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Neurophysiology > Central synapses > Flashcards

Central synapses Flashcards

1
Q

How does the patch-clamp technique allow visually guided recordings from specific neuronal subtypes

A

The blunt electrode tips can be readily observed under a light microscope, ans the target neurons chosen on the basis of morphology and expression of fluorescent proteins

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2
Q

What is the benefit of simultaneous recordings from 2 connected neurons

A

Paired recordings enables precise control of action potential firing in the presynaptic neuron and the recording of a unitary postsynaptic response

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3
Q

Between what size neurons is electrical coupling effective

A

2 neurons of a similar size and thus impedance

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4
Q

What type of neurons do electric synapses occur betwee

A

Mostly occur between the dendrites of neurons of the same subtype

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5
Q

What structure forms electrical synapses

A

2 hemichannels or connexons that are made up of 6 connexins and connect across the intracellular space

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6
Q

What happens to the signal as it propagates through the electrical synapse

A

Attenuated and low-pass filtered meaning a 30mV step depolarisation of the presynaptic neuron produces a 3mV depolarisation of the postsynaptic neuron, and the presynaptic action potentials are only observed as spikelets

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7
Q

What type of communication do electrical synapses allow

A

Graded (proportional to strength of stimulus, not all-or-nothing, can be hyperpolarising or depolarising) and bidirectional communication

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8
Q

Over what distance can electrical synapses allow communication

A

Only allow short-distance communication as dendrites must be local

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9
Q

Examples of amine neurotransmitters

A

Noradrenaline, dopamine, serotonin

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10
Q

Examples of amino acid neurotransmitters

A

Glutamate and glycine

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11
Q

Examples of peptide neurotransmitters

A

Enkephalin and substance P

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12
Q

Example of soluble gas neurotransmitter

A

NO

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13
Q

What are the 2 most common neurotransmitters used in the CNS

A

Half the synapses in CNS use excitatory glutamate, while a quater use inhibitory gamma-aminobutyric acid (GABA)

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14
Q

What does GABA stand for

A

Gamma-aminobutyric acid

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15
Q

What is Dale’s principle

A

All axonal branches of a neuron release the same neurotransmitter substance/s (however, each neuron will often co-release more tan one type of neurotransmitter)

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16
Q

What are the 2 groups that chemical synapses can be sorted into

A

Gray’s Type 1/excitatory glutamergic synapses and Gray’s Type 2/inhibitory GABAergic synapses

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17
Q

What are Gray’s Type 1/excitatory glutamergic synapses

A

Have spherical vesicles, thicker postsynaptic density (asymmetrical), and found on dendritic spines and dendritic shafts

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18
Q

What are Gray’s Type 2/inhibitory GABAergic synapses

A

Flattened or elongated vesicles, symmetrical pre and post synaptic width, occur primarily on dendrite shafts, neuronal cell bodies and the axon initial segment

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19
Q

How is glutamate synthesised

A

Synthesied from glutamine by glutaminase

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20
Q

What concentrates glutamate in vesicles

A

Vesicle glutamate trasporters (vGluTs)

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21
Q

What are the range of ligand-gated ion channels glutamate can activate

A

Ionotropic glutamate receptors (iGluR) are categorised based on the binding/efficacy of different ligands- AMPA, kainate and NMDA receptors

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22
Q

What are the G protein-coupled receptors glutamate can activate

A

Metabotropic glutamate receptors, mGluR

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23
Q

What terminates synaptic transmission of glutamate

A

Glutamate diffuses out of the synaptic cleft and is then removed from the extracellular fluid via excitatory amino acid transporters (EAATs) expressed in presynaptic terminals, postsynaptic neurons and astrocytes

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24
Q

What does the predominant reuptake/recycling pathway appear to be via (which excitatory amino acid transporters) for glutamate

A

Astrocytes- convert glutamate to glutamine via glutamine synthetase, and release it into the extracellular space from which it is taken up by neurons

