NMDA Receptors and Schizophrenia

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Questions and Answers

What is the first step in the life cycle of neurotransmission?

Transmitter Inactivation

Storage

Synthesis (correct)

Receptor Binding

Which ionotropic receptor is associated with serotonin neurotransmission?

AMPA Receptor

5-HT3 Receptor (correct)

nACh receptor

GABAA Receptor

Which of the following ionotropic receptors is primarily involved in mediating excitatory synaptic transmission?

GABAA Receptor

AMPA/Kainate Receptors (correct)

Purines Receptors

Glycine Receptor

Which step in the life cycle of neurotransmission occurs after neurotransmitter release?

Receptor Binding Signup and view all the answers

What type of receptors do NMDA belong to?

Ionotropic Receptors Signup and view all the answers

What type of receptor are NMDA and AMPA classified as?

Ionotropic receptors Signup and view all the answers

Which compound is noted as a pore-blocker of NMDA receptors?

Phencyclidine (PCP) Signup and view all the answers

What is the primary neurotransmitter associated with NMDA receptors in the context of schizophrenia?

Glutamate Signup and view all the answers

How many NMDARs are typically found in a postsynaptic density (PSD) of around 350nm?

20 Signup and view all the answers

In terms of receptor localization, where are NMDA receptors primarily located within the postsynaptic density?

In the center Signup and view all the answers

Which ionotropic receptor family is involved with psychopharmacological effects linked to drugs like ketamine?

Glutamatergic Ionotropic Receptors Signup and view all the answers

What is the estimated number of AMPARs typically found in a PSD compared to NMDARs?

10 to 50 AMPARs Signup and view all the answers

Which of the following is NOT a stated NMDA receptor pore-blocker?

Glutamate Signup and view all the answers

What effect does the RNA editing of GluA2 have on its properties?

Decreases Ca2+ permeability Signup and view all the answers

What happens when the editing site complementary sequence (ECS) is deleted in GluA2?

Impairs GluA2 Q/R RNA editing Signup and view all the answers

Extended exposure to glutamate affects AMPA receptors by causing what change?

Change in the dimer bond at the ligand binding domain Signup and view all the answers

What would be the consequence of an increase in unedited GluA2 mRNA?

Higher calcium permeability Signup and view all the answers

The strong electrostatic repulsion by which amino acid is responsible for the low permeability of AMPA receptor-channels with edited GluA2?

Arginine Signup and view all the answers

What is the outcome in wild-type littermates that possess the normal Q/R editing site compared to those with impaired editing?

More edited GluA2 mRNA Signup and view all the answers

What is one significant consequence of channel closure in AMPA receptors after glutamate exposure?

Loss of synaptic plasticity Signup and view all the answers

Which modification in AMPA receptor composition leads to changes in its calcium permeability?

Editing of the mRNA Signup and view all the answers

What is one of the key factors influencing the magnitude of the postsynaptic response?

The state of the postsynaptic neuron Signup and view all the answers

What is the primary characteristic of ionotropic receptors in terms of synaptic action duration?

They cause fast synaptic actions lasting only milliseconds Signup and view all the answers

How many subunits do ionotropic receptors typically have?

3 to 5 subunits Signup and view all the answers

Which of these receptors is NOT classified as an ionotropic receptor?

Metabotropic glutamate receptor Signup and view all the answers

What structural feature is typical of each subunit in ionotropic receptors?

Four membrane-spanning α-helices Signup and view all the answers

What aspect affects the postsynaptic receptor's response alongside receptor number and neurotransmitter amount?

The 'state' of the receptors Signup and view all the answers

Which ionotropic receptor is specifically known for mediating fast excitatory transmission in the central nervous system?

AMPA receptor Signup and view all the answers

What is the general implication of neurotransmitter release amount on postsynaptic receptors?

It influences the size of the postsynaptic potential Signup and view all the answers

Where are mGluRs primarily located?

On the periphery, outside the main PSD Signup and view all the answers

What is the role of PSD-95 in relation to AMPARs?

It localizes and concentrates AMPARs at postsynaptic sites. Signup and view all the answers

What is the function of TARPs like Stargazin?

They regulate the trafficking and synaptic localization of AMPARs. Signup and view all the answers

How does increasing Stargazin expression affect AMPARs?

