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What is another name for GABA?
What are the two most important neurotransmitters for normal brain function?
- Glutamate - excitatory
- GABA - inhibitory
What 2 neurotransmitters are used by most inhibitory synapses in the CNS?
How is GABA synthesized?
- Precursor for GABA is glucose
- Glucose metabolized to glutamate
- The enzyme glutamic acid decarboxylase (GAD) catalyses conversion of glutamate to GABA
- GABA is then stored in vesicles prior to release.
What does GABA bind to?
- GABA-A (ionotropic)
- GABA-B (metabotropic/ uses G-protein couples receptor)
- ..to inhibit postsynaptic neuron
What is GABA cleared from in the synapse?
- Cleared from synapse by ...
- Na+ dependent transporters in..
- Glia cells and presynaptic neuron
Nearly all excitatory neurons in the CNS are ___, and it is estimated that over __ of all brain synapses release ___.
It is also prevalent in __ __ __ like __ __ and __ __.
- primary sensory neurons
- cone/rod cells and olfactory cells
What is glutamate synthesized from?
- Glutamine (Gln)
- which is taken up into presynaptic terminals by transporters where it is converted to glutamate by..
- enzyme glutaminase.
What happens to the glutamate in the synaptic cleft?
- Removed from synaptic cleft by...
- excitatory amino acid transporters (EAAT's)
- Glutamate transported into glial cells via EAAT is converted to Gln (glutamine) by...
- enzyme glutamine synthetase.
What are the two main receptors for glutamate? What are there purposes?
- (Often post-synaptic membrane has both of these - most central neurones express these)
- They mediate EPSPs in postsynaptic neurons
What are the characteristics of NMDA AMPA and what does this cause?
- For weak stimulation, Na+ ions are mainly only diffused in through the AMPA receptor (as there is magnesium ion blocking pathway in NMDA)
- However, when stimulus is strong enough and the AMPA causes the postsynaptic neuron to strongly depolorise, NMDA receptors allow not only Na+ and K+ but Ca2+ ions in as well
- This Ca2+ ion then acts as important secondary messenger, initiating several signalling cascades
- This includes having more AMPA receptors
- and also initiates retrograde signal generator (like nitric oxide)
- Therefore, response of post-synaptic neuron becomes stronger - the synapse is enhanced
- Thought to be important for long-term potentiation (LTP) and forming memories.
Postsynaptic neurons may also communicate with presynaptic neurons via ___ __ (eg. __ __)
- retrograde neurotransmission
- nitric oxide
Neurotransmission can also occur without conventional synapses (one-to-one synapses). What is this called and describe it briefly.
- Volume neurotransmission
- Chemical messenger can spill over to sites distant to the synapse by diffusion.
- Brain is not only a collection of 'wires' b ut also a sophisticated 'soup' (public channels).
Give an example of volume neurotransmission.
- Action of dopamine in prefrontal cortex
- Very few transporter pumps to terminate action of dopamine in prefrontal cortex (unlike striatum)
- Thus diffuses to extrasynaptic dopamine receptors
- Dopamine (and noradrenaline) 'aerosol' effect functionally important for tuning excitability of many neurons simultaneously in the region.
Neuromodulators - there are over __ of these in the brain that influence synaptic transmission. They vary a lot but typically act on __ timecales than GABA and glutamate.
List 3 biogenic amines that are neurotransmitters. Where are they also active in?
- Also active in the PNS as well as regulating many brain funcitons
How are dopamine and noradrenaline synthesised?
- They are both catecholamine and are derived from common precursor - tyrosine (an amino acid)
- Catalysed by tyrosine hydroxylase (TH)
- and results in the formation of dihyfroxyphenylalanine (DOPA)
- DOPA converted to dopamine by enzyme DOPA decarbocylase
What are 3 functions that are associated with dopamine?
- Initiation of body movements
- Reward and motivation (addiction as well) - mesolimbic dopamine system
- Frontal executive functions (such as working memory) - mesocortical dopamine system
Dopamine is present at highest level in __ __ (or collectively known as __). This received major input from __ __.
- caudate putamen
- substantia nigra
- (plays major role in initiation of body movements)
What is the link between Parkinson's and dopamine?
- Dopamine neurons in substantia nigra degenerate
- leading to characteristic motor symptoms
How is actions of dopamine in synaptic cleft terminated?
- by reuptake of dopamine into presynaptic terminal by dopamine transporter (DAT)
- and by catabolic actions of monoamine oxidase (MAO) and catechol-)-methyl-transferase (COMPT)
Where does noradrenaline mainly orginate from and where does it project to?
- Originate from locus coeruleus - a brain stem nucleus
- projects to a varietyof forebrain targets including...
- cerebral cortex
Noradrenaline influneces what?
- Sleep and wakefulness
- feeding behaviour
How is noradrenaline synthesised?
- Dopaminne converted to noradrenaline by
- dopamine-β-hydroxylase (DBH)
How is noradrenaline action stopped after it's been in the synaptic cleft?
- Cleared by noradrenaline transporter (NET)
- Like dopamine, also degraded by MAO and COMT
Where is serotonin found primarily and where is it projected to?
- Primarily in the raphe region of brainstem
- widespread projections to the forebrain
What functions are associated with serotonin?
- regulate sleep and wakefulness
- circadian rhythms
- behavioural inhibition
- Anti-depressant drugs often act on serotonergic pathways
How is serotonin synthesised?
- From essential dietary amino acid...
- catalysed by tryptophan hydroxylase
How is the effect of serotonin terminated once it's been in the synaptic cleft?
- transport back into presynaptic terminal via specific serotonin transporter (SERT or 5-HTT)
- Many antidepressant drugs are selective SERT inhibitors
How and where is acetylcholine synthesised?
- In presynaptic terminals
- from precursors acetyl coenzyme A and choline
- catalysed by choline acetyltransferase (CAT)
How is the effect of ACh terminated once it's been in the synaptic cleft?
- In contrast to other small-molecule neuromodulators, not by reuptake but by...
- hydrolytic enzyme acetylcholinesterase (AChE)
- Choline produced by ACh hydrolysis is actively transported back into the terminal
What special name is given to synapses and neurons relating to acetylcholine?
What are the main funcitons associated with Ach?
- Cholinergic neurons especially found in...
- basal forebrain with axonal projection to hippocampus and cerebral cortex
What receptors mediate the actions of ACh?
- Muscarinic GPCRs
- Nicotinic ionotropic receptors
List some glutamatergic pathways. (5)
- a) cortical brainstem
- b) cortico-striatal
- c) thalamo-cortical
- d) cortico-thalamic
- e) transcortical
Imagine the diagram of the glutamatergic synapse.
Imagine a GABA synapse.
- 1. synthesis by GAD to glutamate --- GABA
- 2. Storage
- 3. Release by exocytosis
- 4. Bindint to receptors (GABA-B here)
- 5. Binding to presynaptic receptors
- 6. Uptake by glia
- 7. Conversion to glutamine
What are the monoamines split into and what are these then split into?
- tryptophan (which is made into serotonin)
What is serotonin also known as?
Neuromodulatory molecules. What kind of timescale are we talking for monoamines? What about the other type?
- Monoamines - sec/mins
- Neuropeptides - hours/days
What is the principle site of production of noradrenaline? Where is this found?
- Locus coeruleus
- This is a nuclei in the pons involved with physiological responses to stress and panic