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Fundamental Neuroscience > Glutamate and GABA > Flashcards

Glutamate and GABA Flashcards

1
Q

What is glutamate?

(5 marks)

A
  • NOT a neurotransmitter
  • Ionised form of glutamic acid
  • Most abundant AA in the brain
  • Excitatory AA NT and binds to NMDA-R
  • Used by glutamatergic neurons as a transmitter
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2
Q

How is glutamate synthesised?

A

From glutamine by glutaminase and requires energy for ATP

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3
Q

What are the different vesicular glutamate transporters?

(3 marks)

A
  • VGLUT1
  • VGLUT2
  • VGLUT3
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4
Q

Where are VGLUT transporters found?

A

In glutamatergic neurons

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5
Q

Where is VLGUT1, VGLUT2 and VGLUT3 expressed in a rat brain?

(3 marks)

A

VGLUT 1: cortex and hippocampus

VGLUT 2: subcortical structures

VGLUT 3: cortex and hippocampus but less abundant than 1 and 2

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6
Q

What happens in VGLUT2 KO mice?

A
  • Die immediately after birth - shows VGLUT 2 needed for life sustaining functions
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7
Q

What happens in VGLUT 1 KO mice?

A

Survive birthbut begin to die in 3rd week of life

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8
Q

What happens in VGLUT 3 KO mice?

A

Mice viable but completely deaf - inner hair cells of cochlear use glutamate as NT - hairs are still sitmulated but have no glutamate to transfer signal

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9
Q

What does co-expression suggest about glutamate and other NT?

(3 marks)

A
  • One type of vesicle that takes up and releases glutamate
  • Other type of vesicle that takes up and releases other transmitter synthesised by that neuron
  • Shows glutamate also stored and releases as a co-transmitter
  • E.g. DA - glutamate; co-expressing neurons of VTA
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10
Q

What other vesicles are the VGLUT’s co-expressed with and where are they located?

(3 marks)

A
  • VGLUT3 - VMAT2 & VGLUT2 - VMAT2: in DA and 5-HT neurons
  • VLGUT3 - VIAAT: in GABA and glycine neurons
  • VLGUT3 - VAChT: in cholinergic neurons
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11
Q

What happens in glutamate release?

(5 marks)

A
  1. Released into synaptic cleft then rapidly removed by glutamine transporters to cell membrane
  2. Excitatory Amino Acid transporters (EAAT 1-5): take up both glutamate and aspartate
  3. Glutamate can be transported back to nerve terminal by EAAT3 and can be used to reload vesicel by VGLUT or into astrocytes by EAAT1 or EAAT2
  4. Astrocytes then convert glutamine by glutamine synthetase
  5. Glutamate then transported out of astrocytes back to neurons, and converted to glutamate by glutaminase
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12
Q

What does EAAT1 do?

A

Expressed in glial cells of cerebellum and important for normal cerebellar function

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13
Q

What does EAAT2 do?

(2 marks)

A
  • Expressed in astrocytes throughout brain
  • Critical role in taking up glutamate after release (90% of uptake)
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14
Q

What is the danger in having high levels of glutamte in extracellular fluid?

A

It can become cytotoxic, and may produce excessive neuronal excitation and even cell death

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15
Q

What phenotypes are seen in EAAT2 KO mice?

(3 marks)

A

Spontaneous epileptic seizures

More susepctible to experimentally induced seizures

Brain injury and a shortened life span

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16
Q

What is EAAT3 do?

A

Main glutamate transporter throughout the brain

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17
Q

What does EAAT4 do?

A

Mainly expressed by purkinje cells in the cerebellum

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18
Q

Where is EAAT5 located?

hint: i

A

In several types of retina

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19
Q

What happens if you have reduced glutamine synthase?

(3 marks)

its not acc that deep^^ like the answer is not that detailed

A

Brain deformation, seizures and short life span

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20
Q

What is the organisation of the glutamateric system and its physiological functions?

(7 marks)

A
  • Glutamte main NT used by pyramidal neurons in the cortex
  • Found in many excitatory pathways in hippocampus
  • Involved in many different behavioural and physiological functions:
    • synaptic plasticity
    • learning and memory
    • Cell death in some neruonal disorders
    • Development of different psychological disorders
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21
Q

What are the different receptors that glutamate binds to?

