Excitatory Synapses: Glutamate Receptors (AMPA & NMDA)

Excitatory Synapses

Synapses that increase the likelihood that the postsynaptic neuron will fire an action potential, primarily using glutamate as the neurotransmitter.

Inhibitory Synapses

Synapses that decrease the likelihood of postsynaptic neuron firing, predominantly using GABA as their neurotransmitter.

Neuromodulatory Synapses

Synapses that use various neurotransmitters (e.g., dopamine, serotonin) to modulate the activity of larger neuronal populations over longer timescales, influencing states like mood, arousal, and attention.

Dendritic Spines

Small, specialized protrusions on dendrites that are the primary postsynaptic sites for excitatory synapses, acting as compartmentalized biochemical units.

Postsynaptic Density (PSD)

An electron-dense, disc-shaped structure beneath the postsynaptic membrane at excitatory synapses, composed of hundreds of proteins that scaffold receptors and signaling machinery.

EPSP (Excitatory Postsynaptic Potential)

A temporary depolarization of the postsynaptic membrane caused by the flow of positively charged ions (primarily Na^{+} through AMPARs) into the cell.

Ionotropic Glutamate Receptors

A class of ligand-gated ion channels that directly mediate fast synaptic transmission upon glutamate binding, including AMPA and NMDA receptors.

AMPA Receptors (AMPARs)

Primary mediators of the fast excitatory postsynaptic current and most rapid excitatory transmission, permeable mainly to Na^{+} ions and characterized by rapid desensitization. They are tetramers of GLUA1-GLUA4 subunits.

NMDA Receptors (NMDARs)

Receptors crucial for calcium signaling and synaptic plasticity, requiring both glutamate and glycine (or D-serine) binding, and postsynaptic depolarization to relieve a Mg^{2+} block.

Tetramer

A protein complex formed by the assembly of four individual subunits (e.g., AMPA and NMDA receptors).

Clamshell Model

Describes the conformational change of the ligand-binding domain (LBD) in ionotropic receptors, where closure upon ligand binding initiates channel opening.

Mg^{2+} Block

The voltage-dependent block of the NMDA receptor pore by an extracellular Mg^{2+} ion at resting membrane potentials, which is relieved by postsynaptic depolarization.

Coincidence Detector (NMDA Receptors)

NMDA receptors' property of requiring the coincident occurrence of both presynaptic glutamate release and postsynaptic depolarization for activation and Ca^{2+} influx.

ADAR Enzyme

The enzyme (adenosine deaminase acting on RNA) responsible for RNA editing.

GluA2 Q/R Editing

A post-transcriptional RNA editing mechanism, catalyzed by the ADAR enzyme, that converts a glutamine (Q) codon to an arginine (R) codon in the GluA2 subunit’s pore loop, significantly reducing Ca^{2+} permeability of AMPARs in the adult brain.

TARPs (Transmembrane AMPA Receptor Regulatory Proteins)

Auxiliary proteins (e.g., Stargazin) that associate with AMPARs, critical for regulating their trafficking to the membrane, surface expression, and channel kinetics.

Synaptic Plasticity

The ability of synapses to strengthen or weaken over time in response to increases or decreases in their activity, underlying learning and memory.

What are Excitatory Synapses?

Excitatory synapses increase the likelihood that the postsynaptic neuron will fire an action potential. They primarily use glutamate as their neurotransmitter.

What are Inhibitory Synapses?

Inhibitory synapses decrease the likelihood of postsynaptic neuron firing. They predominantly use GABA (gamma-aminobutyric acid) as their neurotransmitter.

What are Neuromodulatory Synapses?

Neuromodulatory synapses use various neurotransmitters (e.g., dopamine, serotonin, acetylcholine, norepinephrine) to modulate the activity of larger neuronal populations over longer timescales, influencing states like mood, arousal, and attention rather than direct signal transmission.

What is Glutamate?

Glutamate is the primary excitatory neurotransmitter in the brain, responsible for fast excitatory postsynaptic responses.

What are Dendritic Spines?

Dendritic spines are small, specialized protrusions found on the dendrites of many neurons, serving as the primary postsynaptic sites for excitatory synapses and acting as compartmentalized biochemical units.