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25
Q

What type of postsynaptic potential is evoked by synaptic glutamate and why

A

iGluR are permeable to cations, so a synaptic glutamate release evokes an EPSP which looks similar in shape to the EPP at the NMJ

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26
Q

Which iGluRs mediates the response in glutamatergic transmission to low-frequency presynaptic action potentials in an active network of neurons

A

EPSPs are mediated by AMPA/kainate, with little contribution from NMDA receptors

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27
Q

What blocks the different iGluRs

A

AMPA and kainate receptors blocked by NBQX

NMDA receptors blocked by alcohol, PVP and APV

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28
Q

What is the reliability of glutamatergic transmission

A

Response to an individual synaptic input can be weak (<0.5mV)
Many central synapses may release only a single vesicle for each PSAP, meaning individual responses are very variable, including failures

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29
Q

Why is synaptic integration necessary

A

A single EPSP is normally not sufficient to depolarise a central postsynaptic neuron to threshold
Integration combines the thousands of weak inputs by central neurons so threshold can be reached

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30
Q

What does temporal integration show that reflects the history of the neuron

A

Release at a given synapse shows short-term plasticity,as it reflects the immediate history of presynaptic activity

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31
Q

What short-term plasticity is shown at a synapse between a cortical glutamatergic pyrimdal nuron and a GABAergic bitufted cell

A

Short-term facilitation of synaptic release, with a train of presynaptic action potentials that gradually get bigger- high-pass filter

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32
Q

What short-term plasticity occurs at a synapse between a cortical glutamatergic pyrimdal nuron and a GABAergic multipolar cell

A

Short-term depression of synaptic release, as action potentials get gradually smaller- low-pass filter

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33
Q

What does the degree of facilitation/depression of synaptic release by short-term plasticity depend on

A

The degree of facilitation/depression depends on the frequency of presynaptic action potentials

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34
Q

What is thought to cause facilitation of presynaptic release (short-term plasticity)

A

Residual Ca2+ in the presynaptic terminal increases the probability of vesicle release following a successive action potential

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35
Q

What is thought to cause depression of presynaptic release (short-term plasticity)

A

The refractory state of the release site following vesicle fusion that continues until a new vesicle can be primed for release

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36
Q

At what synapses is facilitation vs depression of response likely to occur (short-term plasticity)

A

Facilitation- synapses with a low initial probability of release where the effect of residual Ca2+ dominates
Depression- synapses with a high initial probability of release where effect of vesicle depletion dominates

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37
Q

What is the effect of long high-frequency trains of action potentials

A

Even for synapses that show facilitation, long high-frequency trains of action potentials will induce subsequent depression

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38
Q

If short-term plasticity is a feature of all synapses, why is it not obvious at the NMJ

A

The basal EPP exceeds action potential by a safety margin, meaning that despite short-term plasticity, action potentials in the presynaptic motor neuron reliably evoke muscle action potentials even at high spike frequencies

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39
Q

How is GABA synthesied

A

Synthesied from glutamate by glutamate decarboxylase (GAD)

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40
Q

What concentrates GABA in vesicles

A

Vesicle GABA trasporters (vGATs)

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41
Q

What ligand-gated ion channels can GABA release activate

A

GABA-A receptors

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42
Q

What are GABA-A receptors antagonists

A

Picrotoxi and bicucullin

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43
Q

What G protein-coupled receptors can GABA release activate

A

GABA-B receptors

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44
Q

What is an agonist for GABA-B receptors

A

Baclofen

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45
Q

What is an antagonist for GABA-B receptors

A

Phaclofen and saclofen

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46
Q

How is synaptic transmission of GABA terminated

A

GABA diffuses out of the synaptic cleft and is removed from the extracellular fluid by GABA trasporters (GATs) and recycled in a similar way to glutamate

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47
Q

What are GABA-A receptor agonists

A

Benzodiazepans, barbituates, alcohol, neurosteroids

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48
Q

What is the structure of GABA-A receptors

A

Pentameric assemblies of GABA-A receptor subunits- they predominantly have a combination of 2 alpha, 2 beta and a gamma subunit

