Synaptic Transmission

Question 1

What are the two classes of synapse?

Answer 1

Electrical synapses- formed by gap junction connexins, enable direct passive flow of current from one neuron to another

Chemical synapse- use chemicals (neurotransmitters) to stimulate post-synaptic electrical flow (regulated)

Question 2

What is the difference between electrical and chemical synapses?

Answer 2

Electrical synapses are:
Rarer
Bidirectional
Faster (no diffusion of vesicles)
Memebranes are held directly togehter, it is a narrower cleft
Less tightly regulated

Question 3

What is the difference between electrical and chemical synapses in terms of action potential magnitude?

Answer 3

Chemical- pre and post synaptic action potentials all tend to be the same magnitude
BUT
Electrical- there is an attenuation of the current flow which means you lose current and so there is a delay in the action potential between the pre and post synaptic neuron, alongside a smaller magnitude

Question 4

How can gap junctions cause disease?

Answer 4

Proteins that form gap junctions are called connexins which are a large gene family & mutations in these proteins is lined to many different diseases

GJB1 is mutated in sesnory neuropathy called Charcot-Matie-Tooth disease

GJC2- different mutations here give two different diseases: leukodystrophy which is a hypomyelinated condition OR spastic paraplegia 44 which is a non facial motor neuron disease

Question 5

What causes an action potential?

Answer 5

Neurotransmitters are made and packaged into synaptic vesicles, and these are localised near the presynaptic membrane.

When the action potential invades the presynaptic terminal it causes a depolarisation of the membrane and the opening of voltage gated channels, causing an influx of calcium, which is necessary for the final stages of fusion and release of the neurotransmitters.

So neurotransmitter gets released and diffuses across the membrane (cleft) and then binds to receptors on the postsynaptic membrane. This causes the opening of channels either directly if they are ionotropic receptors or indirectly if they are metabotropic ones, and then this gives ion flow which leads to depolarisation (or hyperpolarisation if we are talking inhibitory synapses), and if we get a depolarisation that exceeds the threshold potential then we get an action potential generated.

Question 6

What is an important role of transporters on glia and particualrly astrocytes in terms of neurotransmission?

Answer 6

The are important in the removal of excesss neurotransmitters that are not taken up by receptors and these get recyceled back to neurons.

There can be transporters both pre and post synaptically

Question 7

What are the critera to define a neurotransmitter?

Answer 7

Must be present within the presynaptic neuron
Must be released in response to depolarisation of the presynaptic neuron and the release must also be Ca2+ dependent
Specific receptors must be present on the postsynaptic cell

Question 8

What are the two main classes of neurotransmitter?

Answer 8

1. Small molecule neurotransmitters e.g. glutamate, acetylcholine –> generally these have short term effects
2. Peptide neurotransmitters e.g. CRH, ACTH, Opioids, Neuropepyide Y –> generally these have longer term effects

Both these classes are packaged into distinctive vesicles but these can actually coexist at the same terminal and this is referred to as co-transmitters

Question 9

How are small molecule neurotransmitters packaged up?

Answer 9

They are typically synthesised down in the synaptic terminal, but the enzymes needed to make them are made mostly in the cell body and then transported down to terminals, once packaged, they then tend to be transported slowly in a process called axonal transport

Question 10

How are peptide neurotransmitters packaged up?

Answer 10

These tend to get packaged up into vesicles in the cell body and are transported by a much faster axonal transport processs

Question 11

What are SNARE proteins ?

Answer 11

Proteins with a higher helical content, which are present in some synpatic vesicles and some presynaptic membranes and can interact with coil structures.
These are really important in fusion
They also mediate excytosis

Question 12

What are chaperone proteins invovled in?

Answer 12

Protein folding and unfolding and the assembly and disassembly of complexes

Question 13

What are C2 domains?

Answer 13

A protein domain that binds Ca2+, when C2 domains bind with Ca2+ they have a much higher affinity for the presynaptic membrane so you can see that the influx of calcium helps this protein which is stuck in the membrane to bind to the membrane

Question 14

What is the SNARE-SM protein cycle?

Answer 14

Basically there are SNARE proteins on the presynaptic membrane and synaptic vesicles which are needed to form complexes with chaperone proteins and then as these complexes undergo confirmational changes they bring the membranes closer together so that when they fuse you get the release of the neurotransmitter

Question 15

What toxins are SNARE proteins the targets of?

Answer 15

Botulinum- BoTX mainly affects peripheral and visceral neuromuscular synapses - weakness

Tetanus- TeTX mainly affects inhibitory spinal interneurons- tetanic contractions

Question 16

How are synaptic membranes recycled by clathrin-mediated endocytosis?

Answer 16

As the membrane evaginates it gets coated with this protein called clathrin, clathrin is a triskelion shape so it has three points to it, so its clathrin subunits forming complexes on them, so there are proteins which recognise clathrin, help to internalise these membranes and there’s another one called dynamin which is important for cutting the membranes and allowing the full internalisation to occur.

The whole process happens on a timescale of minutes

Question 17

What does an excess of Glu cause?

Answer 17

Excitotoxicity

Question 18

There are specific inactivating enzymes which can also break down the neurotransmitter- what are some examples?

Answer 18

acetylcholinesterase (AChE)
monoamine oxidase (MAO) & catechol-O-methyltransferase (COMT) for catecholamines (e.g. DA)

Question 19

What are strategies for the up-regulation of neurotransmission?

Answer 19

Either supplement the transmitter or a precursor
Inhibit clearance by transporters
Inhibit breakdown of neurotransmitter

Either supplement the transmitter or a precursor
- e.g. L-DOPA in Parkinson’s

Inhibit clearance by transporters
- e.g. Antidepressants that act on SERT (SSRIs e.g. fluoxetine)

Inhibit breakdown of neurotransmitter
- e.g. AChE inhibitors in AD (Galantamine, Donepezil, Rivastigmine, etc.)

Question 20

What are strategies for down-regulation of neurotransmission?

Answer 20

Presynaptic- problem here is conserved nature of machinery
-local application of BoTX

Postsynaptic- block specific receptors
-e.g. antipsychotics target D2 dopamine receptors & other things – side effects

Question 21

What are the two classes of neurotransmitter receptors?

Answer 21

Ionotropic
Metabotropic

Question 22

What are ionotropic and metabotropic receptors?

Answer 22

Ionotropic- are themselves ion channels, so when the neurotransmitter binds to the receptor then it causes confirmation change in the receptor which is basically the opening of a channel to allow the passage of ions

Metabotropic- the receptor isn’t itself an ion channel, but often it will, through these small g proteins, involve intercellular signalling responses which then cause the opening of separate channels, so these receptors link with these small g proteins which are referred to as metabotropic receptors.