Glutamate: Major Excitatory Neurotransmitter - Key Terms

Vocabulary-style flashcards covering major concepts, components, receptors, cycles, and clinical relevance from the glutamate lecture notes.

Glutamate

The brain’s dominant excitatory neurotransmitter; links neurophysiology, metabolism, and pathology; essential for learning, memory, and fast signaling.

Vesicular Glutamate Transporters (VGLUTs)

Transporters that load glutamate into synaptic vesicles for release during neurotransmission.

Glutamine Cycle

Neuron–astrocyte shuttle: glutamate released, taken up by astrocytes, converted to glutamine, exported and taken up by neurons, then reconverted to glutamate.

EAATs (Excitatory Amino Acid Transporters)

Transporters that clear glutamate from the synaptic cleft to prevent overstimulation and excitotoxicity.

AMPA Receptors (GluA1–GluA4)

Fast ionotropic receptors mediating the majority of fast EPSCs; Ca2+ permeability depends on GluA2 editing.

NMDA Receptors (GluN1, GluN2A–D, GluN3A–B)

Ca2+-permeable, voltage-dependent receptors acting as coincidence detectors; require glutamate and a co-agonist and are central to plasticity.

Kainate Receptors (GluK1–GluK5)

Ionotropic receptors with slower kinetics; modulatory roles pre- and postsynaptically and variable Ca2+ permeability.

Metabotropic Glutamate Receptors (mGluRs)

G-protein-coupled receptors (GPCRs) that modulate signaling and neurotransmitter release; Group I excites, Groups II/III inhibit signaling.

Glutamate Synthesis in Brain

Glucose-derived carbon backbone fed into α-ketoglutarate via glycolysis and the TCA cycle; amino groups come from systemic amino acids (notably BCAAs).

α-Ketoglutarate (α-KG)

TCA cycle intermediate that serves as the immediate carbon precursor for glutamate via transamination.

Transamination

Reaction transferring an amino group to α-KG to form glutamate; catalyzed by AST and BCATs.

Branched-Chain Amino Acids (BCAAs)

Leucine, isoleucine, valine; donor amino groups for brain glutamate synthesis via BCATs.

Glutamate Dehydrogenase

Enzyme involved in reversible conversion between glutamate and α-KG, linking nitrogen and energy metabolism.

Glutamic Acid Decarboxylase (GAD)

Enzyme that converts glutamate to GABA in GABAergic neurons.

GABA

Main inhibitory neurotransmitter in the brain, produced from glutamate via GAD.

Glutathione (GSH)

Tripeptide antioxidant (glutamate–cysteine–glycine) protecting brain cells from oxidative stress.

Glutamine Synthetase (GS)

Astrocytic enzyme converting glutamate to glutamine; ATP-dependent and non-excitotoxic storage form.

Phosphate-Activated Glutaminase (PAG)

Neuron enzyme converting glutamine back to glutamate in mitochondria.

Glutamine Transporters (System N: SN1, SN2)

Export glutamine from astrocytes; sodium-coupled transporters in the glutamate–glutamine cycle.

System A Transporters (SAT1, SAT2)

Neuronal transporters that import glutamine into neurons for reconversion to glutamate.

Glutamate Turnover Rate

Glutamate cycling is rapid and roughly doubles the brain’s glucose turnover rate (~0.8 vs ~0.4 μmol/min/g tissue).

Cerebral Metabolic Rate for Glucose (CMRglc)

Rate of glucose utilization by the brain; typically around 0.4 μmol/min/g tissue in humans.

Astrocyte–Neuron Lactate Shuttle

Metabolic cooperation where astrocytes provide lactate to neurons; linked to energy metabolism during neurotransmission.

Pyruvate Carboxylation (Anaplerosis)

Replenishes TCA intermediates by converting pyruvate to oxaloacetate in astrocytes or malate in neurons.

Glycolysis

Glucose to pyruvate; part of the pathway supplying carbon for glutamate synthesis.

Glutamate Turnover vs Glucose Metabolism

Glutamate turnover is high and interconnected with glucose metabolism and nitrogen balance.

Zinc Transporter ZnT3

Transports zinc into glutamatergic vesicles for co-release with glutamate in a subset of synapses.

Zinc Modulation of NMDA Receptors

Zinc co-released with glutamate can enhance or inhibit NMDA receptor activity depending on concentration.

Direct Glutamate Reuptake (EAAT3/EAAC1)

Neuronal clearance pathway contributing to rapid termination of glutamatergic signaling.

Aspartate as NMDA-Specific Agonist

Released in some contexts and selectively activates NMDA receptors, with unclear exocytotic vesicle packaging.

Aspartate Release Mechanisms

Calcium-dependent release potentially via non-vesicular pathways; NMDA selective action.

LTP (Long-Term Potentiation)

Long-lasting increase in synaptic strength; NMDA receptor activation and AMPA receptor trafficking enable memory formation.

LTD (Long-Term Depression)

Long-lasting decrease in synaptic strength; calcium-dependent phosphatase activity reduces AMPA receptor signaling.

Hebbian Learning

'Cells that fire together, wire together'—principle underlying LTP/LTD and memory encoding.

Hippocampus

Brain region essential for declarative and spatial memory; a model system for studying plasticity.

Trisynaptic Circuit

Hippocampal circuit: perforant path → dentate gyrus → CA3 mossy fibers → CA1 Schaffer collaterals.

Perforant Path

Entorhinal cortex input to dentate gyrus; gateway into the hippocampal circuit.

