Neurotransmitters: Glutamic Acid, Synthesis, Glutaminergic Pathways In The Brain

Essential substances known as neurotransmitters help neurons in the central nervous system (CNS) communicate with one another, which controls a number of physiological functions. Glutamic acid, which differs from inhibitory neurotransmitters such as GABA and glycine, is an excitatory amino acid that is essential to these neurotransmitters. Glutamic acid has a wide-ranging effect because it, like GABA, innervates every cell in the central nervous system. The relevance of synaptic glutamate and GABA in neuronal signalling is highlighted by their millimolar concentrations, in contrast to other neurotransmitters like dopamine and serotonin, which function at micromolar concentrations.

Glutamic Acid

Approximately 80% of brain synapses, especially in dendritic spines, send signals via glutamic acid, which acts as a major mediator of rapid excitatory neurotransmission throughout the central nervous system. It makes up a significant amount of the body's neurotransmitter pool and has the highest concentration of any amino acid neurotransmitter in the brain, reaching 10 millimolar.

Synthesis

In the brain, glutamic acid is synthesised de novo from glucose via two main routes. Glycogen is converted by the tricarboxylic acid cycle to α-ketoglutarate, which is then changed by transaminase activities into glutamic acid. Furthermore, by absorbing glutamate and turning it into glutamine, astrocytes serve a critical role in replenishing synaptic glutamate—completing a cycle that is necessary for prolonged neurotransmission.

Major Glutaminergic Pathways In The Brain

For many primary sensory afferent systems, such as trigeminal nerves, spinal afferents, and retinal ganglion cells, glutamic acid functions as a neurotransmitter. Furthermore, cortical pyramidal neurons' cortico-brainstem networks regulate neurotransmission in brainstem regions linked to other neurotransmitters like norepinephrine, dopamine, and serotonin. Multiple glutaminergic synapses in the temporal lobe circuit play a critical role in the establishment of memory, while other routes control motor and sensory activities.

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Receptors

Ionotropic glutamate receptors and metabotropic glutamate receptors (mGluRs) are the two primary types of receptors via which glutamate carries out its actions. Ionotropic receptors, such as those for NMDA, AMPA, and kainate, operate as ligand-gated ion channels to promote quick neurotransmission. On the other hand, mGluRs control glutaminergic neurotransmission through G protein-coupled pathways, which affects neuronal excitability and synaptic plasticity.

Postsynaptic Density

A complex protein structure called postsynaptic density is vital for intercellular signalling pathways that are necessary for synaptic activation. While receptors like NMDA and AMPA receptors are important for synaptic transmission and plasticity, PSD-95 and cell adhesion molecules contribute to synaptic stability.

Role Of Astrocytes

Through excitatory amino acid transporters (EAATs), astrocytes are essential for controlling synaptic glutamate levels and maintaining accurate neurotransmission. Additionally, they express AMPA receptors to track the release of glutamate from synapses and to adjust glycine levels in order to synchronize with glutaminergic neurotransmission.

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Plasticity In Glutaminergic Neurotransmission

Learning and memory are tightly linked to glutaminergic neurotransmission, with use-dependent changes in synaptic efficacy represented by long-term potentiation (LTP) and long-term depression (LTD). AMPA receptors are inserted or removed from postsynaptic densities throughout these processes, which affect the strength and plasticity of synapses.

Excitotoxicity

Glutamate receptor overactivation can cause excitotoxicity, which exacerbates neuronal degeneration in diseases like Alzheimer's. Memantine is one medication that reduces excitotoxicity by blocking NMDA receptor function, which may have therapeutic advantages.

Neuropsychiatric Implications

Many neuropsychiatric conditions, including alcoholism, depression, and schizophrenia, are linked to glutamatergic dysfunction. In schizophrenia, hypofunction of the NMDA receptor is linked, but in depression, glutamate levels are altered. These illnesses may be treated with drugs that target glutamatergic pathways, indicating the therapeutic potential of modifying glutamate signalling. 

Finally, glutamic acid orchestrates complex signalling pathways that are critical for brain function at the forefront of neurotransmission. Novel therapy approaches for neurological and psychiatric illnesses can be made possible by an understanding of its mechanisms and implications, which provide insights into both abnormal and normal brain physiology.

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Hope you found this blog helpful for your Psychiatry residency Basic Sciences preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.