CH. 8 Glutamate Flashcards
what is glutamates function?
basis of all signalling
projection neurons that use glutamate
cortex pyramidal cells
hippocampus, amygdala, thalamus
other subcortical nuclei
what are the roles glutamate can play?
neurotransmitter
metabolic
how do other neurotransmitters affect glutamate
modulate effects
true or false; some neurons only use ‘classical’ NTs over glutamate
false; glutamate is necessary for signalling
amino acid that glutamate ionizes from
glutamic acid
precursor to glutamate
glutamine
enzyme that synthesizes glutamate from glutamine
glutaminase
how can you tell if glutmate is being used as a transmitter instead of another one of its functions?
glutamate as an NT is transported in vesicles
what are glutmates vesicular transporters called?
VGLUT
what is a good marker for glutamatergic neurons?
VGLUT transporters
what type of VGLUT transporters are there?
VGLUT1
VGLUT2
VLGUT3
what happens when VGLUT knockout occurs? what does this indicate to us?
fatality
necessary for life in all stages
how does glutamate interact with other NTs?
can be a co-transmitter with the ‘primary’ transmitter
what is a way an axon with multiple NTs can organize
separate terminals for separate NTs
name of the transporters that remove glutamate from the synapse after release
EAAT
what does EAAT stand for
Excitatory Amino Acid Transporter
what are the different kinds of reuptake transporters
EAAT1 to EAAT5
where are EAAT1-2 transporters found
astrocyte glia
which glutamate transporters do the most reuptake?
1 and 2 (astorcyte)
where are EAAT3 reuptake transporters found?
postsynapse
what happens to glutamate after astrocyte reuptake?
converted to inactive glutamine
what enzyme converts glutamate to glutamine?
glutamine synthetase
what is a reason glutamate is converted to its inactive form when reuptaken?
any possible leak will only leak inactive glutamine
what happens when glutamate is released in the synapse?
excites
what happens when excitation does not turn off in a neuron
excitoxic effects; kills the neuron
what is a consequence of glutamate’s excitatory effects?
very tightly regulated
what happens with glutamine in the glia
transported back to the presynaptic terminal
can be reactivated here
how can glutamate function as a method in neuroscience studies?
used to make excitotoxic lesions
what kind of receptors does glutamate have?
ionotropic
metobotropic
what are the different kinds of ionotropic glutamate receptors
AMPA
Kainate
NMDA
what is the basis of naming receptors
named after the drug that activated them (agonists)
how are the ionotropic glutamate receptors structured
4 protein subunits
have subsubunits that vary based on function/area
center is ion pore
what do non-NMDA receptors do when activated
depolarizes neuron by allowing entry of NA+
how can non-NMDA receptors sensitivity to glutamate be regulated?
affinity change
removed from membrane
shorter/longer activation period
what causes a non-NMDA receptor to desensitize?
too much stimulation
true or false; sensitization and desensitization occur quickly in neurons like a conveyor belt
true
Kynurgic acid drug function
non-selective/broad spectrum antagonist to AMPA, Kainate, and NMDA receptors
NBQX drug function
competitive antagonist blocks non-NMDA receptors
side effects of high dose NBQX
sedation
reduced locomotion
ataxia
what drug can be used to treat against seizures?
NBQX
what exactly is a seizure
large group of neuronsfiring at the same time instead of in patterns; excitotoxicity occurs
what do NMDA receptor do when activated
allow flow of Na+ and Ca+2 into neuron
what differences does the inflow of Ca+2 in NMDA receptors cause?
greater depolarization
activation of other enzymes leading to longer term changes
what are the coagonists for NMDA receptors
glycine or D-serine
what binding sites can be found on NMDA receptors
glutamate binding site
coagonist binding site
what needs to happen for NMDA receptors to activate
Glutamate binding
coagonist binding
removal of Mg+2 block in pore
what needs to happen to dislodge the Mg+2 block in the NMDA receptor? what does this mean?
membrane depolarization
NMDA is voltage dependent and neuron must already be depoalrized before they activate
what depolarizes NMDA receptors enough for them to activate
multiple AMPA receptor activation
competitive antagonist drug of NMDA receptors
AP-5
what does AP-5 do
blocks glutamate from binding to NMDA receptor
what do non-competitive antagonists do to NMDA receptors
block receptor at a spot other than the glutamate binding area
drugs that block NMDA channel
Phencyclidine (PCP)
ketamine
MK-801
what do non-competitive agonists drugs do at low doses
cause schizophrenia-like symptoms
what do pore plug antaogist drugs do at high doses
cause ataxia and anesthesia
what is a way that a drug can act as a positive allosteric modulator on the NMDA receptor?
increasing affinity or efficacy of the receptor when bound to the coagonist binding site
what are the differences in excitatory effects between AMPA/Kainate and NMDA?
