synapses and neurotransmitters

Question 1

what is an electrical synapse?

Answer 1

an electrical synapse is where neurons are connected by connexin gap junctions that allow ions and therefore depolarisation (and repolarisation) to pass straight from one neuron to the other

Question 2

experimentally how can you tell if a synapse is electrical?

Answer 2

fill one neuron with some dye and see if it passes to another (through gap junctions)
or uses electrodes to hyperpolarise/depolarise the first neuron and see if it’s passed along
use a mutation in the connexin to make it inactive and see if the signal is no longer transmitted

Question 3

what experiment provided the first evidence for a chemical synapse?

Answer 3

the Landendorff experiment on the hear (donor heart stimulated, fluid collected - vagustoff which is acetylcholine, added to recipient heart with nerves removed)

Question 3

chemical synapses use synaptic vesicles or dense-core granules, compare them

Answer 3

synaptic vesicles are clear and small, around half the size
synaptic vesicles use small molecule NTs whereas dense use peptide NTs
small vesicles get filled by transport proteins at the presynaptic terminal while dense are ‘one and done’, meaning they’re packaged at the golgi, so
aren’t recycled by endocytosis and refilled like synaptic vesicles

Question 4

what are electrical synapses good for?

Answer 4

fast communication and synchronisation of neurons

Question 5

how does transmission of an action potential from one neuron to the next work? (snares)

Answer 5

V snares on the vesicle bind with the T snares on the membrane, you’ve also got this protein called synaptotagmin which binds with the docking vesicles
influx of Ca2+ from voltage gated calcium channels

its synaptotagmin that has a conformational change when it binds to Ca2+, snares change too, forcing fusion of vesicle with membrane, NT diffuse across the synapse

Question 6

what two ways can receptors in neurons work?

Answer 6

they can either cause ligand-gated ion channel to open, or activate a G protein via a GPCR that opens an ion channel

Question 7

what are three ways NTs are removed?

Answer 7

1. diffuse away
2. taken up by transporters for recycling in neuron or glia
3. destroyed by enzymes

Question 8

compare electrical and chemical synapses

Answer 8

electrical - signals pass in both directions, chemical is just one direction
electrical - signals are passed directly and can only be attenuated (reduced), chemical signals can be completely transformed/amplified/modulated etc…
electrical are faster, < 0.3 ms, chemical are around 0.3 - 5 ms

Question 9

in neuromuscular junctions, what happens if the motor neuron produces an action potential?

Answer 9

an action potential will always be produced in the muscle cells, they use ACh

Question 10

how are NMJs specialised for fast and reliable transmission?

Answer 10

presynaptic has large number of ‘active’ zones
postsynaptic contains folds densely filled with receptors
these active zones and junction folds are very well aligned

Question 11

how do we know synaptic vesicles are used?

Answer 11

experiments show voltages of uniform increases, because vesicles house the same amount of NT so you can only have like regular levels

Question 12

are all synapses one to one?

Answer 12

no there are many different kinds, many to one, one to many etc…

Question 13

what’s the criteria for a molecule to be classed as a neurotransmitter?

Answer 13

1. present at the presynaptic terminal, you can check this with immunostaining for the molecule or the proteins involved in it’s production
2. released in response to stimulation
3. removal of the molecule stops stimulation
4. acts on postsynaptic neuron

Question 14

what types of neurotransmitters are there?

Answer 14

small molecules like amino acids/amines/modified amino acids/catecholamines - act on LGICs and GPCRs, clear vesicles
large molecules - proteins - dense core granules, only act on GPCRs

Question 15

do NTs do the same thing every time?

Answer 15

no, they can have different effects on different cells and receptors

Question 16

glutamate - what is it, what receptors does it effect, what are it’s general properties?

Answer 16

amino acid, so present in all neurons, uses clear vesicles, usually excitatory
effects 3 ionotropic receptors (named after drugs that work as agonists) AMPA, NMDA, kainate
effects
also works on metabotropic receptors, mGluRs, for example mGluR1, mGluR2 etc…
action is terminated by selective uptake into presynaptic terminals and glia

Question 17

what do AMPA receptors do?

Answer 17

mediate fast excitatory transmission
binding of glutamate causes Na+ and K+ currents resulting in EPSP

Question 18

what do NMDA receptors do?

Answer 18

they often co-exist with AMPA
they have a voltage-dependent Mg2+ block so they actually only open if the neuron is already depolarised, they’re a coincidence detector?
when open they let Ca2+ in leading to downstream signalling

Question 19

what is GABA etc…?

Answer 19

its an amino acid not used to make proteins, its’s actually made from glutamate by removing the carboxyl group
activation is terminated by selective reuptake into PreST and glia
it is normally an inhibitory NT and is the most common inhibitory NT

Question 20

what do GABA-A receptors do? explain why opening chloride channels causes hyperpolarisation in terms of Nernst potentials

Answer 20

they are ligand gated chloride channels
they produce IPSPs
Remember that the membrane potential is described by the Goldman equation, which shows that the membrane potential is influenced more by the ions for which the membrane is more permeable. For example, the resting potential is negative because the membrane is most permeable to K+, which has a very negative Nernst potential; the reason that opening Na+ channels depolarises the cell is that it weights the membrane potential more toward the Nernst potential of Na+, which is very positive. So, when you open a chloride channel, you should understand this conceptually as pushing the membrane potential closer to chloride’s Nernst potential. If you are above that, then you will get hyperpolarised

Question 21

why is the right amount of GABA inhibition so important?

