Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

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
Q

what does GABA influence

A

neuronal survival, neurite outgrowth, synapse formation

26
Q

GABAA membrane depolarisation is sufficiently strong to open what

A

voltage gated Ca2+ channels - signficant increase in calcium - shows gabba infleucnes many important functions
calcium into cell has fundamental effects on cell function

27
Q

outline excitatory GABA responses in embryonic and neonatal cortical slices

A

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
Q

what did a 1980s study on neonatal rats show

A

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
Q

what role do glutaminergic pyramidal cells have

A

pacemakers

30
Q

what does depolarising GABA provide

A

provides tonic excitation to the network (depolarises pyramidal cells all the time, leads to influx of calcium that triggers important things in development)

31
Q

what is the difference between GABAA connections and glutaminergic connections

A

gabaa - permissive
glutaminergic - instructive (determine the 0.3Hz rhythm)

32
Q

why do the depolarising responses disappear in development

A

KCC2 co-transporter that pumps Cl- out of cells will be gradually upregulated

33
Q

what happens when knock out KCC2 for early activity in respiratory neurons

A

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
Q

is GABAA signalling sex-specific

A

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
Q

what is the role of oxytocin

A

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
Q

outline role of GABA in suprachiasmatic nucleus

A

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
Q

outline effects of GABA on SCN

A

opposite effects during day and night
inhibitory during day
excitatory during night

38
Q

how are EGABA distributed in the SCN during night

A

not normally distributed, indicates functional effects of GABA are heterogenous

39
Q

what is the role of day-night antagonism in GABAergic neurotransmission

A

provides SCN with time-dependant gating mechanism
1. dampens propagation of excitatory signals throughout biological clock during day
2. promotes it at night

40
Q

outline GABAergic plasticity in patophysiological conditions

A

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
Q

what are examples of neuronal trauma

A

neurite transection
osmotic imbalance
excess heat

42
Q

outline KCC2-mediated GABAergic plasticity during epilepsy

A

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
Q

what does KCC2 having a high transport affinity for external K+ mean - for stimulating epilepsy

A

increase K+ out is followed by influx of CL- via KCC2 , results in positive shift in EGABA, increased gross excitability

44
Q

outline activity-dependant downregulation in KCC2 expression and function in the hippocampus

A

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
Q

why are males more susceptible to seizures than females

A

may be linked to fact at early developmental stages GABAA signalling remains depolarising for longer in male brain areas involved in seizure network

46
Q

what is the link between GABAA and autism spectrum disorder?

A

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
Q

what may contribute to the prevalence of autism in males

A

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
Q

what can we conclude about GABAA mediated responses

A

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.
© 2024 Bold Learning Solutions. Terms and Conditions