95 and Shank, and the receptors that are responsible for the maintenance of the potentiated synapse. This NMDA-CaMKII-CREB signalling cascade is the primary molecular mechanism of learning and memory.
The clinical importance of glutamate neurotransmission is underscored by the diseases that involve glutamate receptor dysfunction — particularly the stroke and traumatic brain injury (TBI), in which the excessive release of glutamate from dying neurons produces a toxic buildup of extracellular glutamate that overactivates the NMDA receptors on surrounding healthy neurons, producing the excitotoxicity that is one of the primary mechanisms of secondary neuronal damage in these conditions. The NMDA receptor antagonists ketamine, memantine, and dextromethorphan have been studied as neuroprotective agents in stroke and TBI, though their clinical efficacy has been limited by the difficulty of timing the administration appropriately and by the unacceptable psychotomimetic side effects of the NMDA antagonists.
GABA and the Benzodiazepine Mechanism
GABA is the primary inhibitory neurotransmitter in the brain — it is released from inhibitory interneurons (the GABAergic neurons that constitute approximately 20% of the neurons in the cortex and that are the primary mediators of the feed-forward and feedback inhibition that regulates the excitability of all excitatory pathways in the brain). The GABA-A receptor is the primary target of the benzodiazepines (diazepam, alprazolam, clonazepam, and the other sedatives and anxiolytics), the barbiturates, and the alcohol molecule — all of which potentiate the action of GABA at the GABA-A receptor, increasing the frequency or duration of the chloride channel opening that follows GABA binding and producing a net increase in the inhibitory tone of the brain. This benzodiazepine mechanism is one of the most clinically important in all of pharmacology — the benzodiazepines are among the most widely prescribed medications in the world and are the primary treatment for anxiety, insomnia, muscle spasm, and seizure disorders.
Practical Application
Glutamic acid is not typically supplemented directly because it is one of the most abundant amino acids in dietary protein and because the body synthesises it readily from glutamine and from the intermediates of the TCA cycle. The most common approach to supporting GABAergic neurotransmission is through the precursors and modulators of the GABA pathway rather than through glutamate itself — including L-glutamine (the precursor of both glutamate and GABA, at 500-1,000mg daily), GABA itself (at 250-750mg daily, though its oral bioavailability is limited by the blood-brain barrier), and the GABA-A receptor potentiators (including L-theanine at 100-200mg daily, which increases the alpha brain waves associated with relaxed alertness). For comprehensive neurotransmitter support, glutamate and GABA precursors pair well with magnesium glycinate (which reduces the NMDA receptor excitability that underlies some forms of anxiety and insomnia), with pyridoxal-5-phosphate (the active form of B6, which is required for the GABA transaminase reaction), and with the omega-3 fatty acids (which support membrane fluidity and the function of the neurotransmitter receptors in the neuronal membrane).
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