chapter 8- glut & GABA

Chapter 8: Glutamate and 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.

Learning Objectives

• 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.

Overview of Glutamate Function

• 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.

Projection Neurons

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

Glutamate Synthesis

• 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.

Distribution of VGLUTs

• 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.

Glutamate Release and Reuptake

• 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.

Ionotropic Glutamate Receptors

• 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 of AMPA and Kainate Receptors

• 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.

NMDA Receptors

• 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.

NMDA Receptors - Pharmacology

• 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.

Biophysical Properties of NMDA vs AMPA Receptors

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

Metabotropic Glutamate Receptors

• 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.

Key Functions of Glutamate - Synaptic Plasticity

• 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.

Long Term Potentiation (LTP)

• 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 and Late Phases of LTP

• 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.

Glutamate Role in Learning and Memory

• 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.

Evidence of Glutamate's Role

• 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.