19.5 Synaptic Transmission Flashcards
Where are peptide neurotransmitters assembled? Give examples of such neurotransmitters
Synthesised in the rough ER and split in the Golgi Body
Buds off the Golgi body in vesicles which are transported to the membrane
Oxytocin, vasopressin
Which types of receptor generally lead to fast transmission?
Ionotropic Glutamate EPSPs
Ionotropic GABA A receptors IPSPs
Which types of receptors lead to slow transmission? Why?
Metabotropic receptors such as the adrenergic, opioid, and GABAB receptors.
NK1-3 G protein coupled peptide receptors = slow EPSP
Involve changes in the cells metabolism (metabotropic) and second messengers take longer to act
Which is the fast or slow EPSP?
Temporal summation
Two EPSPs are elicited and nervous cell membrane is able to store charge
Presynaptic action potentials are happening in quick succession
What type of summation is shown below?
Spatial summation
Neuron is receiving more than one input so EPSPs summate
Charge spreads out (space constant)
Excitatory postsynaptic potential (EPSP)
A depolarising potential in the postsynaptic neuron; increases probability of postsynaptic neuron firing action potential.
Inhibitory postsynaptic potential (IPSP)
Inhibitory hyperpolarisation of postsynaptic membrane; decreases probability of postsynaptic neuron firing action potential
Synaptic integration
The process by which multiple EPSPs and/or IPSPs combine within one postsynaptic neuron, in some cases triggering one or more action potentials
Pre-synaptic inhibition
Inhibitory neuron fires onto axon terminal of a presynaptic neuron, reducing the amount of neurotransmitter it can release
Main inhibitory NT in CNS
GABA
Main excitatory NT in CNS?
Glutamate
What are the main classes of neurotransmitter in the CNS?
- Amino acids
- Acetylcholine
- Monoamines
What are some examples of amino acid neurotransmitters in the CNS?
- GABA
- Glutamate
- Glycine
What are some examples of monoamines neurotransmitters in the CNS?
- Catecholamines (noradrenaline, dopamine)
- Indoleamines (5-hydroxtryptamine a.k.a. serotonin)
- Others (melatonin, histamine)
What is the criteria to be established as a ‘neurotransmitter’?
- Localised in neurons, and specific to one or more neuronal lineage(s).
- Secreted by neurons.
- Able to activate synapses and be mimicked
How can it be proven that a neurotransmitter is localised in a neuron?
Antibody-staining and immunocytochemistry are generally the best methods to determine this, although looking for the activity of certain enzymes can also be used
How can it be proven that a potential neurotransmitter is actually secreted by neurons?
This can be shown through the detection of constant levels proportional to number of cells when neurons are incubated, and it should be possible to induce release (shown by an increase in concentration in the medium) through processes such as electrical stimulation
How can it be proven that a neurotransmitter can be mimicked?
This can be shown through application of an exogenous source of candidate neurotransmitter to neurons in the absence of the endogenous molecule, or through use of agonists/antagonists for pharmacological interventions that change its ability to stimulate neurons downstream
Approximately what percentage of neurons in the brain are utilising these neurotransmitters:
- Glutamate
- GABA
- Other
- Glutamate -> 60%
- GABA -> 30%
- Other -> 10%
What neurons use glutamate as a Where are glutamate receptors and neurons found in the CNS?
- Cortico-cortical neurons
- Cortico-subcortical neurons
Summarise the synthesis, release, reuptake and recycling of glutamate at a synapse.
- Synthesis starts with glutamine, which is converted to glutamate by glutaminase
- VGLUT1 or 2 or 3 is the transporter that packages the glutamate into vesicles (in exchange for H+)
- Upon an action potential, the calcium flux causes release of the vesicle contents into the synapse
- Na+-dependent transporters reuptake the glutamate into the pre-synaptic neuron and other cells (such as glial cells)
- In glial cells, glutamine synthase is used to produce glutamine again, which is shuttled back to the pre-synaptic neuron using glutamine transporters (SN1/SN2 and then SATs)
What are the different types of glutamate receptor?
[IMPORTANT]
Ionotropic:
- AMPA (use Na+ currents)
- NMDA (use Ca2+/Na+ currents)
- Kainate (use Na+ currents)
Metabotropic:
- mGluR1-8 (lead to rise in IP3)
What is the effect of stimulating ionotropic glutamate receptors?
They trigger a mixed fast EPSPs:
- First, AMPA receptors trigger a fast-onset depolarisation
- This depolarisation releases a voltage-dependent Mg2+ block on the NMDA, which allows further depolarisation
What is the effect of stimulating metabotropic glutamate receptors?
