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Psych 478 > Glutamatergic receptors and systems > Flashcards

Glutamatergic receptors and systems Flashcards

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1
Q

Which metabotropic receptors are members of Group 1?

A

mGluR1, mGluR5

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2
Q

What pathway do Group 1 receptors use?

A
  • Gq → PLC, Ca2+
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3
Q

Where are group 1 receptors found?

A

Post-synaptically

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4
Q

which metabotropoc receptors are part of Group 2?

A

mGluR2, mGluR3

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5
Q

What pathway do Group 2 receptors use?

A
  • Gi → ↓ cAMP
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6
Q

Where are group 2 and 3 receptors found?

A

Pre-synaptically

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7
Q

What are group 2 and 3 receptors’ functions?

A
  • Autoreceptors
  • Modulators on other NT systems
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8
Q

What pathway do Group 3 receptors use?

A
  • Gi → ↓ cAMP
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9
Q

What receptors are part of Group 3?

A

mGluR4, mGluR6, mGluR7, mGluR8

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10
Q

What are common features to all metabotropic glutamatergic receptors?

A
  • Contribute to plasticity of synapses
  • Excitatory or inhibitory depending on signalling, cell types
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11
Q

What is the result of a R1 knockout?

A

motor dysfunction

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12
Q

What are the symptoms of a R1 knockout?

A
  • Ataxia, intention tremor, dysmetria
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13
Q

What area of the brain is impacted by a R1 knockout?

A
  • Cerebellum
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14
Q

What is the result of a R2 knockout?

A

normal synaptic
transmission

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15
Q

What are the symptoms of a R2 knockout?

A

reduced presynaptic inhibition

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16
Q

What area of the brain is impacted by a R2 knockout?

A

Dentate gyrus

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17
Q

What is the result of a R4 knockout?

A

loss of synaptic
efficiency during repetitive activation

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18
Q

What are the symptoms of a R4 knockout?

A
  • maintenance of normal motor function
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19
Q

Where are mGluR generally found?

A

At postsynaptic densities are expressed at the periphery.

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19
Q

What area of the brain is affected by a R4 knockout?

A
  • presynaptic regulation in cerebellum
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20
Q

Where are NMDAR and AMPAR generally found?

A

distributed throughout the PSD.

21
Q

What are NMDA typically found next to?

A

Ca2+-dependent proteins such as CaMKII (Calmodulin-dependent kinase II).

22
Q

Why is the hippocampus important?

A

learning and memory due to the role it plays in LTD and LTP. The variations in synaptic strength produced via these processes is known as synaptic plasticity.

23
Q

What is synaptic plasticity?

A

changes in strength of glutamatergic synapses in response to activity.

24
Q

What is LTP?

A

persistent increase in synaptic
strength following tetanic
activity (100 Hz, 1 s)

25
Q

What is LTD?

A

persistent decrease in
synaptic strength following
slow repetitive activity (1 Hz,
10 min)

26
Q

Describe the hippocampus and plasticity

A
  • Hippocampal plasticity is widely studied due to the role in learning and the well defined circuits (most glutamatergic).
  • Hippocampal slice preparations (ex vivo preparation) leave the PP → DG → CA3 → CA1 circuit intact and accessible.
27
Q

How does LTP occur?

A

Through coincidence detection

28
Q

What does CamKII do?

A
  • Phosphorylates numerous
    cellular targets and initiates
    early-phase of LTP
29
Q

Where is CamKII localized?

A
  • Localizes with NMDA receptors
    (intracellular face)
30
Q

Describe early LTP

A

Ca2+-entry through NMDAR
activates CamKII.

CamKII phorphorylates AMPAR –
increasing their sensitivity to
glutamate.

Signalling cascades increase
trafficking of AMPAR to the
postsynaptic density – increasing
the availability of receptors.

Retrograde messengers signal to
the presynaptic cell initiating
presynaptic changes that increase
glutamate release.

31
Q

Describe late LTP

A
  • Activation of CamKII and PLC converge on another signaling
    kinase, ERK (extracellular-signal regulated kinase)
  • ERK triggers downstream changes including phosphorylation of
    transcription factors
  • Gene synthesis is induced increasing production of AMPA receptors
  • Synthesis processes are important for long-term maintenance of potentiation
32
Q

Describe the link between NMDAR and LTP

A
  • LTP induction depends critically on NDMAR
  • NMDAR overexpression increases learning in mice
  • Mice engineered to overexpress the NR2B subunit
  • Termed Doogie mouse…
  • Increased retention in novel object recognition tasks
33
Q

How is excitotoxicity relevant?

A
  • Glutamate and excitatory analogues
    can be neurotoxic

Agents that can cause lesions: AMPA, kainate, MSG

34
Q

How can glutamatergic agonists cause lesions?

