Topic 11: Glutamate Receptors

Question 1

What are group 1 metabotropic glutamate receptors?

Answer 1

mGluR1, mGluR5

Gq –> PLC, calcium

Question 2

What are group 2 metabotropic glutamate receptors?

Answer 2

mGluR2, mGluR3

Gi –> decreased cAMP

Question 3

What are group 3 metabotropic glutamate receptors?

Answer 3

mGluR4, mGluR6, mGluR7, mGluR8

Gi –> decreased cAMP

Question 4

What are the characteristics of metabotropic glutamate receptors?

Answer 4

group 1 mGluR found mostly post-synoptically

group 2 and 3 are often found pre-synoptically: autoreceptors, modulators on other NT systems

contribute to plasticity of synapses

excitatory or inhibitory depending on siganalling, cell types

Question 5

What are the results of mGluR1 knockout studies?

Answer 5

show motor dysfunction

ataxia, intention tremor, dysmetria

impaired plasticity in the cerebellum

Question 6

What are the results of mGluR2 knockout studies?

Answer 6

show normal synaptic transmission

highly expressed in dentate gyrus

KO shows reduced presynaptic inhibition

Question 7

What are the results of mGluR4 knockout studies?

Answer 7

show loss of synaptic efficiency during repetitive activation

presynaptic regulation in cerebellum

maintenance of normal motor function

Question 8

What is glutamate receptor distribution?

Answer 8

at postsynaptic densities mGluR are expressed at the periphery

AMPAR and NMDAR are distributed throughout the PSD

NMDAR are tightly coupled to calcium-dependent proteins such as CaMKII (Calmodulin-dependent kinase II)

Question 9

What is synaptic plasiticity?

Answer 9

changes in strength of glutamatergic synapses in response to activity

Question 10

What is long-term potentiation (LTP)?

Answer 10

persistent increase in synaptic strength following tetanic activity

100 Hz, 1 second

Question 11

What is long term depression (LTD)?

Answer 11

persistent decrease in synaptic strength following slow repetitive activity

1 Hz, 10 minutes

Question 12

What is plasticity in the hippocampus?

Answer 12

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 13

What is CaMKII?

Answer 13

CaMKII is coupled to NMDAR

calcium-calmodulin dependent protein kinase II (CaMKII)

localizes with NMDA receptors (intracellular face)

phosphorylates numerous cellular targets and initiates early-phase of LTP

Question 14

What is early long term potentiation?

Answer 14

calcium-entry through NMDAR activates CamKII

CamKII phosphorylates AMPAR - increasing their sensitivity to glutamate

signaling 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 15

What is late-phase long term potentiation?

Answer 15

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 16

How are the NMDA receptors involved in long term potentiation?

Answer 16

LTP induction depends critically on NDMAR

NMDAR overexpression increases learning in mice

mice engineered to overexpress the NR2B subunit

increased retention in novel object recognition tasks

Question 17

What is the excitotoxicity of glutamate?

Answer 17

glutamate and excitatory analogues can be neurotoxic

MSG can induce lesions

occurs through over activation of glutamatergic neurons

increased intracellular calcium to dangerous levels

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

Question 18

What is Lytigo-bodig disease?

Answer 18

a neurodegenerative disease that manifests similar to ALS and Parkinson’s

localized in Guam

local cycad seeds contain beta-methyl-amino-L-alanine (BMAA)

seeds eaten by fruit bats, accumulates in fat stores, fruit bats eaten by locals

BMAA potent excitotoxin at AMPA, kainate, and NMDA receptors

Question 19

How does EAAT2 dysfunction lead to excitotoxicity?

Answer 19

a mutation found in ALS patients leads to increased intracellular calcium in motor neurons, which stresses mitochondria

mitochondria produce reactive oxygen species (ROS) that are toxic and also inhibit EAAT2 on astrocytes

EAAT2 dysfunction leads to glutamate accumulation and excitotoxicity in motor neurons

Question 20

How does ischemia lead to excitotoxicity?

Answer 20

ischemic stroke results in loss of blood flow to regions of the CNS

lack of oxygen 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 21

What is necrosis?

Answer 21

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 22

What is apoptosis?

Answer 22

programmed cell death

calcium influx activities 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 23

What is cell death?

Answer 23

two modes of cell death are initiated by ischemic/glutamatergic injury

apoptosis is regulated cell death and results in controlled removal of cell material by phagocytic cells

necrosis results in cell lysis and release of cellular contents

Question 24

What is glutamatergic cell death?

Answer 24

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

in animal models, NMDA or AMPA antagonists reduce the volume of injury in ischemic stroke: 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 25

How does glutamate lead to excitotoxicity?

Answer 25

glutamate can cause over-excitation leading to cell death by necrosis or apoptosis

Question 26

What is epilepsy?

Answer 26

heterogeneous group of neurological disorders characterized by epileptic seizures

abnormal excessive or synchronous neuronal activity in the brain

commonly convulsive (60%)

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 27

How are epileptic seizures are dependent on glutamatergic signaling?

Answer 27

pharmacological activation of glutamatergic signaling can initiate seizures in animal models: kainate, AMPA, domoic acid are convulsants

early seizure activity is dependent on AMPA receptor activation: antagonist 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 28

What are the genetic causes of epilepsy?

Answer 28

glutamatergic changes are found in many heritable cases of epilepsy

heterogenous - over 200 identified mutations in heritable epilepsy

glutamate receptors: AMPA, kainate, and NMDA receptor subunits altered

glutamate transporters: EAAT1 and 2 show alterations in patients

astrocytic glutamate recycling: glutamine synthetase, glutamate dehydrogenase

Question 29

What is epilepsy treatment?

Answer 29

anticonvulsants/antiepileptic drugs (AEDs) are one of the few drug classes that is not tested against placebo: for ethical reasons new AEDs are tested and approved initially as adjunctive therapies with an existing medication

AEDs typically target Na+ channel activity or increase inhibitory signaling by affecting GABA

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

surgical resection of seizure focus remains a common treatment of drug-resistant epilepsy

Question 30

What is a corpus callostomy?

Answer 30

is another common technique used to treat epilepsy

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

side effects include speech irregularities - inability to engage in spontaneous speech, inability to follow verbal commands using non-dominant hand, and alien hand syndrome