AMPA; high and fast peak activation and degrades quickly
NMDA; shorter peak of activation but longer change in depolarization. alters firing patterns (promotes burst firing)
how are the different effects of ionotropic glutamate receptors measured?
patch clamp recordings of isolated AMPA or NMDA activation
how many metabotropic glutamate receptors are there and what are they called
8, mGluR
where are mGluR 1 and 5 found
postsynapse
where are mGluR 2-4 and 6-8 found?
presynapse
what are the functions of the presynaptic mGluR
surpress glutamate release as autoreceptors or heteroreceptors
L-AP4 drug function
agonist of mGluR 4/6/7/8 autoreceptors
what brain functions do mGluRs participate in
widely distributed
locomotion
motor coordination
cognition
mood and pain perception
what is the most studied function of glutamate receptors
synaptic plasticity for learning/memory
how can we measure alterations in the activity of synapse
measuring changes in synaptic strength
how do we measure synaptic strength
changes in post synaptic potential measured with electrophysiological methods
larger EPSP is higher strength
what does LTP stand for?
long-term potentiation
what is LTP?
model of underlying formation of memory
what are the steps of an experiment that showed LTP? what were the results?
- measure the subthreshold EPSP of a cell with a low frequency stimulation to establish the baseline
- stimulate cell with high frequency
- stimulate with low frequency subthreshold current again
vigourous activation causes baseline EPSP to increase long-term in strength and therefore male it more likely to cause AP
how does LTP work in general on our memories?
initial experience; group of neurons fire in a certain pattern
recalling the experience; group of neurons fire in the same pattern of the original experience
phases of LTP
early phase
late phase
steps of early phase LTP
high frequency activates NMDA receptor and Ca+2 enters post synapse
Ca+2 activates kinases including CaM kinase
what are the results of early phase LTP
CaM kinase takes extra AMPA receptors and puts them in the membrane
other kinases induce formation of retrogade messenger
dendritic spine structure changes to make them more excitable
synaptic strength increases
what does the retrograde messenger do?
sends NO to the pre-synapse that facilitates more NT release
how does CaM change AMPA receptors chemically
adds phosphorous to them which gives them a higher affinity for the membrane
what is the structural change that occurs in the post synapse?
spines get thicker
what happens in late phase LTP?
same as early phase, but synthesizes proteins that make the changes last longer
how does late phase LTP trigger the synthesis of new proteins?
cell nucleus DNA activation is changed to make different proteins
what happens if you block NMDA receptors
cannot do LTP
what happened to rats placed in the MWM that had NMDA receptors blocked
control rats used cues to find platform and got quicker with more trials
NMDA antagonist rats showed no increased efficiency to finding the platform
what happens with glutamate activity increase?
slightly improves learning
what happens if you block AMPA receptors
cells cannot function correctly
what are ampakines? what do they do?
positive allosteric modulators of AMPA receptors
prolong open time and reduce desensitization
what was found in monkey study when using ampakines
higher doses of ampakines improved cognitive task of matching objects
what happens when glutamate activity is highly increased?
excitotoxicity
what is excitotoxicity? what are the different types?
prolonged depolarization of neurons that leads to damage or death
necrosis, apoptosis
what is necrosis?
fast death of cells
what happens during necrosis
ion channels stay activated
too many ions enter the cell
cell swells
death by lysis
what is lysis
bursting of cells due to ruptures in the cell membrane
what is another name for apoptosis?
programmed necrosis
what is apoptosis
slow cell death through biochemical events
what causes apoptosis
long exposure to low concentrations of ions
Ca+ trigger ‘death’ enzymes instead of regular ones when the cell gets too much
what kind of excitotoxicity depends on NMDA receptor activation?
apoptosis
true of false; lysis occurs in necrosis and apoptosis
false; lysis does not occur in apoptosis
what is a natural cause of excitotoxicity
brain ischemia
what is a brain ischemia
interuption of blood flow to the brain because of a stroke/heart attack
why does a brain ischemia cause excitotoxicity
blood cannot reach brain
oxygen is not coming to the brain
K+/ Na+ pump does not function
cell depolarizes
cell cannot reset properly and calcium builds up
calcium build up triggers ‘death’ enzymes
how do NMDA antagonists work against brain ischemia effects?
they don’t
if already in apoxic state, killer enzymes have already been triggered and will continue to kill cells days afterwards
why is it not plausible to administer drugs that will deactivate killer enzymes
they may have affinity for other enzymes necessary for proper function
