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Chapter 7: Glutamate and GABA

Chapter 7: Glutamate and GABA. Glutamate An amino acid Used throughout the body Building proteins Helps with energy metabolism Also serve as NTs excitatory. synthesis. Glutamine can be converted to glutamate via the enzyme glutaminase. Vesicular glutamate transporter.

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Chapter 7: Glutamate and GABA

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  1. Chapter 7: Glutamate and GABA • Glutamate • An amino acid • Used throughout the body • Building proteins • Helps with energy metabolism • Also serve as NTs • excitatory

  2. synthesis • Glutamine can be converted to glutamate via the enzyme glutaminase

  3. Vesicular glutamate transporter • VGLUT1, VGLUT2, and VGLUT3 • Package glutamate into vesicles • Different parts of the brain use different VGLUTs • Not really known why

  4. Reuptake • Excitatory amino acid transporter (EAAT1-EAAT5) • EAAT3 is main neuronal transporter • EAAT1 and EAAT2 are actually found on astrocytes • This relationship may occur because extracellular glutamate is dangerous • Spreading ischemia

  5. 7.3 Cycling of glutamate and glutamine between glutamatergic neurons and astrocytes • Astrocytes breakdown glutamate • Into glutamine • via the enzyme glutamine synthetase • Then the astrocytes release the glutamine so it can be picked up by neurons and converted back to glutamate • This complex system may help prevent the toxicity of extracellular glutamate

  6. Glutamate is the workhorse transmitter for excitatory signaling in the nervous system • Glutamate is found throughout the brain, so we won’t have specific pathways for this neurotransmitter • Involved in many behavioral and physiological functions, but perhaps the most important is synaptic plasticity • Changes in the strength of connections • Learning and memory

  7. Receptors • Ionotropic glutamate receptors • 3 subtypes • AMPA • Named for the drug AMPA (a selective agonist of this receptor) • Most fast excitatory responses to glutamate occur through this receptor • Kainate • Named for the drug Kainic acid (a selective agonist) • NMDA • Named for N-methyl-D-aspartate (NMDA; selective agonist)

  8. The AMPA and Kainate receptors mediate the flow of Na+ • Excitatory post synaptic potentials • NMDA receptors mediates Na+, but also Ca++ • CA++ works as a second messenger • Thus, NMDA receptors can directly activate a second messenger system

  9. 7.4 All ionotropic glutamate receptor channels conduct Na+ ions into the cell

  10. NMDA receptors • NMDA receptors require two different neurotransmitters to open the channel • 1) Glutamate • 2) Glycine or D-serine • Glycine (or D-serine) has its own binding site. • Thus glycine (or D-serine) is considered to be a co-agonist. • Usually the co-agonist binding site is occupied though, so the presence or absence of glutamate determines channel opening

  11. NMDA receptor • There are two other binding sites on NMDA receptors that affect their function • Both of these receptor locations are inside the channel • Magnesium receptor • Mg++ • Phencyclidine receptor • PCP

  12. Mg++ • When the cell membrane is at resting potential (-60 or -70 mv). • Mg++ binds to its location within the channel. • Thus, even if glutamate (and glycine or D-serine) bind to the receptor the ions cannot flow.

  13. However, if the membrane becomes somewhat depolarized the Mg++ will leave its binding site and exit the channel. • Now the channel will allow the flow of ions if glutamate and the co-agonist are present.

  14. NMDA receptor (coincidence detector) • Thus, the NMDA channel will open only if other receptors are active simultaneously • Two events must occur close together in time. • So channel will only open if • 1) glutamate is released onto NMDA receptor • 2) the cell membrane is depolarized by a different excitatory receptor.

  15. PCP • This receptor recognizes • Phencyclidine (PCP) • Ketamine (Special K) • MK-801 (dizocilpine; a research drug) • Most of the behavioral effects of PCP and Ketamine are the result of antagonizing the NMDA receptor

  16. NMDA receptors and learning and memory • Classical conditioning is based on the close timing of two events • Bell  Food • The NMDA receptor may be a biochemical mechanism that allows for these kinds of associations. • NMDA antagonism impairs learning and memory • The hippocampus has a high density of NMDA receptors • NMDA receptors are critically involved in synaptic plasticity • Long-term potentiation (LTP)

  17. LTP • LTP is a persistent (at least 1 hour) increase in synaptic strength. • Produced by a burst of activity from the presynaptic neuron

  18. LTP studies • Get a slice from the rat hippocampus and keep alive in Petri dish. • It is common to stimulate CA3 region which synapses with cells in CA1 • 100 stimulations in 1 second • Tetanic stimulation (tetanus) • Measure response of CA1 neurons • You can produce similar effects in other parts of the pathway, however.