(4 marks)

A

Ionotropic ones (fast signalling):

  • AMPA receptors
  • Kainate receptor
  • NMDA recepror

Metabottropic ones use secondary messengers so have slow signalling

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22
Q

What are ionotropic glutamate receptors depolarised by?

(4 marks)

A
  • Depolarise post synaptic membrane creating an excitatory response
  • AMPA and kainate receptors - depolarised by Na+ flow
  • NMDA receptors depolarised by both Ca2+ & Na+
  • Made of 4 subunits but 3 receptor subtypes have different subunits resulting in different phsyiological function
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23
Q

What happens when rats/mice are treated with NBXQ?

(7 marks)

A
  • AMPA and kainate antagonists
  • Blocks AMPA nd Kainate receptors
  • Animals exhibit:
    • sedation
    • reduced locomotor activity
    • ataxia
    • protection against seizures
24
Q

What is seen in high doses of NBXQ in humans?

(2 marks)

A
  • Poor performance in retard task
  • Protection agaisnt electrically or chemical induced seizures
25
Q

Why does NMDA receptor have to be depolarised despite having glutamate bound to it for the channel to open?

(2 marks)

A
  • Mg2+ is also bound to NMDA and blocks it
  • For block to be removed it has to be depolarised
26
Q

What needs to bind at the same time to opne the NMDA receptor channel?

(2 marks)

A
  • Glutamate and glycine or Dserine
  • Co-agonist binding site is occupied most of the time so its the presence of glutamate that is the more important factor in determining channel opening
27
Q

What drugs are recognised by another binding site and block the NMDA receptor?

(3 marks)

A
  • PCP
  • Ketamine
  • MK-801
28
Q

What are the metabotropic receptors of glutamate and what do they do?

(3 marks)

A
  • mGluR1 to mGluR8
  • Couple to G proteins and inhibit cAMP formation
  • Others activate phosphoinsitide second messenger system (mGluR1 & 5)
  • On nerve terminals some act as presynaptic autoreceptors to inhibit glutamate release
29
Q

What does L-AP4 (L-2-amino-4-phosphonobutyrate) do?

A

Selective agonist for glutamate autoreceptors and suppresses glutamatergic synaptic transmission

30
Q

What do metabotropic receptors do throughout the brain?

(5 marks)

A
  • Locomotor activity
  • Motor co-ordination
  • Cognition
  • Mood and pain perception

mGluR drugs being developed for treatment of mant psychiatric disorders

31
Q

What behavioural process are AMPA and NMDA receptors implicated in?

A
  • learning and memory
32
Q

What are Nootropics?

A

Drugs that work to improve cognitive function:

  • some work in cholinergic system, others affect neurotransmitter glutamate by targeting glutamate receptor
33
Q

What do ampakines do?

(2 marks)

A
  • Enhance action of AMPA receptors by reducing rate of desnesitisation
  • Shown to also enhacne cognitive function in animal models
34
Q

What are the 3 lines of evidence that have linked NMDA receptors with learning?

(3 marks)

A
  1. Treatment with NMDA receptors antagonists leads to impaired spatial learning - hippocampus high density of NMDA receptors
  2. Doogie mouse genetically engineered to overexpressed NR2B subunit of NMDA receptor - showed improved learning and memory and enhanced LTP
  3. NMDA receptors play key role in LTP occurs at glutamatergic synapses
35
Q

What does injection of monosodium glutamate in young mice do and what does this show?

(2 marks)

A

Damages arcuate nucleus of hypothalamus - important in endocrine system

Same effect seen in kainate and NMDA receptors - see damage at post synaptic sites but not at nerve terminals

36
Q

What is hte excitoxicity hypothesis?

A

Effects of excessive exposure to glutamate are caused by the prolonged depolarisation of receptive neruons which leads to their enventual damage or death

37
Q

How does cell death happen by necrosis or apoptosis?

(4 marks)

A
  • Necrosis:
    • charactersised by lysis due to osmotic swelling
    • If glutamate concentration has lowered or exposure time is reduced, then cell death takes several hours - dependent on NMDA receptor activation
  • Death occurs by apoptosis which leads to DNA to break up
38
Q

How can excitoxicity occur in humans and what is the cause?