A
  • Occurs through over activation of
    glutamatergic neurons
  • Increased intracellular Ca2+ to dangerous
    levels
35
Q

What are the pathogenic effects of these lesions?

A
  • Contributes to pathogenesis of ischemia,
    ALS, traumatic brain injury, alcoholism,
    Huntington’s disease, multiple sclerosis
36
Q

Describe lytigo-bodig disease

A
  • Lytigo-bodig disease is a
    neurodegenerative disease that
    manifests similar to ALS and
    Parkinson’s
  • Localized in Guam
  • Local cycad seeds (Cyas circinalis)
    contain β-methyl-amino-L-alanine
    (BMAA)
  • Seeds eaten by fruit bats, accumulates
    in fat stores
  • Fruit bats eaten by locals
  • BMAA is a potent excitotoxin at AMPA,
    kainate, and NMDA receptors
37
Q

What leads to the inhibition of EAAT2 on astrocytes?

A

ALS mutation

38
Q

What causes blood flow loss in ischemic stroke?

A

Cause of Loss of Blood Flow:

  • Lack of O2 and glucose causes energy failure
  • Energy-dependent processes fail (e.g. Na+/K+ ATPase)
  • Loss of ionic gradients causes glutamatergic synapses to dump glutamate
  • Increased intracellular Ca2+ (exocytosis)
  • Failure of EAAT transport (depends on ion gradient) reverses glutamate flow
39
Q

Describe necrosis

A
  • Uncontrolled cell death
  • Na+ and Cl- influx to cell causes
    hypertonicity
  • Osmosis causes cell swelling (edema)
  • Swelling leads to rupture of the cell
    membrane and cell lysis
40
Q

Describe apoptosis

A
  • Programmed cell death
  • Ca2+ influx activates intracellular
    pathways
  • Mitochondrial generation of ROS
  • Depolarization and swelling of mitochondria
  • Mitochondrial damage leads to
    formation of pores in mitochondrial membrane
  • Cytochrome C escapes
  • Initiates apoptosis
41
Q

Describe possible treatments for glutamatergic cell death

A
  • NMDA and AMPA receptors are interesting targets for neuroprotective agents in ischemia

Findings from animal research:

  • In animal models, NMDA or AMPA antagonists reduce the volume of injury in ischemic stroke

Issues:

  • Translation to humans is difficult
  • Timing of intervention is challenging
  • Clinical trials for stroke are very difficult due to the acute nature of
    injury
42
Q

What are the characteristics of epilepsy?

A
  • Abnormal excessive or synchronous neuronal activity in the brain
  • Commonly convulsive (60%)
43
Q

Describe onset of epilepsy

A
  • In developed world onset is typically in children
  • Febrile seizures most common seizure disorder in children
  • 25% of those with seizures have an epileptic syndrome
44
Q

Describe the link between epilepsy and glutamatergic signalling

A
  • Epileptic seizures are dependent on glutamatergic signalling
  • Pharmacological activation of glutamatergic signalling can initiate
    seizures in animal models
  • Kainate, AMPA, domoic acid are convulsants
  • Early seizure activity is dependent on AMPA receptor activation
  • Antagonists of AMPAR can prevent seizure onset (e.g. NBQX)
  • As seizures intensify and spread NMDA receptors are involved
  • Antagonists of NMDAR can reduce intensity and duration of seizures (e.g. MK801)
45
Q

What is found in many heritable cases of epilepsy?

A

Glutamatergic changes

  • Heterogeneous – over 200 identified mutations in heritable epilepsy
  • Glutamate receptors
  • AMPA, kainate, and NMDA receptor subunits altered
  • Glutamate transporters
  • EAAT 1 and 2 show alterations in patients
  • Astrocytic glutamate recycling
  • Glutamine synthetase, glutamate dehydrogenase
46
Q

Describe AEDs

A
  • Anticonvulsants/antiepileptic drugs (AEDs) are not tested against placebo for ethical reasons

New AEDs are tested and approved initially as adjunctive therapies with an existing medication

*Targets: Na+ channel activity or increase inhibitory signaling by affecting GABA

47
Q

What are the issues with AEDs?

A
  • 30% of patients are unresponsive to AED therapy
  • AEDs often lose effectiveness over time
48
Q

Describe alternative treatments

A
  • Surgical resection of seizure focus remains a common treatment of drug-resistant
    epilepsy

Hemispherectomy

Function: Seizure focus and damaged tissue removed.

Corpus callosotomy

49
Q

Describe corpus callosotomy

A

Corpus callosotomy is effective at
decreasing the frequency and amplitude of seizures by disrupting bilateral synchronous discharges.

50
Q

Describe side effects of corpus callostomy

A

speech irregularities – inability to
engage in spontaneous speech, inability to follow verbal commands using non-dominant hand, and alien hand syndrome.

Psych 478 (28 decks)

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