Glutamatergic receptors and systems

Question 1

Which metabotropic receptors are members of Group 1?

Answer 1

mGluR1, mGluR5

Question 2

What pathway do Group 1 receptors use?

Answer 2

• Gq → PLC, Ca2+

Question 3

Where are group 1 receptors found?

Answer 3

Post-synaptically

Question 4

which metabotropoc receptors are part of Group 2?

Answer 4

mGluR2, mGluR3

Question 5

What pathway do Group 2 receptors use?

Answer 5

• Gi → ↓ cAMP

Question 6

Where are group 2 and 3 receptors found?

Answer 6

Pre-synaptically

Question 7

What are group 2 and 3 receptors’ functions?

Answer 7

• Autoreceptors
• Modulators on other NT systems

Question 8

What pathway do Group 3 receptors use?

Answer 8

• Gi → ↓ cAMP

Question 9

What receptors are part of Group 3?

Answer 9

mGluR4, mGluR6, mGluR7, mGluR8

Question 10

What are common features to all metabotropic glutamatergic receptors?

Answer 10

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

Question 11

What is the result of a R1 knockout?

Answer 11

motor dysfunction

Question 12

What are the symptoms of a R1 knockout?

Answer 12

• Ataxia, intention tremor, dysmetria

Question 13

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

Answer 13

• Cerebellum

Question 14

What is the result of a R2 knockout?

Answer 14

normal synaptic
transmission

Question 15

What are the symptoms of a R2 knockout?

Answer 15

reduced presynaptic inhibition

Question 16

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

Answer 16

Dentate gyrus

Question 17

What is the result of a R4 knockout?

Answer 17

loss of synaptic
efficiency during repetitive activation

Question 18

What are the symptoms of a R4 knockout?

Answer 18

• maintenance of normal motor function

Question 19

Where are mGluR generally found?

Answer 19

At postsynaptic densities are expressed at the periphery.

Question 19

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

Answer 19

• presynaptic regulation in cerebellum

Question 20

Where are NMDAR and AMPAR generally found?

Answer 20

distributed throughout the PSD.

Question 21

What are NMDA typically found next to?

Answer 21

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

Question 22

Why is the hippocampus important?

Answer 22

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.

Question 23

What is synaptic plasticity?

Answer 23

changes in strength of glutamatergic synapses in response to activity.

Question 24

What is LTP?

Answer 24

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

Question 25

What is LTD?

Answer 25

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

Question 26

Describe the hippocampus and plasticity

Answer 26

* 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.

Question 27

How does LTP occur?

Answer 27

Through coincidence detection

Question 28

What does CamKII do?

Answer 28

* Phosphorylates numerous cellular targets and initiates early-phase of LTP

Question 29

Where is CamKII localized?

Answer 29

* Localizes with NMDA receptors (intracellular face)

Question 30

Describe early LTP

Answer 30

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.

Question 31

Describe late LTP

Answer 31

* 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

Question 32

Describe the link between NMDAR and LTP

Answer 32

* 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

Question 33

How is excitotoxicity relevant?

Answer 33

* Glutamate and excitatory analogues can be neurotoxic Agents that can cause lesions: AMPA, kainate, MSG

Question 34

How can glutamatergic agonists cause lesions?

Answer 34

* Occurs through over activation of glutamatergic neurons * Increased intracellular Ca2+ to dangerous levels

Question 35

What are the pathogenic effects of these lesions?

Answer 35

* Contributes to pathogenesis of ischemia, ALS, traumatic brain injury, alcoholism, Huntington’s disease, multiple sclerosis

Question 36

Describe lytigo-bodig disease

Answer 36

* 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

Question 37

What leads to the inhibition of EAAT2 on astrocytes?

Answer 37

ALS mutation

Question 38

What causes blood flow loss in ischemic stroke?

Answer 38

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

Question 39

Describe necrosis

Answer 39

* 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

Question 40

Describe apoptosis

Answer 40

* 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

Question 41

Describe possible treatments for glutamatergic cell death

Answer 41

* 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

Question 42

What are the characteristics of epilepsy?

Answer 42

* Abnormal excessive or synchronous neuronal activity in the brain * Commonly convulsive (60%)

Question 43

Describe onset of epilepsy

Answer 43

* 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

Question 44

Describe the link between epilepsy and glutamatergic signalling

Answer 44

* 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)

Question 45

What is found in many heritable cases of epilepsy?

Answer 45

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

Question 46

Describe AEDs

Answer 46

* 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

Question 47

What are the issues with AEDs?

Answer 47

* 30% of patients are unresponsive to AED therapy * AEDs often lose effectiveness over time

Question 48

Describe alternative treatments

Answer 48

* Surgical resection of seizure focus remains a common treatment of drug-resistant epilepsy Hemispherectomy Function: Seizure focus and damaged tissue removed. Corpus callosotomy

Question 49

Describe corpus callosotomy

Answer 49

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

Question 50

Describe side effects of corpus callostomy

Answer 50

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