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49
Q

What postsynaptic potential results from activation of GABA-A receptors by GABA

A

GABA-A receptors are permeable to Cl- and HCO3-, thus activation tends to cause a net influx of anions and membrane hyperpolarisation

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50
Q

Study evidencing the action of inhibitory GABAergic synapses

A

Miles et al, 1996- Presynaptic action potentials in a GABAergic basket cell evoke an IPSP on a pyrimidal neuron- inhibition is strong enough for the activation in one inhibitory neuron to prevent spiking in the postsynaptic neuron

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51
Q

How do benzodiazepines act as agonists on GABA-A receptors

A

They change the effect GABA has when it binds to the channel at the same time, by increasing the frequency of single channel opens and prolonging synaptic inhibition
They cause stronger inhibitory postsynaptic potentials and the behavioural consequences of this

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52
Q

What are benzodiazepines widely used as

A

Anxiolytics, hypnotics, anticonvulsants and myorelaxants, showing the importance of synaptic inhibition in controlling excitability in the CNS

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53
Q

How does termination for central synapses vs the NMJ differ

A

Non-cholinergic transmission is largely terminated by diffusion and reuptake, while at the NMJ termination is mostly done by degradation by enzymes

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54
Q

Hos are the effects of neurotransmitters paracrine

A

Only have an effect in the vicinity of where they’re secreted

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55
Q

What is neuromodulation

A

The paracine spillover effects of neurotransmitters, which modulate synaptic function and cellular excitability across volumes of tissue, and exert slow modulatory effects large via activating GPCRs

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56
Q

What is synaptic plasticity

A

Activity-dependent changes in synaptic strength that outlast the direct effects of neurotrasmitter release

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57
Q

What is long-term synaptic plasticity thought to be important for

A

Behavioural learning and memory

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58
Q

What are the 4 main transmitter systems used for long-range and diffuse modulation of brain state

A

Acetylcholine, serotonin, dopamine and noradrenaline

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59
Q

Where are cholineragic neurons found in the brain

A

Cortical-projecting cholinergic neurons are found in the basal forebrain, while brain stem cholinergic neurons are found in the dorsolateral pontine tegmental area

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60
Q

What is the acetylcholine transmitter system involved in

A

Gating attention and learning- if you stick an electrode into the pedunculopontine nucleus you can wake up a sleeping animal

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61
Q

What are the receptors for the acetylcholine transmitter system

A

nAChR and mAChR (m1-5 subtypes), involved in slow signalling)

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62
Q

What disease is linked to degradation of cholinerguc basal forebrain neurons

A

Alzheimer’s- Donepezil, an AChE inhibitor is prescribed for mild to moderate dementia, by stopping the breakdown of ACh

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63
Q

How can muscarinic antagonists like benzatropine be helpful in relief of tremors for Parkinson’s Disease

A

Likely due to effects on signalling from cholinergic interneurons in the striatum

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64
Q

Where are serotonergic neurons found in the brain

A

Raphe nuclei, distributed across the brainstem

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65
Q

What is the serotonergic transmitter system involved in

A

Involved in regulating mood and gating pain perception

Activity of serotonergic neurons is suppressed when we are attending to a stimulus closely, then increased by reward

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66
Q

What receptors are used by the serotonergic transmitter system

A

7 receptor families, 5-HT 1-7

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67
Q

How does ecstacy link to the serotonergic transmitter system

A

Ecstacy inhibits and reverses serotonin uptake, causing it to accumulate in the extracellular space causing feelings of wellbeing and emotional warmth

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68
Q

Clinical applications of drugs affecting the serotonergic system

A

Prozac (antidepressant) is an SSRI

Risperidone (antipsychotic) is a non-selective 5HT2 receptor antagonist

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69
Q

What are the 4 major dopaminergic pathways in the brain

A

Nigrostriatal pathway, mesolimbic pathway, mesocortical pathway, tuberoinfindibular pathway

