BB30044: GABA (SW)
1.Introduction: role of GABA in brain function
The major inhibitory neurotransmitter in the adult brain – an amino
acid
A third of all synapses in the brain are GABAergic
About 20% of the brain’s neurons are GABAergic interneurons –
provide local modulatory input (axons project within the same brain
region)
GABAergic projection neurons are less common – provide
innervation from one brain region to another, e.g. striatal medium
spiny neurons (involved in HD)
GABA can inhibit action potential firing in 2 ways:
1. PHASIC INHIBITION: GABA released from presynaptic nerve
endings and leads to short-term inhibition of postsynaptic action
potential firing.
2. TONIC INHIBITION: long-term inhibition of action potential firing
SUMMATION of postsynaptic inputs:
Can measure summation by recording changes in postsynaptic
membrane potential in response to stimulation of excitatory
(glutamatergic) and/or inhibitory (GABAergic) inputs
Stimulating a single excitatory (glutamatergic) input gives a sub-
threshold EPSP
However, stimulating several excitatory (glutamatergic) inputs
shifts membrane potential to exceeds threshold EPSP, triggering
depolarisation and inducing action potential.
Stimulating a single inhibitory (GABAergic) input alone produces a
hyperpolarising IPSP (intracellular charge more negative than
extracellular), reducing the likelihood of AP firing
Stimulating glutamate and GABA inputs simultaneously produces
a summation of IPSP and EPSP which cancel out – postsynaptic
neuron remains below the threshold for AP firing.
TEMPEROSPATIAL influences: spatial relationship is important – the
closer synapses are, the greater the summation of depolarisation
will be. Temporal relationship also important – stronger summation
of neurons fire simultaneously.
Summation is important in explaining why there are so many
GABAergic synapses. Their integrative role with glutamate means
they regulate firing of neurons and prevent overexcitation by
glutamate-mediated toxicity.
2.The GABAergic synapse
, GABA is synthesised
from glutamate by the
enzyme glutamic acid
decarboxylase (GAD)
Extra reading: activity of GAD is
inhibited by pyridoxal 5-phosphate
(the active form of
vitamin B6) , which is a
necessary cofactor for
the synthesis of GABA.
Activity of GAD was
significantly lower in the
aged rat brain relative to
young animals. Rate of
activation of GAD by
vitamin B6 was also
elevated in aged brain, perhaps due
to conformational changes of enzyme pyridoxal 5-phosphate during
aging, reducing its affinity for GAD. Vitamin B6 suggested to restore
activity of brain GAD in aged rat brains.
GABA is packaged into vesicles by vesicular GABA transporter
(vGAT)
GABA is released by exocytosis and acts on postsynaptic (&
presynaptic) receptors
Released GABA is taken up into neurons and glia by GABA
transporter (GAT) – pathway in glia breaks down and converts GABA
in mitochondria
3.GABA receptors
TWO classes of GABA receptor:
1. GABAA receptor is IONOTROPIC & mediates fast inhibitory signals
Ion channel found at postsynaptic and extrasynaptic sites.
2. GABAB receptor is METABOTROPIC & mediates slow inhibitory
modulation
Acts as a dimer, found at postsynaptic and presynaptic sites.
Both types of receptor inhibit depolarisation and reduce the
likelihood of action potential firing (inhibitory)
Both receptors are targeted by clinically important drugs to
influence GABAergic function
These drugs are widely used in the treatment of anxiety disorders,
epilepsy, insomnia, spasticity & other pathophysiological conditions
(next lecture)
4.GABAA receptors
1.Introduction: role of GABA in brain function
The major inhibitory neurotransmitter in the adult brain – an amino
acid
A third of all synapses in the brain are GABAergic
About 20% of the brain’s neurons are GABAergic interneurons –
provide local modulatory input (axons project within the same brain
region)
GABAergic projection neurons are less common – provide
innervation from one brain region to another, e.g. striatal medium
spiny neurons (involved in HD)
GABA can inhibit action potential firing in 2 ways:
1. PHASIC INHIBITION: GABA released from presynaptic nerve
endings and leads to short-term inhibition of postsynaptic action
potential firing.
2. TONIC INHIBITION: long-term inhibition of action potential firing
SUMMATION of postsynaptic inputs:
Can measure summation by recording changes in postsynaptic
membrane potential in response to stimulation of excitatory
(glutamatergic) and/or inhibitory (GABAergic) inputs
Stimulating a single excitatory (glutamatergic) input gives a sub-
threshold EPSP
However, stimulating several excitatory (glutamatergic) inputs
shifts membrane potential to exceeds threshold EPSP, triggering
depolarisation and inducing action potential.
Stimulating a single inhibitory (GABAergic) input alone produces a
hyperpolarising IPSP (intracellular charge more negative than
extracellular), reducing the likelihood of AP firing
Stimulating glutamate and GABA inputs simultaneously produces
a summation of IPSP and EPSP which cancel out – postsynaptic
neuron remains below the threshold for AP firing.
TEMPEROSPATIAL influences: spatial relationship is important – the
closer synapses are, the greater the summation of depolarisation
will be. Temporal relationship also important – stronger summation
of neurons fire simultaneously.
Summation is important in explaining why there are so many
GABAergic synapses. Their integrative role with glutamate means
they regulate firing of neurons and prevent overexcitation by
glutamate-mediated toxicity.
2.The GABAergic synapse
, GABA is synthesised
from glutamate by the
enzyme glutamic acid
decarboxylase (GAD)
Extra reading: activity of GAD is
inhibited by pyridoxal 5-phosphate
(the active form of
vitamin B6) , which is a
necessary cofactor for
the synthesis of GABA.
Activity of GAD was
significantly lower in the
aged rat brain relative to
young animals. Rate of
activation of GAD by
vitamin B6 was also
elevated in aged brain, perhaps due
to conformational changes of enzyme pyridoxal 5-phosphate during
aging, reducing its affinity for GAD. Vitamin B6 suggested to restore
activity of brain GAD in aged rat brains.
GABA is packaged into vesicles by vesicular GABA transporter
(vGAT)
GABA is released by exocytosis and acts on postsynaptic (&
presynaptic) receptors
Released GABA is taken up into neurons and glia by GABA
transporter (GAT) – pathway in glia breaks down and converts GABA
in mitochondria
3.GABA receptors
TWO classes of GABA receptor:
1. GABAA receptor is IONOTROPIC & mediates fast inhibitory signals
Ion channel found at postsynaptic and extrasynaptic sites.
2. GABAB receptor is METABOTROPIC & mediates slow inhibitory
modulation
Acts as a dimer, found at postsynaptic and presynaptic sites.
Both types of receptor inhibit depolarisation and reduce the
likelihood of action potential firing (inhibitory)
Both receptors are targeted by clinically important drugs to
influence GABAergic function
These drugs are widely used in the treatment of anxiety disorders,
epilepsy, insomnia, spasticity & other pathophysiological conditions
(next lecture)
4.GABAA receptors
