Glutamatergic receptors and systems Flashcards
Which metabotropic receptors are members of Group 1?
mGluR1, mGluR5
What pathway do Group 1 receptors use?
- Gq → PLC, Ca2+
Where are group 1 receptors found?
Post-synaptically
which metabotropoc receptors are part of Group 2?
mGluR2, mGluR3
What pathway do Group 2 receptors use?
- Gi → ↓ cAMP
Where are group 2 and 3 receptors found?
Pre-synaptically
What are group 2 and 3 receptors’ functions?
- Autoreceptors
- Modulators on other NT systems
What pathway do Group 3 receptors use?
- Gi → ↓ cAMP
What receptors are part of Group 3?
mGluR4, mGluR6, mGluR7, mGluR8
What are common features to all metabotropic glutamatergic receptors?
- Contribute to plasticity of synapses
- Excitatory or inhibitory depending on signalling, cell types
What is the result of a R1 knockout?
motor dysfunction
What are the symptoms of a R1 knockout?
- Ataxia, intention tremor, dysmetria
What area of the brain is impacted by a R1 knockout?
- Cerebellum
What is the result of a R2 knockout?
normal synaptic
transmission
What are the symptoms of a R2 knockout?
reduced presynaptic inhibition
What area of the brain is impacted by a R2 knockout?
Dentate gyrus
What is the result of a R4 knockout?
loss of synaptic
efficiency during repetitive activation
What are the symptoms of a R4 knockout?
- maintenance of normal motor function
Where are mGluR generally found?
At postsynaptic densities are expressed at the periphery.
What area of the brain is affected by a R4 knockout?
- presynaptic regulation in cerebellum
Where are NMDAR and AMPAR generally found?
distributed throughout the PSD.
What are NMDA typically found next to?
Ca2+-dependent proteins such as CaMKII (Calmodulin-dependent kinase II).
Why is the hippocampus important?
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.
What is synaptic plasticity?
changes in strength of glutamatergic synapses in response to activity.
What is LTP?
persistent increase in synaptic
strength following tetanic
activity (100 Hz, 1 s)
What is LTD?
persistent decrease in
synaptic strength following
slow repetitive activity (1 Hz,
10 min)
Describe the hippocampus and plasticity
- 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.
How does LTP occur?
Through coincidence detection
What does CamKII do?
- Phosphorylates numerous
cellular targets and initiates
early-phase of LTP
Where is CamKII localized?
- Localizes with NMDA receptors
(intracellular face)
Describe early LTP
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.
Describe late LTP
- 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
Describe the link between NMDAR and LTP
- 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
How is excitotoxicity relevant?
- Glutamate and excitatory analogues
can be neurotoxic
Agents that can cause lesions: AMPA, kainate, MSG
How can glutamatergic agonists cause lesions?
- Occurs through over activation of
glutamatergic neurons - Increased intracellular Ca2+ to dangerous
levels
What are the pathogenic effects of these lesions?
- Contributes to pathogenesis of ischemia,
ALS, traumatic brain injury, alcoholism,
Huntington’s disease, multiple sclerosis
Describe lytigo-bodig disease
- 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
What leads to the inhibition of EAAT2 on astrocytes?
ALS mutation
What causes blood flow loss in ischemic stroke?
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
Describe necrosis
- 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
Describe apoptosis
- 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
Describe possible treatments for glutamatergic cell death
- 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
What are the characteristics of epilepsy?
- Abnormal excessive or synchronous neuronal activity in the brain
- Commonly convulsive (60%)
Describe onset of epilepsy
- 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
Describe the link between epilepsy and glutamatergic signalling
- 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)
What is found in many heritable cases of epilepsy?
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
Describe AEDs
- 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
What are the issues with AEDs?
- 30% of patients are unresponsive to AED therapy
- AEDs often lose effectiveness over time
Describe alternative treatments
- Surgical resection of seizure focus remains a common treatment of drug-resistant
epilepsy
Hemispherectomy
Function: Seizure focus and damaged tissue removed.
Corpus callosotomy
Describe corpus callosotomy
Corpus callosotomy is effective at
decreasing the frequency and amplitude of seizures by disrupting bilateral synchronous discharges.
Describe side effects of corpus callostomy
speech irregularities – inability to
engage in spontaneous speech, inability to follow verbal commands using non-dominant hand, and alien hand syndrome.
