Glutamate Neurotransmission

Glutamate

• Glutamate is a versatile molecule utilized by all cells for protein synthesis and other functions in the central nervous system (CNS).
• It is the brain's most abundant amino acid and acts as an excitatory neurotransmitter, triggering an excitatory response in the postsynaptic neuron.
• Neurons and glial cells contain substantial glutamate levels, with glutamatergic neurons having higher concentrations.
• These neurons keep the glutamate used for neurotransmission separate from the glutamate used for other cellular activities, which makes it challenging to identify glutamatergic cells.
• Vesicular glutamate transporters (VGLUTs) are exclusively found in cells that use glutamate for neurotransmission.
• Most glutamatergic neurons use VGLUT 1 or VGLUT 2; VGLUT 3 is less common.
• Glutamine is a precursor molecule.
• Glutaminase then converts glutamine into glutamate.

Glutamate Uptake

• Excitatory amino acid transporters (EAATs) are responsible for glutamate uptake.
• EAAT 1 is located in astrocytes in the cerebellum and is important for cerebellar function.
• EAAT 2, found in astrocytes throughout the brain, accounts for approximately 90% of glutamate uptake in the brain.
• Excessive glutamate levels can lead to cell death.
• EAAT 3 is found in postsynaptic neurons.
• EAATs 4 and 5 are located in the cerebellum and retina, respectively.
• After uptake via EAAT 1/EEAT 2, astrocytes convert the majority of glutamate into glutamine using glutamine synthase.
• Glutamine is then transported out of astrocytes, picked up by neurons, and converted back to glutamate using glutaminase.

Glutamate Receptors

• Glutamate receptors are involved in many excitatory neuronal pathways and come in two main types: ionotropic and metabotropic.
• There are three subtypes of ionotropic receptors: AMPA, Kainate, and NMDA.
• Ionotropic receptors depolarize the postsynaptic cell membrane, leading to an excitatory response and increasing the likelihood of an action potential.
• AMPA and kainite receptors facilitate the flow of Na+ ions into the cell.
• NMDA receptors facilitate the flow of both Na+ and Ca+ ions into the cell.
• There are eight subtypes of metabotropic receptors, mGluR1 through mGluR8, widely distributed throughout the brain.
• Metabotropic receptors participate in locomotor activity, cognition, and pain reception.

Learning and Memory

• AMPA and NMDA receptors play a significant role in learning and memory.
• Psychiatric disorders, like autism, are linked to cognitive impairment and dysregulation of glutamate receptors.
• Research is focused on finding new glutamatergic compounds, such as AMPA receptor positive allosteric modulators, which have shown enhanced learning and memory in animal experiments but have not yet translated into clinical benefits.
• Strong activation of NMDA receptors leads to the strengthening of synapses, known as long-term potentiation (LTP).

Mechanisms of LTP

• LTP, discovered by Bliss & Lomo, is when synaptic connections are strengthened for at least one hour.
• Activation of NMDA receptors is essential for LTP.
• LTP occurs in many brain regions, but is most extensively studied in the hippocampus, specifically at the pyramidal neurons of the CA₁ region, which receive excitatory glutamatergic inputs from CA3 neurons via the Schaffer collaterals.
• Low levels of excitation result in a small EPSP (excitatory postsynaptic potential) produced by activation of AMPA receptors.
• A large EPSP results from prolonged activation of AMPA receptors, which allows magnesium (Mg2+) ions to dissociate from NMDA receptor channels
• The influx of CA+ (a second messenger) then leads to rapid expansion of dendritic spines and insertion of additional AMPA receptors on the spine membranes.

Consequences of High Levels of Glutamate

• The excitotoxicity hypothesis states that excessive glutamate exposure leads to prolonged depolarization of receptive neurons, resulting in cell damage or cell death (necrosis), which is different from apoptosis (natural cell death).
• Excitotoxic brain damage is implicated in several psychiatric disorders and implicated in Parkinson's and Alzheimer's research.

GABA

• GABA is the primary inhibitory neurotransmitter in the CNS.
• Inhibitory transmission is just as crucial as excitatory transmission.
• Blocking the action of GABA can lead to convulsions or death.
• GABA is produced by GABAergic neurons and serves primarily as a neurotransmitter.
• The vesicular GABA transporter (VGAT) transports GABA into synaptic vesicles.
• GABA is removed from the extracellular space by GAT-1 and GAT-2 (expressed in neurons and astrocytes) and GAT-3 (expressed in astrocytes).

GABA Metabolism

• Upon reuptake, GABA can be converted back into glutamate.
• When taken up by astrocytes, GABA is converted to glutamate, which is then converted to glutamine.
• Once glutamine is taken up by neurons, it is converted back to glutamate and used to resynthesize GABA.
• GABA-T, found in both GABAergic neurons and astrocytes, breaks down GAT-2 and 3.
• Many nerve terminals in the brain use GABA as their neurotransmitter.
• GABAA (ionotropic) receptors allow the flow of Cl- ions into the cell, inhibiting cell firing by hyperpolarizing the membrane.
• GABAB receptors are metabotropic.
• BZDs (e.g., diazepam/Valium) and barbiturates are GABAA receptor positive allosteric modulators.
• Pre-surgical anesthetics and ethanol alcohol are also GABAA receptor positive allosteric modulators.
• Vigabatrin (Sabril) inhibits GABA-T, resulting in an anticonvulsant effect used to treat certain types of epilepsy, especially infantile spasms.

Clinical Use

• Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for anxiety disorders.
  • SSRIs have disadvantages, including a delayed onset of action, partial effectiveness, and side effects.
• BZDs are fast-acting but have more adverse side effects and are used to treat anxiety, usually for acute treatment of ataxia, slurred speech, and fatigue.
  • Long-term treatment with BZDs carries the potential for misuse, tolerance, rebound anxiety, and memory impairment.
• BZDs are often used for short-term relief of anxiety symptoms or as an adjunct to bridge the gap in efficacy for SSRIs.

Ketamine

• Ketamine was first used as a rapid-acting IV anesthetic.
• IV Ketamine and esketamine spray (Spravato) are used to treat treatment-resistant depression with a rapid reduction of depressive symptoms in about 60-75% of individuals.
  • Most other medications require weeks to months to have an effect, and Ketamine has a variable and short duration of action.
• Ketamine is a noncompetitive antagonist of NMDA receptors.
• The use of Ketamine to treat psychological disorders remains controversial.