Amino Acid Neurotransmitters Flaschards

Vocabulary flashcards summarizing major terms, structures, enzymes, receptors, and clinical concepts related to glutamatergic and GABAergic neurotransmission, synaptic plasticity, excitotoxicity, and neuropsychiatric disorders.

Glutamate

Primary excitatory neurotransmitter in the brain, accounting for ~80 % of synaptic transmission and neuronal ATP use.

Blood-Brain Barrier (BBB) Exclusion of Glutamate

Peripheral glutamate does not cross the BBB; brain glutamate is synthesized de novo from glucose via the TCA cycle.

α-Ketoglutarate

TCA-cycle intermediate transaminated into glutamate during de novo synthesis in neurons.

Vesicular Glutamate Transporters (vGluT)

Proteins that package glutamate into synaptic vesicles; constitute the neurotransmitter pool (~20 %).

Excitatory Amino Acid Transporters (EAAT1 & EAAT2)

High-affinity, Na⁺-dependent astrocytic transporters that clear glutamate from synapses and prevent excitotoxicity.

Glutamine Cycle

Astrocytic conversion of glutamate → glutamine (via glutamine synthetase) and neuronal reconversion to glutamate; accounts for ~40 % of glutamate turnover.

AMPA Receptor (AMPAR)

Ionotropic glutamate receptor mediating fast EPSCs; composed of GluR1–GluR4 subunits, with GluR2 editing controlling Ca²⁺ permeability.

Kainate Receptor (KAR)

Ionotropic receptor that can regulate presynaptic glutamate release and also couple to metabotropic signaling.

NMDA Receptor (NMDAR)

Voltage-dependent glutamate receptor requiring Mg²⁺ unblock, glutamate, and a co-agonist (glycine/D-serine); highly Ca²⁺ permeable.

NR2A Subunit

NMDAR subunit enriched in corticolimbic regions of the mature brain; shapes receptor kinetics.

NR2B Subunit

NMDAR subunit predominant in immature cortex; confers high Ca²⁺ permeability and longer open time.

Metabotropic Glutamate Receptors (mGluRs)

GPCR family that modulates synaptic activity; divided into Groups I, II, III based on signaling and pharmacology.

Group I mGluRs (mGluR1 & mGluR5)

Activate PLC/IP₃ pathway, increase neuronal excitability, and often localize postsynaptically.

Group II mGluRs (mGluR2 & mGluR3)

Inhibit adenylyl cyclase and reduce excitability and transmitter release.

Group III mGluRs (mGluR4, 6, 7, 8)

Predominantly presynaptic receptors that inhibit neurotransmitter release.

Postsynaptic Density-95 (PSD-95)

Scaffolding protein anchoring NMDARs and organizing signaling complexes at excitatory synapses.

Neuroligin–Neurexin Complex

Synaptic adhesion molecules that stabilize excitatory synapses; mutations are linked to autism spectrum disorders.

Silent Synapse

Synapse containing only NMDARs; requires AMPAR insertion for functional transmission.

TARPs (Transmembrane AMPA Receptor Regulatory Proteins)

Proteins facilitating AMPAR trafficking and gating, essential for synaptic plasticity.

PICK1

Protein that binds AMPARs and regulates their internalization during LTD.

GlyT1

Astrocytic glycine transporter (3 Na⁺/glycine) that controls extracellular glycine levels and NMDAR co-agonism; target for cognition-enhancing drugs.

D-Serine

Endogenous co-agonist at the NMDAR glycine site, synthesized by serine racemase mainly in forebrain neurons.

Serine Racemase (SR)

Enzyme converting L-serine to D-serine; risk gene (SRR) for schizophrenia.

D-Amino Acid Oxidase (DAAO)

Enzyme degrading D-serine; high expression in cerebellum/brainstem lowers local D-serine levels.

Hebb’s Rule

Principle that synaptic efficacy increases when presynaptic and postsynaptic neurons are activated together.

Long-Term Potentiation (LTP)

Persistent strengthening of synapses (e.g., after 100 Hz tetanus) requiring NMDAR activation and AMPAR insertion.

Long-Term Depression (LTD)

Persistent weakening of synapses following low-frequency stimulation, mediated by AMPAR removal.

D-Cycloserine (DCS)

Partial agonist at the NMDAR glycine site that enhances fear extinction and is investigated for schizophrenia therapy.

Excitotoxicity

Neuron death caused by excessive activation of ionotropic glutamate receptors leading to Na⁺/Ca²⁺ overload.

Necrosis (Acute Excitotoxic Death)

Rapid cell swelling and lysis due to massive ion influx during excitotoxicity.

Apoptosis (Excitotoxic)

Programmed cell death triggered by sustained Ca²⁺ elevation, mitochondrial damage, and caspase activation.

Memantine

Weak, noncompetitive NMDAR antagonist that reduces chronic excitotoxicity; approved for mild-to-moderate Alzheimer disease.

γ-Aminobutyric Acid (GABA)

Principal inhibitory neurotransmitter in the CNS, synthesized from glutamate.

Glutamic Acid Decarboxylase 65 (GAD65)

Synaptic enzyme isoform responsible for vesicular GABA synthesis; knockout mice are seizure-prone.