There are 8 different types of mGluR:
- Some lead to slow excitatory effects
- Some lead to slow inhibitory effects
Therefore, the effect depends on the particular synapse.
What are some putative functions of glutamate as a NT in the brain?
[IMPORTANT]
It is the main excitatory NT in the CNS:
- Memory -> Mediates LPT (long term potentiation: a persistent increase in synaptic strength following high-frequency stimulation of a chemical synapse)
Explain this graph
The NMDA receptor transmits Na+ like the AMPA receptor across the membrane but can also carry Ca2+ in addition to this, so while it may take longer for it to respond to stimulation by glutamate and its agonists, the depolarising response is greater as a result of the influx of divalent ions.
Why is the inward ionic current of NMDA receptors said to be ‘voltage dependent’?
At a normal negative resting potential Mg2+ ions clog the pore preventing other ions from flowing through
Mg2+ leaves the pore when the membrane is depolarised (generally after activation of neighbouring AMPA channels)
NMDA is transmitter gated and volatge dependent
Is glycine excitatory or inhibitory as a neurotransmitter?
Inhibitory
What neurons use GABA as a neurotransmitter?
- Local circuit interneurons in the cerebral cortex
- Sub-cortical neurons
What neurons use glycine as a neurotransmitter?
Interneurons in the spinal cord
Summarise the synthesis, release, reuptake and recycling of GABA at a synapse.
- Synthesis starts with glutamine, which is converted to glutamate by glutaminase
- Glutamate is then converted to GABA by glutamate decarboxylase
- VGAT is the transporter that packages the GABA into vesicles (in exchange for H+)
- Upon an action potential, the calcium flux causes release of the vesicle contents into the synapse
- Na+-dependent transporters reuptake the glutamate into the pre-synaptic neuron and other cells (such as glial cells) -> GAT1 pre-synaptically and GAT3 on glial cells
- In glial cells, GABA transaminase is used to produce glutamate again, which is converted to glutamine by glutamine synthase
- Glutamine is shuttled back to the pre-synaptic neuron using glutamine transporters (SN1/SN2 and then SATs)
What are the different types of GABA receptor?
[IMPORTANT]
- GABAA -> Ionotropic, Cl- channel
- GABAB -> Metabotropic, Gi-coupled
What is the effect of stimulating ionotropic and metabotropic GABA receptors?
[IMPORTANT]
- Ionotropic GABAA receptors evoke fast inhibitory postsynaptic potentials (IPSPs) -> Due to influx of chloride.
- After this, there is a slower, longer-lasting hyperpolarisation due to the metabotropic GABAB receptors -> Due to the opening of potassium channels.
- The metabotropic GABAB receptor also lead to decreased calcium influx (due to closing of calcium channels) and decreased intracellular cAMP
Give an example of a benzodiazapine and what its effect is on the GABAA receptor.
[IMPORTANT]
- Valium is an example
- Benzodiazapines have neuromodulatory action
- They increase the affinity of the receptor for GABA and increase the probability that GABA will open the channel
- Thus, this leads to increased CNS inhibition
What are some putative functions of GABA as a NT in the brain?
[IMPORTANT]
It is the major inhbitory NT involved in:
- Movement control -> In the basal ganglia
- Downregulation of anxiety and epilepsy
What are some examples of drugs that:
- Inhibit GABA breakdown
- Mimick GABA actions
[IMPORTANT]
- Inhibit GABA breakdown -> Valproate [IMPORTANT]
- Mimick GABA actions -> Benzodiazepines, Barbiturates (Note that these are not GABA receptor agonists, but neuromodulators that sensitise the receptor to GABA)
Glycine binds to and activates
Glycine receptors; Cl- channels
Main neurotransmitter released from neurons with cell bodies in the locus coeruleus
Noradrenaline
The transmitter in the iris causing dilation of the pupil
Noradrenaline
The principle transmitter produced by the locus coeruleus neurons
Noradrenaline
Catecholamines
Noradrenaline and dopamine
Indoleamines
Serotonin 5-HT and melatonin
Where are the major sites of production for dopamine?
Substantia nigra pars compacta and ventral tegmental area
Where are the major sites of production for serotonin/ 5-HT?
reticular formation and nucleus raphe.
The effect of dopamine on the indirect pathway in the basal ganglia
Inhibitory
(Acts on D2 receptors )
The effect of dopamine on the direct pathway in the basal ganglia
Excitatory
(Acts on D1 receptors)
The major neurotransmitter that, when deficient, is associated with depression
Serotonin
Where are the cell bodies of noradrenergic neurons?
