chapter 8- glut & GABA

Glutamate Overview
- A key neurotransmitter in the brain, functioning in synaptic transmission and plasticity.
- Importance: Major excitatory neurotransmitter, central to learning and memory processes.

Understand the synthesis, transport, and metabolism of glutamate.
Know the different subtypes of glutamate receptors and their effects on neural activity.
Learn the pharmacology and mechanisms of action of glutamate-related drugs.
Understand key functions mediated by glutamate, particularly synaptic plasticity and learning/memory.

Glutamate provides a rapid excitatory signal to neurons, modified by classical neurotransmitters influencing its excitatory effects.
Glutamate is the ionized form of glutamic acid, existing in various metabolic roles aside from neurotransmission.
Difficult to assign specific functional roles due to presence throughout brain functions.

Major types using glutamate include:
- All pyramidal cells in the cerebral cortex.
- Projection neurons in the hippocampus, amygdala, thalamus, and other subcortical nuclei.

Synthesized from glutamine by the enzyme glutaminase.
Vesicular Transporters: Three isoforms (VGLUT1-VGLUT3) transport glutamate into synaptic vesicles exclusively in glutamatergic neurons.
- VGLUT transporters are critical markers indicating glutamate utilization.
- Knockout mutations of these transporters are generally fatal.

Mapping in rat brain shows VGLUTs can exist alongside other neurotransmitter markers indicating co-transmitter capabilities.
Varying synapse appearances can resemble either monoamine or glutamate synapses.

Majority of glutamate uptake occurs via astrocytes which convert glutamate into glutamine using glutamine synthetase to prevent excessive excitation.
Excitatory Amino Acid Transporters (EAAT1 - EAAT5) responsible for reuptake from synapse, with 90% of uptake by EAAT1-2 located on astrocyte glia and EAAT3 on postsynaptic membranes.
The partnership in glutamate metabolism is crucial between glia and neurons.

Types:
- AMPA: Agonist α-Amino-3-hydroxy-5-Methyl-4-isoxazolePropionic Acid.
- Kainate: Agonist kainic acid.
- NMDA: Agonist N-Methyl-D-Aspartate.
Structure: Composed of four subunit proteins with variations leading to additional subtypes influencing pharmacology.

Activation permits Na+ entry leading to neuron depolarization.
- Constant activation occurs with sufficient glutamate stimulation; high stimulation levels can cause receptor desensitization.
Pharmacology:
- NBQX: A competitive antagonist blocks AMPA and Kainate receptors but not NMDA.
- High doses of these antagonists lead to sedation, reduced locomotion, ataxia, and seizure protection.

Unique characteristics include allowing flow of both Na+ and Ca2+, causing greater depolarization compared to AMPA/Kainate.
Dual binding required for activation: glutamate and co-agonists (glycine or D-serine).
- Mg2+ ions block the channel at rest and dissociate upon depolarization (voltage-dependent block).
NMDA receptor activation can be set up through preceding AMPA receptor stimulation leading to depolarization.

Antagonists:
- Competitive: Block glutamate binding (e.g., AP-5 or APV).
- Non-competitive: Block the receptor independently of glutamate binding (e.g., PCP, ketamine).
Glycine-binding Site: Some drugs block this site, acting as non-competitive antagonists; agonists enhance NMDA receptor activity.

NMDA induces larger and longer-lasting depolarizations compared to AMPA as shown in studies.
NMDA receptor activity influences neuron firing patterns.

Eight metabotropic receptors (mGluR 1-8) operate through G-proteins and second messenger systems.
Localization: mGluR-1 and mGluR-5 are typically postsynaptic; others are primarily presynaptic.
- Presynaptic mGluRs can act as autoreceptors/heteroreceptors, suppressing the release of glutamate or other neurotransmitters (e.g., L-AP4 suppresses glutamate release).
mGluRs play roles in various functions (e.g., locomotion, motor, coordination, cognition, mood, and pain perception) and are targets for drugs in neuropsychiatric disorders.

Synaptic strength alterations are essential for learning, typically assessed through changes in postsynaptic potential (larger EPSP indicating increased strength).
Glutamate receptors significantly contribute to synaptic plasticity and memory formation.

Procedure:
- Step 1: Low-frequency presynaptic stimulation creates a baseline EPSP without action potentials.
- Step 2: High-frequency stimulation (tetanic) induces strong action potential firing in postsynaptic neurons.
- Step 3: Return to low-frequency stimulation yields a significantly enhanced EPSP, indicating a potentiated input.
- Potential duration: Changes can last from days to years.

Early Phase: Involves NMDA receptor activation and Ca2+ entry, activating kinases (e.g., Calcium-Calmodulin Kinase) which enhance synaptic strength through insertion of AMPA receptors and retrograde messages like nitric oxide.
Late Phase: New protein synthesis is necessary for maintaining long-term changes in synaptic strength.

NMDA receptor blockade impairs learning in various systems (e.g., hippocampus involvement in tasks like the Morris Water Maze).
NMDA antagonists often correlate with impaired LTP formation; blocking NMDA during high-frequency activation prevents LTP establishment.

Tasks reliant on spatial navigation (like the Morris Water Maze) show NMDA antagonists severely impair learning efficiency.
Enhancements in glutamatergic activity (e.g., usando Ampakines, which prolong AMPA receptor activity) can further improve cognition in healthy and cognitively impaired animal models.