Answer 21

too much = coma/loss of consciousness
too little = siezures

Question 22

how can GABA-A be modulated and include examples of how we use it?

Answer 22

using allosteric drugs that can bind to the receptor with GABA
examples include benzodiazepines like diazepam used to treat anxiety
barbiturates - sedatives and anti-convulsants

Question 23

what do GABA-B receptors do?

Answer 23

they are metabotropic
they have diverse effects in different cells so can
1. open K+ channels - brings membrane closer to K+ equilibrium potential = inhibitory (prolonged)
2. close Ca2+
3. trigger second messengers like cAMP

they are often autoinhibitory - present on the presynaptic membrane

Question 24

glycine is also a neurotransmitter - what does it do?

Answer 24

glycine, an amino acid, inhibits neurons by activating a glycine-gated chloride channel
however it can also bind to NMDA glutamate receptors (the ones that are often with AMPA and only activate once depolarisation ahs already occurred

Question 25

what is meant by dendritic integration?

Answer 25

EPSPs from dendrites passively propagate to the soma where their effects combine and there’s loads of Na+ channels and an AP occurs

Question 26

what is meant by shunting inhibition?

Answer 26

when an inhibitory synapse is closer to the soma than an excitatory synapse, so for example GABA-A receptors are letting chloride in right by the soma and keeping it at -60 mV, stopping EPSPs from propagating through that area

Question 27

when would GABA-A not produce an IPSP?

Answer 27

when the membrane potential is already close to chloride’s nernst potential of -65 ish, because then very few chloride ions will actually move
instead chloride moves in whichever way brings the cell’s V closer to chloride’s nernst potential, keeping the cell at around -65 mV

Question 28

what are the typical nernst potentials of K+, Na+ and Cl-?

Answer 28

K+ = -90 mV
Na+ = +55 mV
Cl- = -65 mV

Question 29

how is ACh produced and removed?

Answer 29

AcetylCoA + choline
catalysed by choline acetyltransferase/ChAT

removal = AChE (acetylcholinesterase) breaks it down into acetic acid and choline, taken back to neuron by choline transporter

Question 30

what are nicotinic receptors?

Answer 30

they are ACh gated Ca+/Na+ gated channels in neuromuscular junctions/central nervous system
v. quick

Question 31

muscarinic receptors?

Answer 31

ACh metabolic GPCRs
M1, 3, 5 are excitatory using Gq
M2 and 4 are inhibitory using Gi

Question 32

how do botox and black widow spider venom cause paralysis?

Answer 32

by blocking release of ACh

Question 33

how do pesticides, nerve gas and some alzheimer’s effect ACh pathways?

Answer 33

block AChE, ACh can therefore not be broken down, in Alzheimer’s neuron loss is compensated for by prolonging any ACh still produced

Question 34

what are some antagonists of ACh receptors?

Answer 34

nicotinic - curare
muscarinic - atropine

Question 35

what are some mono/catecholamines that are NTs?
how are they stored and removed?

Answer 35

adrenaline, noradrenaline, dopamine and serotonin (5-HT)
packed into vesicles by VMATs - vesicular monoamine transporters

they can be taken back in by transporters or destroyed by monoamine oxidase/COMT

Question 36

what typical receptor type do mono/catecholamines use?

Answer 36

metabotropic, tho serotonin has 7 receptors, one of which is a LGIC

Question 37

how are these catecholamines linked?

Answer 37

they’re all edits of each other, made in the same pathway

Question 38

explain dopamine’s role in motor control

Answer 38

dopaminergic neurons in the substantia nigra, with axons going to the striatum, they modulate activation of motor cortex

Question 39

parkinson’s is a result of losing dopaminergic neurons in the substantia nigra
what are some possible treatments and their limitations?

Answer 39

aim to cause increase in dopamine -
1. cant be adminstered directly as it cannot cross the blood-brain barrier
2. could prevent its destruction by inhibiting monoamine oxidase but this would effect other monoamine NTs

Question 40

what do antipsychotics do and what side effects can they have as a result?

Answer 40

block dopamine receptors, can cause Parkinson’s like symptoms due to dopamine’s role in motor control

Question 41

dopamine is involved in the reward pathway - describe this pathway and what medication it is a target of
what drugs block dopamine and noradrenaline reuptake?

Answer 41

neurons on the ventral tegmental area project to the cortex and limbic area, forming the mesolimbic pathway
this pathway is a target of drug addiction

cocaine and amphetamines

Question 42

where are receptors for noradrenaline found in the brain

Answer 42

found in the locus coeruleus (brainstem), involved in loads of things, including awake vs asleep, attention etc…

Question 43

where are serotonergic neurons found?

Answer 43

the raphe nuclei (brainstem) with several functions, works with the locus coeruleus

Question 44

antidepressants that target serotonin do so in what way?

Answer 44

they block it’s reuptake, tricyclics are less used as they also block noradrenaline, selective reuptake inhibitors
monoamine oxidase inhibitors are used to prevent serotonin breakdown

Question 45

what do:
1. opioid peptides
2. ATP
3. endocannabinoids
4. nitric oxide

do as neurotransmitters?

Answer 45

1. regulate pain
2. often a cotransmitter and works on metabotropic and ionotropic
3. endocannabinoids - lipid soluble, so Ca2+ triggers synthesis and it can diffuse right across, uses retrograde signalling so goes from post to pre, binds to GPCRs
4. nitric oxide is made on demand, acts locally, quickly degraded, doesn’t affect a receptor, it causes guanylate cyclase to activate a signalling cascade