Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

Disorders of the Nervous System > GABAergic signalling in health and disease > Flashcards

GABAergic signalling in health and disease Flashcards

1
Q

what is GABA

A

gamma amino butyric acid
primary inhibitory neurotransmitter
widely distributed

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

what are the subtypes of gaba

A

2 ionotropic 1 metabotropic
GABAA and GABAC ionotropic - Cl- channel linked, GABAB changes permeability for K+

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

outline GABAA receptor

A

pentameric complex - 5 subunits
mediates most inhibitory neurotransmission in adult brain - target for many drugs and therapeutic compounds

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

what forces act on the movement of ions across membranes

A
  1. chemical gradients
  2. electrical gradients
  3. equilibrium
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

how is equilibrium for Cl- flux calculated

A

Nernst equation - calculates equilibirum potential 11x more chloride outside than inside
-62mV = in is more negative than outside (11x higher than inside), no net movement across membrane

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

what is equilibrium

A

reached when concentration and voltage gradients have the same energy, they oppose eachother and there is no net movement of Cl- across membrane

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

how does passive flux of Cl- out of the cell happen

A

membrane potential changes, cl- is negatively charged so repels chloride from cytoplasm and there is passive efflux of chloride, it moves out

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

how does passive flux oc Cl - into the cell happen

A

voltage gradient has less energy than concentration gradient, which dominates
cl- passively leaks into cell and is actively transported out of cell by specialised transporter molecules

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

what is synaptic inhibition

A

small hyperpolarisation is sufficient to prevent membrane from reaching threshold to generate action potentials
- membrane is slightly more negative = harder to reach threshold potential

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

in certain conditons GABAA can be DEPOLARISING and even sometimes EXCITATORY - when?

A

early development, in some phases of circadian rhythm
trauma and epilepsy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what does GABAA plasticity depend on?

A

chloride homeostasis
- concentration ratio maintained across cell membrane

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

what is EGABA

A

gaba reversal potential
at EGABA, gaba responses change polarity, it depends on chloride concentration

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what is gaba reversal potential

A

membrane potential at which gaba responses change polarity from hyperpolarising to DEPOLARISING

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

when does EGABA shift to more depolarising levels

A

when there is an increase in intracellular chloride - big depolarising response maybe even action potential depending on how much chloride is in cell

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

what are changes in Cl in and EGABA mediated by

A

secondary active transporters that either take up or extrude CL-

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what is the difference between primary and secondary active transporters?

A

primary - pump that depends on metabolic energy ATP, constantly pumps sodium out of cell and potassium in against gradient
secondary = derive energy from ionic concentration differences in sodium or potassium

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

what is Cl- uptake mediated by

A

Na+, K+, 2Cl- co-transporters (NKCCs)
Na+ independant anion exchangers (AEs)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

what is Cl- extrusion mediated by

A

K+, Cl- co-transporters (KCCs)
Na+ dependant anion exchangers (NDAEs)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

what does activity in KCC mean for GABAA

A

decrease in intracellular chloride activates GABAA which opens channel, chloride moves along electrochemical gradient, which is now bigger because less cl- inside cell due to extrusion, chloride moves in and hyperpolarises - normal synaptic inhibition

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

what does high activity in NKCC mean for gabaa

A

inwardly directed sodium gradient - influx driving cl- into cytoplasm, higher intracellular cl concentration activates gabaa channel, now have efflux of cl-, negative charge moving out so inside becomes more positively charged - depolarising gabaa response

21
Q

what are cation chloride co-transporters

A

large transmembrane glycoproteins
NKCC1 is prominently expressed in CNS
KCC2 is exclusively expressed in mature neurons

22
Q

what is KCC2 largely responsible for

A

low CL- in mature cells

23
Q

when are GABAA responses depolarizing

A

when they elicit a cl- efflux
happens when:
chloride extruded from cell is weaker (less KCC2 activity)
or when chloride uptake by cell is stronger (more NKCC1 activity)

24
Q

outline early GABAA responses

A

depolarising because little KCC2 and NKCC1 is prominent
as development progresses, downregulation of NKCC1 and upregulation of KCC2 = signficant reudction of intracellular chloride
activate GABAA receptor = influx of negative charges - hyperpolarisation