What is the Postsynaptic Density (PSD)?

The Postsynaptic Density (PSD) is an electron-dense, disc-shaped structure immediately beneath the postsynaptic membrane at excitatory synapses, composed of hundreds of proteins that scaffold key excitatory receptors and signaling molecules.

What is an EPSP (Excitatory Postsynaptic Potential)?

An EPSP (Excitatory Postsynaptic Potential) is a temporary depolarization of the postsynaptic membrane caused by the flow of positively charged ions (primarily Na^{+} through AMPARs) into the cell.

What is a Tetramer?

A tetramer is a protein complex formed by the assembly of four individual protein subunits, as seen in ionotropic glutamate receptors like AMPA and NMDA receptors.

What are AMPA Receptors (AMPARs)?

AMPA Receptors (AMPARs) are ionotropic glutamate receptors primarily responsible for the rapid, depolarizing phase of the EPSP through Na^{+} ion influx, exhibiting rapid desensitization upon glutamate binding.

What are NMDA Receptors (NMDARs)?

NMDA Receptors (NMDARs) are ionotropic glutamate receptors crucial for calcium signaling and synaptic plasticity. They are unique in requiring both glutamate and glycine (or D-serine) binding and the relief of a voltage-dependent Mg^{2+} block by postsynaptic depolarization for activation.

Describe the Clamshell Model.

The Clamshell Model describes the conformational change of the ligand-binding domain (LBD) in ionotropic receptors, where upon specific ligand binding, the LBD closes like a clamshell, initiating the opening of the ion channel pore.

What is the Mg^{2+} Block in NMDA Receptors?

The Mg^{2+} Block is the voltage-dependent physical blockage of the NMDA receptor pore by an extracellular Mg^{2+} ion at typical resting membrane potentials (\approx -70 \text{ mV}). This block is only relieved when the postsynaptic membrane is sufficiently depolarized.

Why are NMDA Receptors considered 'Coincidence Detectors'?

NMDA Receptors are considered 'Coincidence Detectors' because their activation and subsequent Ca^{2+} influx require the coincident occurrence of both presynaptic glutamate release (glutamate binding) and postsynaptic depolarization (to relieve the Mg^{2+} block).

What is the ADAR Enzyme?

The ADAR (adenosine deaminase acting on RNA) enzyme is responsible for the Q/R RNA editing event, particularly in the GluA2 subunit of AMPA receptors.

Explain GluA2 Q/R Editing.

GluA2 Q/R Editing is a critical post-transcriptional RNA editing mechanism, catalyzed by the ADAR enzyme, that changes a glutamine (Q) codon to an arginine (R) codon in the GluA2 subunit's M2 pore loop. This editing significantly reduces the Ca^{2+} permeability of AMPARs, making most adult AMPARs predominantly Na^{+}-permeable.

What are TARPs (Transmembrane AMPA Receptor Regulatory Proteins)?

TARPs (Transmembrane AMPA Receptor Regulatory Proteins) are auxiliary proteins that physically associate with AMPARs. They are critical for regulating AMPAR trafficking to the membrane, stable anchoring at the postsynaptic density, surface expression, and modulating channel kinetics.

What is Stargazin?

Stargazin (TARP \gamma2) is a specific and well-characterized Transmembrane AMPA Receptor Regulatory Protein (TARP). Mutations in stargazin disrupt AMPAR trafficking to the membrane, leading to severe motor coordination problems (ataxia-like phenotypes) in mutant mice.

What is the Ligand-Binding Domain (LBD)?

The Ligand-Binding Domain (LBD) is an extracellular domain present in each ionotropic receptor subunit. It forms a bi-lobed structure (clamshell) that binds specific ligands (e.g., glutamate for AMPARs; glutamate or glycine for NMDARs) and, upon closure, induces conformational changes to open the ion channel pore.

What is the Pore Loop (M2 region)?

The Pore Loop (M2 region) is a re-entrant segment within each receptor subunit that dips into the membrane without fully crossing it, forming a crucial part of the ion channel pore. It critically determines the channel's ion selectivity and conductance.