Mossy Fibers

Dentate gyrus axons projecting to CA3; known for powerful, regulated synapses.

Schaffer Collaterals

CA3 to CA1 synapses; classic site for NMDA-dependent LTP studies.

Entorhinal Cortex Pathways to CA1

Direct entorhinal-to-CA1 input that bypasses dentate/CA3; parallel input to CA1.

CA1–Subiculum Output

CA1 pyramidal cells project to subiculum and cortex, feeding memory consolidation.

AMPA Receptors (GluA1–GluA4) Trafficking

Dynamic insertion/removal at the PSD during LTP/LTD to modify synaptic strength.

Glutamate Receptor Subunits (GluN1, GluN2A–D, GluN3A–B)

NMDA receptor subunit composition determines kinetics, pharmacology, and brain-region-specific roles.

Flipping/Flopping (AMPA)

Alternative splice variants in GluA1–GluA4 affecting desensitization and current duration.

GluA2 Q/R Editing (ADAR2)

RNA editing at the Q/R site converts Q to R, reducing Ca2+ permeability and increasing safety.

Q/R Site Editing

Single amino acid change in GluA2 (Q to R) that limits Ca2+ entry and alters conductance.

ADAR2

RNA-editing enzyme that edits the GluA2 Q/R site; essential for survival.

NMDA Mg2+ Block

Voltage-dependent block that requires depolarization to relieve; enables coincidence detection.

Silent Synapses

Synapses with NMDA receptors but lacking AMPA receptors; unsilenced by LTP via AMPA recruitment.

PSD (Postsynaptic Density)

Protein-dense complex beneath the postsynaptic membrane orchestrating signaling and receptor organization.

PSD-95

Major scaffolding protein with PDZ, SH3, GK domains; anchors receptors and links signaling to cytoskeleton.

Neuroligin–Neurexin Adhesion

Trans-synaptic adhesion molecules aligning pre- and postsynaptic sites.

CASK

MAGUK protein linking presynaptic release machinery to postsynaptic scaffold.

Shank-Homer-GKAP-SAP97 Complex

Scaffolding proteins organizing receptor signaling complexes in the PSD.

Palmitoylation

Lipid modification anchoring PSD proteins to membranes and lipid rafts.

Lipid Rafts

Membrane microdomains organizing receptors and signaling complexes.

GluN2A vs GluN2B Distribution

Differential regional expression and kinetics; GluN2B is prominent early and slower; GluN2A increases with maturation.

GluN3 Subunits

Modulatory NMDA subunits that reduce Ca2+ permeability when included.

mGluR Group I (mGluR1/5)

Gq-coupled; activate PLC/IP3/DAG; increase intracellular Ca2+ and PKC; enhance excitability and plasticity.

mGluR Group II/III (mGluR2/3, 4–8)

Gi/o-coupled; inhibit AC → lower cAMP/PKA; presynaptic autoreceptors that dampen glutamate release.

Presynaptic mGluRs (Group II/III)

Autoreceptors that reduce transmitter release by inhibiting Ca2+ influx via voltage-gated channels.

P/Q-type Ca2+ Channels

Primary presynaptic calcium channels inhibited by presynaptic mGluRs, reducing vesicle release.

Autoimmune Glutamate Receptor Encephalitis

Disorders where autoantibodies target glutamate receptors (NMDA, AMPA, mGluR1), causing seizures and cognitive symptoms but often reversible with immunotherapy.

Anti-NMDA Receptor Encephalitis

Autoantibodies against NMDA receptor subunits (NR1/NR2) causing memory loss, psychosis, seizures; responsive to immunotherapy.

NMDA Receptor Antibodies to NR1/NR2

Autoantibodies that cross-link NMDA receptors, reducing synaptic density and signaling.

NMDA Receptor Antagonists (Memantine, Ketamine)

Drugs that block NMDA receptors to reduce excitotoxic signaling in disease or anesthesia.

RNA Editing (ADAR Family)

Post-transcriptional modification of RNA to diversify receptor function; ADAR2 edits GluA2 Q/R site.

GluD1/Glud2 (Delta Family)

Delta family NMDA-like receptors with uncertain fast glutamatergic roles; involved in development.

GluA2 Editing Knockouts

Mice with unedited GluA2 show seizures and early death due to Ca2+ overload; editing is essential for survival.

GluN1 Knockout (Global)

Loss of NMDA receptor assembly/function causes perinatal lethal respiratory failure.

GluN1 Knockout (CA1)

Region-specific knockout disrupts LTP in CA1 and impairs hippocampal-dependent memory.

Co-Release of Glutamate with Zinc

Subsets of vesicles co-pack zinc with glutamate, modulating receptor activity and plasticity.

Aspartate vs Glutamate in Signaling

Aspartate selectively activates NMDA receptors and may function as a modulatory transmitter; not vesicularly loaded.

Direct vs Indirect Pathways to Memory

Direct entorhinal-to-CA1 input supplements trisynaptic processing; hippocampus and cortex coordinate memory.

Phosphorylation of AMPA Receptors (GluA1)

Kinase-mediated changes increasing AMPA receptor conductance and trafficking during LTP.

Calcineurin/PP2B (Protein Phosphatases)

Ca2+-dependent phosphatases driving AMPA receptor internalization during LTD.

NO Signaling (nNOS) as Retrograde Messenger

Ca2+-dependent NO production by nNOS modulates presynaptic release after postsynaptic Ca2+ entry.

Glycine/D-Serine as NMDA Co-Agonists

Ligands required at NMDA receptors alongside glutamate for channel opening.