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70
Q

What is the dopaminergic transmitter system involved in

A

Regulating movement, signalling rewards, learning

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71
Q

What receptors does the dopaminergic transmitter system

A

D1 type (D1 and D5) and D2 type (D2, D3, D4) receptors

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72
Q

Examples of addiction linked to dopaminergic transmitter system

A

Cocaine inhibits dopamine reuptake, leading to euphoria and reinforcing of behaviour through feelings of reward
Partial dopamine receptor agnoists help relapse to tobacco smoking as drug recreates reward feeling

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73
Q

Clinical application of drugs related for dopaminergic transmitter system

A

DA neurons in the substantia nigra degenerate in Parkinson’s Disease, leading to slower/loss of movement, and symptoms are treated with a dopamine precursor L-DOPA

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74
Q

Where are noradrenergic neurons found in the brain

A

Major source of noradrenaline in the brain is neurons located in the locus coeruleus

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75
Q

What is the noradrenergic system involved

A

High levels during arousal and stress, orientation to a new stimulus
Involved in regulating arousal and gating pain ‘flight, fright, fight’

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76
Q

What receptors does the noradrenergic system use

A

a (a1 and a2) and beta (B1 and B2) adrenoceptors

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77
Q

Clinical application of drugs linked to the noradrenergic system

A

B-adrenoceptor antagonists (propanolol) are anxiolytic

Norarenaline reuptake inhibitors and MAO inhibitors are antidepressant

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78
Q

What do metabotropic receptors do

A

Mediate neuromodulation by activating intracellular transduction pathways via G proteins (GPCRs

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79
Q

How are ionotropic receptors different to metabotropic receptors

A

Ionic receptors directly form an ion pore (ligand-gated ion channels), while metabotropic receptors activate intracellular transduction pathways via G proteins

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80
Q

What types of neurotransmitter receptors are metabotropic

A

All dopamine and noradrenaline receptors are metabotropic
6/7 5HT receptors are metabotropic, with only 5-HT3 receptors being ligand-gated ion channels
Acetylcholine can also act at metabotropic muscarinic AChR

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81
Q

What is the structure of GPCRs

A

7 transmembrane domains, are often dimers, 2 of the extracellular loops form transmitter binding sotes, 2 can bind to and activate G proteins

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82
Q

What are the G proteins that GPCRs couple to

A

GTP-binding heterotrimeric Gproteins consisting of Ga, Gbeta and Ggamma subunits- the identities of the G proteins determine which downstream pathway is modulated following receptor activation

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83
Q

How can metabotropic receptors affect ion channels indirectly

A

Can indirectly open or close ion channels via a second messenger cascade- fairly slow, taking at least a few 10s of milliseconds

84
Q

How are heterotrimeric G proteins classified

A

According to the type of alpha subunit they contain, can be sorted into 3 canonical classes

85
Q

What are the 3 canonical classes of heterotrimeric G proteins

A 
Galpha s (stimulatory)
Galpha i (inhibitory)
Ga q
86
Q

What is the Galpha s (stimulatory) class of heterotrimeric G proteins

A

Activate plasma membrane adenylyl cylases, increasing the cytosolic secondary messenger cAMP

87
Q

What is the Galpha i (inhibitory) class of heterotrimeric G proteins

A

Inhibits most adenylyl cyclases, allowing cAMP to fall

88
Q

What is the Galpha q class of heterotrimeric G proteins

A

Activates phospholipase Cbeta that cleaves the signalling molecules of the plasma membrane, generating several second messengers including IP3 that release Ca2+ and activate phosphorylation by protein kinase C

89
Q

What structural features suggests neuromodulatino occurs largely via volume/paracrine transmission

A

Only a small percentage of the boutons of monoaminergic and cholinergic axons form synapses and have a clear postsynaptic specialisation, and the GPCRs are not clustered around the release sites

90
Q

What does it mean to say neuromodulation occurs via volume/paracrine transmission

A

Signals diffuse through extracellular source from source to target cells via energy gradients leading to diffusion

91
Q

What amount of tissue will axonal release of transmitter along a chain of boutons affect

