Chapter 8 - Glutamate Organization and Function

Pathways of Glutamate

Pyramidal Neurons of the cortex

Parallel fibers of the cerebrum

Excitatory pathways in the hippocampus

Glutamate Functions

Synaptic Plasticity

Learning and memory

possibly psychopathologic disorders

AMPA Receptor

Ionotropic - 4 subunits

Most fast excitatory responses to glutamate

Kainate Receptors

Ionotropic - 4 subunits

Named after the selective agonist kainic acid (from seaweed)

NBQX

An antagonist that blocks AMPA and Kainate receptors, but not NMDA receptors

Leads to sedation, ataxia, reduced locomotor activity, deficient rotarod performance, and protection against seizures

NMDA Receptor

Ionotropic - 4 subunits

Allows both Na+ and Ca2+ to pass, also acts as a second messenger

To open requires simultaneous binding of glutamate and a co-agonist (glycine or d-serine)

Binding site for Mg2+ which blocks the receptor, and leaves when cell is depolarized

Coincidence Detection

when both the NT and a co-agonist happen to bind to their respective binding sites at the same time

d-serine

formation of this co-agonist primarily occurs in neurons, and must be synthesized enzymatically from l-serine to d-serine

NMDA Uncompetitive Antagonists

The receptor must be opened/activated before they can work and bind to its binding site

PCP and Ketamine

MK-801 (used in research)

Memantine treats AD

Ketamine/PCP

Disrupts cognition

Higher affinity

Acts on a variety of NMDA receptors

Memantine

Enhances cognition

Has a lower affinity for NMDA receptors (no long-term blockage)

Only acts on the receptor channel under the conditions of excessive GLUT levels

Targets extrasynaptic NMDA receptors

Metabotropic Group 1 Receptors

mGluR1 and mGluR5

Located post synaptically, uses the PI system

Excitatory

Metabotropic Group 2 Receptors

mGluR2 and mGluR3

Located pre-synaptically and acts as auto or hetero receptors to inhibit release of Glut or other NT

Metabotropic Group 3 Receptors

mGluR4 and mGluR6-8

reduces transmitter relase by inhibiting cAMP

Located pre-synaptically and acts as auto or hetero receptors to inhibit release of Glut or other NT

Fragile X syndrome

Caused by mutations in FMR1 gene on the X chromosome

More common in men

Long-term depression (LTD)

Fixed by antagonist for mGluR5

Metabotropic Glutamate Receptor Theory

Loss of FMRP causes exaggerated group 1 mGluR-related fucntions:

Leads to dendritic spine abnormalities and elevated LTD

Positive Allosteric Modulators of AMPA

Cognitive enhancers, allowing for Glut to exert prolonged excitatory effects

Only shown in animal trials

Long Term Potentiation

The coincidence detector feature of NMDA (two binding NT)

When the cell is depolarized via AMPA receptors, it causes the Mg2+ ion to unblock the receptor. More AMPA receptors will be added, increasing the chance of depolarization for NMDA receptors.

Tetanic Stimulus

the burst of activity in the presynaptic neuron

Early LTP

Lasts for a few hours

Late LTP

lasts for days or months

Induction Phase

during and immediately after tetanic stimulation

The learning/study phase

Expression Phase

the resulting increase of synaptic strength

Testing

Results in receptor trafficking

Excitotoxicity Hypithesis

Too much glut leads to prolonged depolarization which kills cells via necrosis or cell programmed death

mediated by AMPA and Kinate receptors

Necrosis

bursting of the cell due to osmotic swelling as the consequence of prolonged glut receptor activation

Apoptosis

Programmed cell death

involves a cascade of biochemical events that lead to the disruption of cell nucleus, DNA breakup and ultimately cell death'

no lyse (burst), they are cleared away by other cells by phagocytosis

Necroptosis

Programmed cell death

Cell swells and forms protrusions (blebs), breaks up the cytoplasm, and then disintegrates

Domoic Acid

Algal toxin found in contaminated seafood

Ischemic Core

Direct area that is blocked and dies 

Ischemic Penumbra

the larger area of tissue that is effected by the block

Ischemic Glutamate Release

An excess of glutamate is released, and then flows to extrasynaptic NMDA receptors that signal cell death