Pons and medulla
What enzyme do adrenergic neurons contain that noradrenergic neurons do not?
They contain phenylethanolamine N-methyl transferase (PNMT) which converts noradrenaline to adrenaline
Which noradrenergic receptors are located in the CNS?
Beta 1 and 2
Alpha 1 and 2
NOT beta 3
What adrenergic receptor is mostly expressed in the cerebellum?
Beta 2
What is the general function of noradrenergic neurons?
Locus coerleus neurons are silent during sleep
Noradrenaline is involved in arousal and wakefullness
Blood pressure regulation - noradrenaline released on neurons in the medulla
What amino acid is noradrenaline synthetised from?
Tyrosine
Which enzyme breaks down noradrenaline? How can this be manipulated pharmacologically?
Monamine oxidase breaks down noradrenaline (deamination)
Found intracellularly
MAO can be inhibited by phenelzine to increase the intracellular stores of noradrenaline = treat depression
What is dopamine formed from?
Tyrosine –> L-DOPA –> Dopamine
What types of receptor does dopamine act on?
D1 and D5 = Gs linked excitatory role
D2 ,3 and 4 = Gi linked inhibitory both presynaptic and post synaptic
What are the functions of dopaminergic neurons?
-Motor control: nigrostriatal pathway
-Behavioural effects: mesolimbic pathway (reward and motivation) and mesocortical pathway (cognition)
-Endocrine control of prolactin secretion (tuberhypophyseal system)
What does 5-HT regulate in the brain?
Sleep wake cycle and mood
Anxiety and fear
Nausea
Cognition and impulse control
Which is the only ionotropic 5-HT receptor? What is it gated to?
5-HT3 receptor is an ionotropic sodium channel
What are the majority of 5-HT receptors?
Metabotropic GPCRs
Summarise the synthesis, release, reuptake and recycling of ACh at a synapse.
- Synthesis starts with choline, which is combined with acetate by a choline acetyl transferase (CAT)
- VAChT is the transporter that packages the ACh into vesicles (in exchange for H+)
- Upon an action potential, the calcium flux causes release of the vesicle contents into the synapse
- There is no specific transporter for ACh, so it is broken down on the post-synaptic cell membrane by acetylcholinesterase (AChE)
- Na+-dependent transporters reuptake the choline into the pre-synaptic neuron
What are the different types of ACh receptor?
[IMPORTANT]
- Muscarinic (metabotropic) -> Gq/i-coupled
- Nicotinic (ionotropic) -> Na+ channels
Both are found in the CNS and periphery.
What are some putative functions of ACh as a NT in the CNS?
[IMPORTANT]
Cholinergic neurons rich in basal forebrain (nucleus basalis), septo-hippocampal pathway, and striatum:
- Memory
- Movement
- Reward and motivation
How are receptor numbers up and down regulated?
Extreme stimulaiton of receptors = epigentic changes that produce more receptors
Lack of receptor activation = decreased number of receptors to minimise the energy spent on them
What is a short way to modulate receptor action? Give an example
Covalent modificatin = phosphorylation
Gs coupled receptors activate PKA which phosphorylates potassium channels increasing depolarisation of the neuron
How does receptor desensitisation occur?
Chronic stimulation or blockade
What is Tardive dyskinesia?
common disorder that results from desensitisation to dopaminergic signalling, with involuntary, repetitive body movements such as grimacing, sticking out the tongue, and jerking movements, being fairly common side effects after months or years of use
Which pathway has been abused in Tardive dyskinesia?
the dopaminergic nigrostriatal pathway, which is a part of the basal ganglia system that inhibits a lot of random body movements during normal physiology.
What are the signs of Tardive dyskinesia?
Repetitive body movements such as grimacing, sticking out the tongue, and jerking movements
What is long-term potentiation (LTP)?
- A type of synaptic plasticity where the synapse becomes sensitised - in the hippocampus, for example, it causes an increased efficacy of the CA3 - CA1 synapse
- If tetanus occurs, there is an influx of Ca2+ as the NMDA receptors are unblocked
- This causes a maintained increase in the sensitivity of the synapse, due to an increase in the EPSP amplitude
What is long-term depression (LTD)?
- This correlates to a decreased efficacy of the synapse (e.g. between CA3 and CA1 in the hippocampus)
- Occurs after low-frequency stimulation and is thought to deactivate certain synapses (thought to be a cellular level plasticity mechanism for forgetting)
- Continued low-frequency stimulation (1Hz for 15mins) results in depression of the EPSP for extended amounts of time