(2 marks)

A
  • Consumption of domoic acid
  • Victims experience:
    • headache, dizziness mental confusion
39
Q

How does excitotic brain damage occur?

(3 marks)

A
  • By brain ischaemia - an interruption of blood flow
  • Major release of glutamate occurs in affected area
  • Treatment with NMDA receptors antagonist can reduce cell loss (not yet successful for humans)
40
Q

How does GABA synthesis occur? What blocks it?

(3 marks)

A
  • Made from glutamate catalysed by glutamic acid decarboxylase (GAD)
  • Synthesised by GABAergic neurons
  • GABA synthesis is blocked by allyglycine, thiosemicarbazide and 3-mercaptopropionic acid
41
Q

What id the process of GABA release and inactivation?

(7 marks)

A
  • GABA moves inot vesicles by VGAT
  • VGAT (aka VIAAT) also transports glycine
  • GABA is removed by transporters:
    • GAT-1: found in nerve terminals and important for reuptake
    • GAT-2: reuptake GABA which is later converted into glutamate
    • GAT-3: found in astrocytes
    • GABA then metabolised to glutamate and succinate by GABA aminotransferase
42
Q

How do astocytes assist in the remake of GABA?

(2 marks)

A
  • In astrocytes, glutamate is converted to glutamine by glutamine synthetase
  • Glutamine can be released by astrocytes, taken up by neurons and converted back to glutamate and used to remake GABA
43
Q

Outline the main components of the GABAergic system.

(3 marks)

A
  • Hippocampus and cortex: found in internurons
  • Projection neurons
  • Striatum - seen especially when DA input to striatum is fucked as seen abnormal firing of GABAergic neurons
  • ^^^ causes motor abnormalities
44
Q

What are the receptors for GABA?

(2 marks)

A
  • GABAA receptor - ionotropic
  • GABAB receptor - metabotropic
45
Q

How do GABAA receptors cause inhibtion of the post synaptic cell?

(1 mark)

A
  • Allow Cl- to flow from outside to inside of the cell causing hyperpolarisation
  • And subsequently inhibition of the postsynaptic cell
46
Q

What is the main agonist for GABA?

A
  • Muscimol
  • Gives perecption of objects being larger than they are
47
Q

How does Biscuculline affect GABA?

(2 marks)

A
  • Competitive agonist for GABAA receptor
  • Blocks GABA from binding to GABAA receptors - when taken systematically has potent convulsant effect
48
Q

What do Pentylenetrazel (metrazol) and picrotoxin do?

(2 marks)

A
  • Convulsant drugs that inhbit GABAA receptors
  • Do this by acting at sites distinct from GABA binding site
49
Q

How does BDZ bind to GABA - what mental illness is this meant to help?

(4 marks)

A
  • Binds to GABAA receptors at site distinct from GABA binding site
  • Increases potency of GABA to open receptor channel but can’t open channel without GABA and presence of subunits:
    • γ, α1, 2 or 3 and ß subunits
  • Reduces anxiety
50
Q

What kind of receptor is the GABAB receptor and what effect does it have?

(2 marks)

A
  • Metabotropic - need 2 different subunits to assemble in membrane for it to work properly
  • Have inhbitory affect on post synaptic cells by inhbiting cAMP formation and K+ channel opening
51
Q

Where in the brain is GABA found?

A

Forebrain

52
Q

How is GABA linked to epilepsy?

A

Some forms of epilepsy due to GABAA receptor subunit mutations

53
Q

What affect does selective inhbitory tigabine for GAT-1 affect GABA transmission?

(2 marks)

A
  • Increases extracellular GABA levels and enhances GABAergic transmission in several brain areas
  • Can be used to treat epilepsy as reduces seizure onset
54
Q

What is vigabatrin and its function?

(2 marks)

A
  • Irreversible inhbitor of GABA-T and prevents GABA catabolism
  • Used to treat some forms of epilepsy but can affect vision, by impacting GABAergic interneurons in retina
55
Q

How does GABAB location affect glutamatergic synapses?

(2 marks)

A
  • Found postsynaptically on glutamatergic synapses and can therefore reduce the activity of glutamatergic synapses
  • This will increase variation between GABA ans glutamatergic activity

Fundamental Neuroscience (19 decks)

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