It increases their presence in the membrane. Signup and view all the answers

What happens to the functional AMPARs in the cerebellum of stg mice?

They completely lack functional AMPARs despite normal GluA expression. Signup and view all the answers

What is the effect of increased PSD-95 expression on AMPARs?

It increases AMPAR presence in the synapse. Signup and view all the answers

What is the role of Stargazin's PDZ domain?

To anchor AMPARs to the synapse. Signup and view all the answers

Which receptors are primarily affected by TARPs?

Ionotropic glutamate receptors. Signup and view all the answers

What was observed with exogenous glutamate application in controlled levels of Stargazin?

A normal increase in response due to adequate AMPARs. Signup and view all the answers

Study Notes

NMDA Receptors, Hallucinations and Schizophrenia

HaInogenic compounds like PCP, Ketamine, and MK-801 block NMDA receptors, disrupting synaptic transmission and causing altered perceptions and cognitive dysfunction.ons, often associated with various psychiatric conditions.
The glutamate hypothesis of schizophrenia proposes that dysregulation of glutamate, particularly at the NMDA receptor level, plays a critical role in the pathophysiology of schizophrenia. This hypothesis is supported by observations that decreased NMDA receptor function may lead to symptoms such as hallucinations, impaired cognition, and negative symptoms, indicating a complex interplay between neurotransmitter systems in mental health disorders.

NMDA Receptors and Glutamate Excitotoxicity

Glutamate excitotoxicity is an overstimulation of neurons by glutamate.
This occurs when glutamate binds to NMDA receptors.

Lecture Outline

Glutamatergic ionotropic receptors include AMPA, Kainate, and NMDA receptors.

Distribution of Ionotropic Glutamate Receptors: Postsynaptic Density (PSD)

The postsynaptic density (PSD) contains a variety of proteins including ionotropic receptors.
NMDA receptors are located in the center of the PSD, while AMPA receptors are more peripherally located.
A typical PSD is approximately 350nm long and contains about 20 NMDA receptors and 10-50 AMPA receptors.

The Life Cycle of Neurotransmission

The life cycle of neurotransmission consists of several steps:
- synthesis
- storage
- release
- receptor binding
- inactivation

Ionotropic and Metabotropic Receptors

Ionotropic receptors are fast acting, with effects occurring over milliseconds, while metabotropic receptors are slower, with effects persisting for seconds to minutes.

Ionotropic Receptor Families

Ionotropic receptors are composed of 3 to 5 subunits.
Each subunit has a membrane domain with four membrane-spanning alpha helices (M1-M4) and a short extracellular C-terminus.

AMPA Receptors: Subunit Composition

AMPA receptors can have various subunit compositions.
The GluA2 subunit exhibits low calcium permeability due to a strong electrostatic repulsion by an arginine.
RNA editing switches a single amino acid in GluA2 reducing calcium permeability.
Deletion of the editing site complementary sequence (ECS) in the intron impairs GluA2 Q/R RNA editing.
Deletion of the ECS leads to approximately 25% unedited GluA2 mRNA at the Q/R site compared to wild-type littermates.

AMPA Receptors: Desensitization

Prolonged exposure to glutamate can lead to a change in the dimer bond at the ligand binding domain, resulting in channel closure.
mGluRs are located on the periphery of the PSD.

AMPA Receptor Trafficking

The PSD-95 protein binds to NMDA receptors, AMPA receptors, and other proteins, concentrating these receptors at the synapse.
Transmembrane AMPA receptor regulatory proteins (TARPs) regulate the trafficking, synaptic localization, and gating of AMPA receptors.
AMPAR trafficking is complex and tightly controlled.
TARP composition differs across the brain.

TARPs: Stargazin

Stg mice lack Stargazin, leading to a deficiency in functional AMPARs in the cerebellum.
Increasing Stargazin expression increases the presence of AMPARs in the membrane, but does not alter evoked responses.
Stargazin guides AMPARs to the membrane and anchors them to the synapse via its PDZ domain.

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Description

Explore the role of NMDA receptors in schizophrenia, including the impact of hallucinogens like PCP and Ketamine. Understand glutamate excitotoxicity and the distribution of ionotropic glutamate receptors within the postsynaptic density.