Summary
Summary - Physiology and Pharmacology of the CNS (5BBM0218)
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- Kings College London (KCL)
Summary of all lecture notes for exam revision. With these notes, I achieved a 1st in second year.
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PHARM AND PHYS OF CNSMade up of two parts, where each part is worth 50%:
Multiple choice single best answer
Based on lectures, tutorials and workshops
45 questions
No negative marking
Essays
Based on lectures, tutorials and workshops
Choose 1 essay from a choice of 6 (OR 5?) (where typically there will be 3
Physiology-theme and 3 Pharmacology-theme essay choices)
Exam duration = 1 hour and 40 minutes
Students are recommended to spend 1 hour on the MCQs and 40 mins on the essay (1000 words maximum).
Neurotransmitter release
Types of NT release:
- Spontaneous, no action potential involved, calcium dependent
- Asynchronous, action potential may be involved, but not in time with the NT release, calcium
dependant
- Calcium independent (e.g. reverse transportation) see transporters lecture (Dr Thomas)
- Synchronous, action potential and calcium dependent – most powerful
Synchronous NT release
1. Presynaptic Depolarisation
2. Calcium Entry
3. Vesicle Movement & Priming
4. Vesicle Docking
5. Vesicle Fusion
6. Vesicle Recycling
- Presynaptic truncated axon – voltage gated sodium and calcium channels
- Neurotransmitter stored in vesicles released into synaptic cleft , activates postsynaptic vesicles
- Neurotransmitter matched to receptor
- Neurotransmitter packaged in vesicles not floating in cytosol
- Depolarisation by action potential
- Calcium signal leads to movement of vesicles to the membrane
, - Receptors on dendrites generate excitatory signals or inhibitory post synaptic signals
- Neurotransmitter can lead to excitatory depolarisation or inhibition
- Inhibitory input – cell body hyperpolarises
- Excitatory input – axon hillock (spike initiation zone) full of sodium and potassium channels
leads to depolarisation by opening of Na+ channels
- Myelinated axon leads to saltatory conduction
- Nodes of Ranvier are gaps between myelin
- In presynaptic terminal most are calcium channels – depolarisation leads to entry of calcium
- Rapid increase in voltage – narrow action potential allows a high frequency of firing, ns
measures how frequent action potentials are fires, more important
- Difference in shape of action potential in nodes of Ranvier vs presynaptic terminal
- Wide action potential involving influx of calcium (like in heart) – calcium channels tend to
stay open longer than sodium channels do
Calcium Entry
1mM conc of calcium in blood
Resting calcium lower inside of cells, 1000 x less – huge conc gradient
,Regulation of Calcium Entry & NT release
GPCR – inhibition
LGIC – upregulation (ligand gated ion channels)
Vesicular Movement & Priming
- There is a lot of discussion on what is “Priming”:
- Steps before Docking/Fusion of vesicles, but may involve some Docking events
- Movement of the vesicle towards the Docking sites (Positional Priming)
- Molecular changes that allow Docking and Fusion (Molecular Priming)
Vesicular Docking – uses SNARE proteins
- Snaptobrevin (red) on the neurotransmitter vesicle
- Syntaxin-1 and SNAP-25 on presynaptic membrane
- All have a SNARE motif – sequence of amino acids, domain required for all 3 proteins
- Two have transmembrane domain
- Syntaxin-1 coupled to SNAP-25
- When vesicle gets close to membrane SNARE proteins cause a docking event
- They help to bring the two membranes into close proximity by forming a tight complex of
coiled-coil structures. This complex then drives the fusion of the two membranes and the
release of the vesicular contents into the target compartment.
- Botox cleaves snare proteins so vesicles cant dock
Vesicular Fusion – uses synaptotagmin-1 proteins
, - The increase in calcium concentration (after presynaptic membrane depolarisation) triggers
the binding of calcium ions to synaptotagmin on the vesicle membrane
- Leads to a conformational change in synaptotagmin that promotes the fusion of the vesicle
membrane with the plasma membrane.
- Synaptotagmin has to bind to calcium ions and PIP 2 in order to be active and fuses the
vesicle with the pre synaptic membrane
Vesicular Recycling
- Synaptobrevin (and synaptotagmin) re inserted into vesicle
- Intracellular vesicular transporter fill the vesicle back up with neurotransmitter
Glutamate major excitatory neurotransmitter in CNS – acts on NMDA and AMPA receptors –
inotropic glutamate receptors – depolarisation
GABA major inhibitory neurotransmitter in CNS – acts on inotropic GABA receptors (chloride ion
channels) – hyperpolarisation
AMPA receptors are the most common type of ionotropic glutamate receptor in the brain. They are permeable to positively
charged ions such as sodium and potassium, and their activation results in a rapid depolarization of the postsynaptic
membrane. This depolarization can trigger an action potential in the postsynaptic neuron, leading to the transmission of
the synaptic signal. AMPA receptors are also important in the induction of long-term potentiation (LTP), a cellular
mechanism of learning and memory.
NMDA receptors, on the other hand, are less common than AMPA receptors and have unique properties. In addition to
being permeable to sodium and potassium ions like AMPA receptors, NMDA receptors are also permeable to calcium ions.
The activation of NMDA receptors requires both the binding of glutamate and the presence of a co-agonist molecule, such
as glycine or D-serine. Furthermore, NMDA receptors are voltage-dependent and require a depolarization of the
postsynaptic membrane to remove a magnesium ion that blocks the ion channel pore. Due to their unique properties,
NMDA receptors are involved in a variety of functions, including synaptic plasticity, learning, and memory.
- Can get more than one type of neurotransmitter released from the same neurone
- Co-release when two different neurotransmitters are released from the same terminal
- Mixtures of neurotransmitter within the vesicle – E.g. noradrenaline with ATP release
- Or have two families of vesicles within the same terminal that hold different
neurotransmitter
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