  19. Box 7.1 Role of Glutamate Receptors in Long-Term Potentiation (Part 4)

  20. Synaptic activity at test pulse • Test pulse elicits release of a small amount glutamate from CA3 axons onto CA1 • Glutamate binds to AMPA receptors and NMDA receptors • Channel does not open because membrane not depolarized enough to dislodge Mg++

  21. Synaptic activity during tetanus • More glutamate is released • Prolonged activation of AMPA • Depolarization dissociates Mg++ • NMDA channel opens • Na+ enters • More importantly Ca++ enters

  22. Ca++ Works as a second messenger • Increases the sensitivity of receptors to glutamate • Inserts more AMPA receptors into the membrane. • May also produce presynaptic changes that increase glutamate release from terminal button • Retrograde messenger • Nitric oxide? • These effects increase the strength of the synapse

  23. Doogie mouse • Genetically engineered to have a more efficient NMDA receptor. • Also may have more NMDA receptors than normal mice • Show enhanced LTP • Show improved learning and memory • Enhanced fear conditioning • Learn Morris water maze more quickly

  24. Object recognition • Novel-object-recognition • Explore 2 objects for 5 minutes • Wait 1hour, 1 day, 3 days, or 1 week • Present 2 objects 1 novel and 1 familiar • Animals tend to prefer to examine the novel object • Can only have this preference if they remember

  25. 7.8 Enhanced memory shown by Doogie mice in the novel-object-recognition task

  26. Metabotropic glutamate receptors • mGluR1-mGluR8 • Some serve as autoreceptors • mGluR1 has been implicated in movement • Knockout mice • No mGluR1 – inactivity • MGluR1 only in cerebellum • Normal movement • Implies mGluR1 in cerebellum is required for normal movement

  27. High levels of glutamate can be toxic • Injection of monosodium glutamate (MSG) caused retinal damage in mice • Lucas and Newhouse (1957) • Olney (1969) showed MSG causes brain damage in young mice • Now known that glutamate causes lesions in any brain area when injected directly into that area. Young or old

  28. Excitotoxicity hypothesis • Excitotoxicity hypothesis • The damage produced by exposure to glutamate is caused by a prolonged depolarization of receptive neurons • Studied in cultured nerve cells • Strong activation of NMDA receptors most readily causes cell death • Though AMPA and Kainate activation can also cause cell death • If both NMDA and non NMDA receptors are activated by substantial amounts of glutamate there is a large percentage of cell death in a few hours.

  29. Necrosis vs Apoptosis • When many cells die in a few hours this is called necrosis • Cells burst (called lysis) due to swelling • However, there can also be delayed responses that can continue for hours after initial exposure • Apoptosis (programmed cell death). • No lysis • Do not spill contents into extracellular space.

  30. Apoptosis occurs normally during development • Selective pruning • Can also be elicited by ingesting toxins • Domoic acid • Excitatory amino acid contained in marine algae. • When marine animals eat this algae they concentrate the toxin • If consumed by humans can lead to neurological problems • Headache • Dizziness • Muscle weakness • Mental confusion • Loss of short-term memory • Regulated for humans, but can affect other wild life • Dolphins • Sea birds

  31. Ischemia • Ischemia occurs whent there is disruption of blood flow to brain (or part of the brain). • Massive release of glutamate in affected area • Prolonged NMDA receptor activation • In animal studies treatment with NMDA antagonists reduces damage • Clinical studies with humans not so successful • Some researchers are considering drugs that block the co-agonist location • Glycine blockers • Fewer side effects (than drugs like PCP)

  32. y-aminobutyric acid (GABA) = gamma-aminobutyric acid • Synthesis • Precursor • Glutamate • Enzyme • Glutamic acid decarboxylase (GAD)

  33. Drugs that block GABA synthesis • Reduce GABA levels • Cause convulsions • Provides evidence that inhibitory effects of GABA are important in controlling brain excitability

  34. Transporters • Vesicular GABA transporter (VGAT) • Puts GABA into synaptic vesicles • GABA transporters • GAT-1, GAT-2, and GAT-3 • GAT-1 primary neuronal GABA transporter • Drugs that block GABA transporters • Prevent seizures • GAT-1 blocker is most studied • tiagabine (Gabatril) • Used as a treatment for epilepsy

  35. Breakdown of GABA • GABA aminotransferase (GABA-T) • Converts GABA into • Glutamate • Succinate • In astrocytes • Glutamate is converted to glutamine • By glutamine synthetase • Then released to be recycled by cells just like for Glutamate cells • Drugs that block GABA-T • Used as anticonvulsants

  36. GABA receptors • Only two • GABAA (ionotropic) • GABAB (metabotropic) • GABAA is the receptor that is relevant to us

  37. GABAA • GABAA controls a chloride channel • Notice that there are additional binding sites • Picrotoxin (antagonist) • Blocks the channel if occupied • Causes convulsions • Synthetic versions used to be used to induce convulsions to treat depression

  38. GABAA • Benzodiazepines • valium • Barbiturates • These drugs enhance the effectiveness of GABA. • Open the Cl- channel more effectively. • Alcohol works similarly at the GABA channel • These drugs tend to reduce anxiety • anxiolytic

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