25
what does GABA influence
neuronal survival, neurite outgrowth, synapse formation
26
GABAA membrane depolarisation is sufficiently strong to open what
voltage gated Ca2+ channels - signficant increase in calcium - shows gabba infleucnes many important functions calcium into cell has fundamental effects on cell function
27
outline excitatory GABA responses in embryonic and neonatal cortical slices
Egaba more positive than Vrest in early development -> gaba depolarises developing neocortical cells Egaba is most positive in youngest precursor cells (VZ) progressively shifts to more negative values with development - determined by Cl gradient, which decreases intracellularly with development
28
what did a 1980s study on neonatal rats show
electrode in pyramidal cell saw spontaneous GABAergic responses (GDP = giant depolarising potentials) P4 pyramidal cells in rats Bicuculline (GABAAR antagonist) - membrane hyperpolarisation, reduced synaptic noise and blocked GDPs
29
what role do glutaminergic pyramidal cells have
pacemakers
30
what does depolarising GABA provide
provides tonic excitation to the network (depolarises pyramidal cells all the time, leads to influx of calcium that triggers important things in development)
31
what is the difference between GABAA connections and glutaminergic connections
gabaa - permissive glutaminergic - instructive (determine the 0.3Hz rhythm)
32
why do the depolarising responses disappear in development
KCC2 co-transporter that pumps Cl- out of cells will be gradually upregulated
33
what happens when knock out KCC2 for early activity in respiratory neurons
rhythmic discharges in wild type mice die at birth from suffocation no rhythmic activity in KO mice neuronal CL- intrusion is ineffective GABAA responses remain excitatory prevent synchronous patterned motor activity
34
is GABAA signalling sex-specific
yes occurs earlier in females correlates with developmental expression profile of chloride transporters ESTRADIOL - predominant sex hormone in females - upreguklates KCC2 mRNA TESTOSTERONE - male, downregulates KCC2 mRNA, effect is via GABAA receptors and Ca2+ channels - CREB - important for sexual differentiation example of developmental plasticity
35
what is the role of oxytocin
at birth oxytocin (hormone essential in labour) triggers transient disappearance of depolarising GABAA receptors in CA3 pyramidal cells demonstrates important interaction between oxytocin production in mother and changes innCL- homeostaiss in foetus - protects foetal neurons during delivery
36
outline role of GABA in suprachiasmatic nucleus
SCN received info on light brightness and duration (day vs night) from retina dispatches info to parts of brain and body controlling circadian rhythmicity SCN neurons are pacemakers - most GABAERGIC changes in GABAA activity throughout clock influence SCN output during day and night (different gating mechanism)
37
outline effects of GABA on SCN
opposite effects during day and night inhibitory during day excitatory during night
38
how are EGABA distributed in the SCN during night
not normally distributed, indicates functional effects of GABA are heterogenous
39
what is the role of day-night antagonism in GABAergic neurotransmission
provides SCN with time-dependant gating mechanism 1. dampens propagation of excitatory signals throughout biological clock during day 2. promotes it at night
40
outline GABAergic plasticity in patophysiological conditions
GABAA receptor -mediated responses after trauma are DEPOLARIZING (because of increase in intracellular calcium) there is excessive release of glutamate, leading to elevated ca2+ intracellularly, excitotoxic cellular damage and cell death
41
what are examples of neuronal trauma
neurite transection osmotic imbalance excess heat
42
outline KCC2-mediated GABAergic plasticity during epilepsy
increasing intracellular K+ concentration can stimulate epilepsy and generate functionally excitatory GABAA response because KCC2 has high transport affinity for external potassium = leads to epileptic state
43
what does KCC2 having a high transport affinity for external K+ mean - for stimulating epilepsy
increase K+ out is followed by influx of CL- via KCC2 , results in positive shift in EGABA, increased gross excitability
44
outline activity-dependant downregulation in KCC2 expression and function in the hippocampus
epileptiform activity induced by Mg2+ decrease of KCC2 immunofluorescent staining KCC2 downregulation mediated by BDNF acting on TrkB receptors KCC2 downregulation has fast onset and lasts long
45
why are males more susceptible to seizures than females
may be linked to fact at early developmental stages GABAA signalling remains depolarising for longer in male brain areas involved in seizure network
46
what is the link between GABAA and autism spectrum disorder?
developmental shift from excitation to inhibition in GABAA responses is delayed in autism this is interesting because ASD is more prevalent in males than females
47
what may contribute to the prevalence of autism in males
perinatal exposure to high levels of testosterone also may be polymorphisms in GABAA receptor subunits: may also be linked to susceptibility traits for autism -> factors controlling GABAA signalling important in pathogenesis of disease
48
what can we conclude about GABAA mediated responses
rapidly switch from inhibition to excitation through simple mechanism of modifying intracellular concentration of chloride via up or downregulation of cation chloride cotransporters

Disorders of the Nervous System (19 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions