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Read Soon's notes along with lecture slides with these notes
- 1 Lecture Outcomes
- 2 Synapses
- 3 Dendritic spines
- 4 Synapse location
- 5 Gap junctions underlie 'electrical' synapses
- 6 Electrical synapses in mammals
- 7 Chemical synapses
- 8 Simple chemical synaptic transmission
- 9 Sequence in neurotransmission
- 10 Sample structure of a metabotropic and a glutamate ionotropic receptor
- 11 Glutamatergic ion channels
- 12 The fast EPSP is composed of AMPA and NMDA components
- 13 The two classes of postsynaptic receptor
- 14 Removing neurotransmitter
- 15 What makes a synapse inhibitory or excitatory?
- 16 Presynaptic inhibition (and autoinhibition)
- 17 Co-transmission
- 18 Neuromodulatory systems
- 19 A neuromodulatory effect of noradrenaline
- 20 Determinants of synaptic strength
- 21 Glutamate excitotoxicity
- 22 Ischaemia
- 23 Necrotic cell death
- 24 When things go bad
- 25 Glutamate excitotoxicity and apoptosis
- Distinguish between electrical and chemical synapses;
- List the key processes that occur at a chemical synapse that lead to neurotransmitter release;
- Distinguish between ionotropic and metabotropic receptors;
- Explain the difference between excitatory and inhibitory synapses;
- Explain the difference between a strong and a weak synapse and the role of neuromodulation.
- Explain how ischemia leads to glutamate excitotoxicity
- Neurons make crazily close connections between membranes (synapses; a few nm)
- One cell may make contacts with 1000 other cells (dendritic field)
- There is divergence: one neuron innervating many neurons, and convergence: many neurons innervating one neuron
- More important than the number of cells is number of contacts: so we have dendritic spines to increase the surface area of the dendritic field to produce many more thousands of contacts
- Dark smudgey line on a micrograph is a synapse - pre and postsynaptic densities (because there are many proteins crammed together closely)
- Spines are not static: they're involved in learning and memory and plasticity of the nervous system. They can grow and regress (growth = looking for more connections, regression = falling away). They compartmentalise information (biochemical events in one spine may not spread the whole way through the neuron: might just strengthen one synapse only).
- Axo-dendritic: Most excitatory synapses are in the spines (90%) and most of those are on dendrites.
- Axo-somatic: Synapses on the body of the neuron are inhibitory
- Axo-axonic: Presynaptic nerve terminal synapses are on just before the terminal of the other neuron. This is usually inhibition.
Gap junctions underlie 'electrical' synapses
- Direct excitation would be like epilepsy (all neurons excited; no mechanism for inhibition). The reason there is inhibition is that we have chemical connections as well
- Some electrical connections are present in embryonic development and also in invertebrates, but the mammalian adult brain has no direct electrical connection through neurons
- If there is electrical connection, it is through gap junction (similar to that connecting all smooth muscles together to get annular contraction)
- Gap junctions = pairs of channels that meet up, allowing ions to pass from one cell to the other. They're regulatable, but not very flexible.
Electrical synapses in mammals
- In development, clusters of gap junctions are present together and allow electrical contact.
- During development, GABA acts as an excitatory transmitter, and later on it becomes an inhibitory transmitter
- Chemical synapses produce more flexibility
- Electrical: there is A-B bijection of excitability. Chemical synapses are unidirectional (A affects B).
- It's not the same every time, it's modifiable because we can change how much neurotransmitter goes out
- We can have inhibition and excitation
Simple chemical synaptic transmission
- Excitatory and Inhibitory Post‐Synaptic Potentials:
- Caused by presynaptic release of neurotransmitter
- EPSP:Transient postsynaptic membrane depolarization
- IPSP:Transient hyperpolarisation of postsynaptic membrane potential
Sequence in neurotransmission
- Synthesis of neurotransmitter molecules; packaged in vesicles (organelles and tubules, for synthesising the stuff)
- Action potential arrives at the presynaptic terminal
- Voltage-gated Ca channels open. Ca enters.
- A rise in Ca triggers fusion of synaptic vesicles with the presynaptic membrane (vSNAREs etc). You need to also return vesicle so you don't lose membrane
- Transmitter molecules diffuse across the synaptic cleft and bind to specific receptors on teh postsynaptic cell
- Bound receptors activate the postsynaptic cell.
- A neurotransmitter breaks down, is taken up by the presynaptic terminal or other cells, or diffuses away from the synapse.
- Some neurotransmitters have transporters to suck the neurotransmitter back into the presynaptic neuron. Some NTs have enzymes to break down the NT. Peptides etc can just drift away.
Sample structure of a metabotropic and a glutamate ionotropic receptor
- Two kinds of glutamate receptor: one is GPCR (metabotropic), the other is ligand-gated ion channel (ionotropic).
Glutamatergic ion channels
- Kainate and AMPA are roughly the same, but NMDA is different. See evolutionary tree.
The fast EPSP is composed of AMPA and NMDA components
- Resting EPSP (-80mV): Small bit is NMDA, mostly is AMPA
- NMDA channel is blocked by Mg under resting conditions even though glutamate binds. This channel normally passes a lot of calcium, but Mg is getting in the way.
- If you depolarise the channel and make it more active, NMDA can let Ca come through. Example stimulus = long-term, high frequency stimulation
- Sodium depolarises the postsynaptic neuron and causes electrical changes, while Ca actually does stuff (prolonged effects on postsynaptic)
The two classes of postsynaptic receptor
- Metabotropic are slow and amplifying, while ionotropic are fast and weak
- GPCR's G proteins may activate many many things inside the cell, relatively quickly (they're promiscuous and jump between substrates)
- GPCRs can change gene transcription, to change the behaviour of the neuron long-term
- NB: PKA = protein kinase A
- The receptor itself very rarely may become endocytosed and suck in the receptor with the NT and digest the NT
- Most natural agonists are on and off the receptor all the time (not heroin)
- Usually it's reuptaken by the presynaptic neuron; instead of then being reused, they're usually just broken down
- Peptides: diffusion is common
What makes a synapse inhibitory or excitatory?
- Glutamate is the major excitatory transmitter
- GABA is the major inhibitory transmitter in upper brain (GABAa = chloride channels letting in negative, GABAb = K+ channels, letting out positive), while glycine is the main one for the spinal cord
- While both GABAa and GABAb are inhibitory in the CNS, there are differences: 1) GABAa is for Cl influx and is a ligand-gated ion channel. 2) GABAb is for K efflux and is a metabotropic receptor
- Actually, NTs aren't inhibitory or excitatory: the receptor itself determines what will happen
- There are many many receptors, each of which have different properties (e.g. 5HT1b and 5HT1a; these receptors for serotonin have opposite effects)
- During development, there is a change in the chloride equilibrium from inside and outside, so the receptor and NT haven't changed but their effect has changed from excitatory to inhibitory
Presynaptic inhibition (and autoinhibition)
- Axoaxonic stimulation reduces the volume of neurotransmitter released by the target neuron (reducing its ability to pass on info)
- Usually done by blocking Ca+ channels or hyperpolarising membranes
- Vesicles may contain >1 NT
- Large, dense-cored vesicles contain proteins and peptide, while small vesicles contain small things like glutamate
- Weak stimulation = release small vesicles (excitatory - glutamate)
- High frequency (strong stimulation) = docking of larger vesicles (a different effect: longer-term change in postsynaptic excitability)
- This is called modulation
- Glutamate is not interesting (it will muck around with how you think: NMDA receptors are a target for antipsychotics)
- These pictures show the various pathways with these interesting effects that change mood, drives and behaviours
A neuromodulatory effect of noradrenaline
- Blocks adaptation by closing K+ channels
- You get more firing due to a single stimulus: more bang for your buck.
- This means that you get more postsynaptic firing as a result of an incoming action potential than you would normally
Determinants of synaptic strength
- Synapses in the CNS are usually weak
- CNS needs a lot of coordination of neurons to get things done (so that the sum potential is big enough)
- In the periphery, there are very large fast EPSP, where a single axon to a single cell may cause an action potential
- This is why in the CNS we have spatial summation: a thousand neurons going into a single neuron
- We also have time summation: keep firing over and over to get summation of the fast EPSPs (summing to form a staircase)
- Elevated levels of glutamate cause neurons to die
- Calcium-induced changes (due to glutamate) in postsynaptic membrane are the basis of learning and memory, but also cause excitotoxicity
- An ischaemic event can cause neurons to die, and then they release glutamate, which indirectly kills more neurons
- Necrosis occurs where there is genuinely ischaemia
- Apoptosis occurs where there is this high glutamate field around the ischaemic area
Necrotic cell death
- Note also that influx of sodium may reverse glutamate transporter, so we get glutamate pumped out of the cell
When things go bad
- Depolarisation due to glutamate causes NMDA receptors to be activated, causing calcium influx (there is a huge gradient for calcium to come in)
Glutamate excitotoxicity and apoptosis
- 1 Ischaemia leads to necrosis through oxygen deprivation
- 2 large amounts of glutamate released
- 3 Glutamate activates NMDA receptor
- 4 This allows Na+ and Ca2+ influx into cells
- 5 Ca2+ dependant proteases etc activated (aka apoptotic pathway activation)
This leaves a ring of apoptosis around the original necrosis.