Glutamic Acid Decarboxylase 67 (GAD67)

Widely distributed isoform producing cytosolic GABA; knockout mice die at birth.

GABA Transaminase (GABA-T)

Enzyme that catabolizes GABA to succinic semialdehyde; target of anticonvulsants like vigabatrin.

Succinic Semialdehyde Dehydrogenase (SSADH)

Converts succinic semialdehyde to succinate, returning carbon skeletons to the Krebs cycle.

Vigabatrin

Irreversible (suicide) inhibitor of GABA-T used to treat epilepsy; risk of visual field defects.

Valproic Acid (VPA)

Broad-spectrum anticonvulsant that competitively inhibits GABA-T, elevating brain GABA levels.

Tiagabine

Selective GABA transporter (GAT1) inhibitor that increases extracellular GABA; antiepileptic drug.

GABA Transporters (GAT1–GAT4)

Na⁺-dependent transporters that remove GABA from synapses into neurons and astrocytes.

Corticolimbic GABAergic Interneurons

Local inhibitory neurons that tightly control excitatory pyramidal cell output in cortex and limbic structures.

Parvalbumin-Positive Interneuron

Fast-spiking GABAergic cell (e.g., chandelier cell) critical for cortical timing; deficits linked to schizophrenia.

Purkinje Cell

Cerebellar GABAergic neuron providing the sole inhibitory output of the cerebellar cortex.

GABAA Receptor

Ligand-gated Cl⁻ channel forming heteropentamers; mediates fast inhibitory neurotransmission.

Muscimol

Potent plant-derived agonist at GABAA receptors.

Benzodiazepines

Allosteric modulators that increase the frequency of GABAA Cl⁻ channel opening; anxiolytic and sedative.

Barbiturates

Drugs that prolong GABAA Cl⁻ channel open time; can cause fatal respiratory depression.

Allopregnanolone

Endogenous neurosteroid that positively modulates GABAA receptors; formulation brexanolone approved for postpartum depression.

Bicuculline

Competitive antagonist at GABAA receptors; pro-convulsant.

Picrotoxin

Noncompetitive blocker of the GABAA Cl⁻ channel; induces seizures.

δ-Subunit-Containing GABAA Receptor

Extrasynaptic receptor mediating tonic inhibition; highly sensitive to ethanol and neurosteroids.

Zolpidem

Hypnotic that selectively targets α1-subunit-containing GABAA receptors, minimizing muscle-relaxant effects.

GABAB Receptor

Metabotropic G-protein-coupled receptor functioning as obligatory heterodimer (GABAB1 + GABAB2).

Baclofen

Selective GABAB receptor agonist used as a muscle relaxant.

γ-Hydroxybutyrate (GHB)

Drug acting via GABAB receptors; approved for narcolepsy but abused as a sedative.

Ischemic Stroke Excitotoxicity

ATP depletion reverses EAATs, causing glutamate flood, NMDAR overactivation, and neuronal death.

β-Amyloid (Aβ1-42)

Peptide that increases NMDAR sensitivity and impairs glutamate uptake, contributing to Alzheimer excitotoxicity.

Ketamine

Noncompetitive NMDAR antagonist with rapid antidepressant effects and ability to mimic schizophrenia symptoms.

Serine Racemase Gene (SRR)

Encodes serine racemase; polymorphisms confer schizophrenia risk via reduced D-serine production.

CACNA1C

Gene for L-type Ca²⁺ channel; shared risk locus for schizophrenia and bipolar disorder.

GRIN2A

Gene encoding an NMDAR NR2A subunit; implicated in psychiatric disorders.

Dopamine Hypothesis Limitation

D2 antagonists leave most patients disabled, prompting focus on glutamate/GABA theories of schizophrenia.

Chandelier Cell

Parvalbumin-positive interneuron targeting pyramidal axon initial segments; dysfunction reduces cortical inhibition in schizophrenia.

D-Serine/Glycine Modulatory Site (GMS)

Co-agonist binding site on NMDAR required for channel opening; therapeutic target in schizophrenia.

Glycine-Site Agonists (e.g., D-Serine)

Compounds that enhance NMDAR function; show modest benefits for negative and cognitive symptoms of schizophrenia.

Tonic vs Phasic NMDAR Activity

Memantine blocks pathological low-level activity (tonic) while sparing normal synaptic (phasic) transmission.

Anxiety-Related GABA Deficit

Lower cortical GABA levels and reduced benzodiazepine binding seen in panic disorder and major depression.

Allosteric Neurosteroid Deficit in MDD

Reduced plasma/CSF levels of GABAA-positive neurosteroids; normalized by SSRI therapy.

Esketamine

S-ketamine enantiomer approved for treatment-resistant depression and acute suicidality; rapid-acting NMDAR blocker.

Ethanol Acute CNS Effects

Enhances GABAA receptor function and inhibits NMDARs, producing sedation and memory impairment.

Delirium Tremens

Severe withdrawal state caused by GABAA downregulation and NMDAR upregulation after chronic alcohol use.

Acamprosate

Anti-craving drug for alcohol use disorder that modulates NMDA (originally thought to act on GABAA) receptors.

Fetal Alcohol Syndrome (FAS)

Developmental disorder from prenatal ethanol exposure; NMDAR inhibition leads to neuronal apoptosis, microcephaly, and characteristic facial features.