A

A large volume (diffuse signal)

92
Q

How does diffusion of neurotransmitter in the extracellular space affect the concentration of neurotransmitter

A

The conc of neurotransmitter experienced by the receptors will be in the order of a few micromolar (they are located pre-, peri- and extrasynaptically)

93
Q

What is the effect of low neurotransmitter conc on GPCRs in paracrine transmission

A

GPCRs have sufficient sensitivity to be activated by these low neurotransmitter concentrations, and can amplify the signal via the intracellular signalling cascades

94
Q

Examples of the divergent targets of GPCRs

A

Ion channels and gene expression

95
Q

What is slow paracrine transmission by GPCRs sufficient for

A

Mediating behaviourally-relevant changes in arousal, mood etc..analogous to traansmission used by post-ganglionic neurons in the ANS

96
Q

Why are the neuromodulatory systems attractive drug targets for treating nervous system disorders

A

For neuromodulation via paracrine transmission, different signals have to be conveyed by the activation of a specific set of synapses by the specific neurotransmitter

97
Q

How can fast transmission lead to slow transmission

A

The release of glutamate and GABA leads to spillover into the extracellular space, which can activate their metabotropic receptors mGluR and GABA-B
Allows local modulation of neuronal processing depending on current levels of cell activity- more local activity means more spillover

98
Q

What are the 3 principal targets of neuromodulation by paracrine spillover

A

Presynaptic release, postsynaptic response, neuronal excitability

99
Q

How can presynaptic release be targeted by neuromodulation

A

Presynaptic GPCRs can modulate ion channels and terminal excitability and Ca2+ influex
Neuromodulation tends to decrease evoked reelase

100
Q

How can postsynaptic response be targeted by neuromodulation

A

Postsynaptic GPCRs can modulate ligand-gated ion channelss and thus alter the response to vesciular release

101
Q

How can neuronal excitability be targeted by neuromodulation

A

GPCRs located on the soma/dendrites can regulate membrane polarisation, synaptic integration, and spiking patterns in response to sustained depolarisation t

102
Q

How can GPCRs on the soma/dendrites alter the spiking patterns in reponse to sustained depolarisation

A

eg opening/closing channels to alter neuronal excitability

eg spike frequency adaption- slowing in firing rate over time

103
Q

What is a central pattern generator

A

A network of neurons that generate a sequence of motor outputs, necessary for behaiviours like walking, swallowing and coughing

104
Q

Neuromodulation in the lamprey spinal cord- what controls alternating left-right locomotor activity in each segment along the spnial cord during swimming

A

Fast synaptic communication within the spinal CPG

105
Q

Neuromodulation in the lamprey spinal cord- how can the CPG by regulated by neuromodulation

A

An isolated spinal cord has an inactive CPG, but can be activated by application of glutamate to mimic supraspinal drive, suggesting neuromodulation can turn neuronal circuits on/off (Harris-Warrick and Cohen, 1984)

106
Q

Neuromodulation in the lamprey spinal cord- how can the CPG by altered by 5HT

A

Application of 5HT reduces burst frequency and prolongs intersegmental lags, suggesting neuromodulation can speed up or slow down output (Harris-Warrick and Cohen, 1984)

107
Q

How can synaptic plasticity vary among synapses

A

Some synapses adapt very quickly, while others require chronic changes in activity patterns, depending on cell type, brain region and developmental stage

108
Q

What is one form of synaptic plasticity

A

Long-term potentiation (LTP) that depends on NMDA receptors at many glutamatergic synapses (Bliss and Lomo, 1973)

109
Q

Study showing NMDA receptor-dependent long term potentiation- low stimulation frequency

A

Each pathway is stimulated alternately every 30s (low stimulation frequency), and the 1 hour baseline period shows the responses are stable over time (Bliss and Lomo, 1973)

110
Q

Study showing NMDA receptor-dependent long term potentiation- what happens to the tetanized pathway immediately following high stimulation frequency

A

When the tetanized pathway then receives 100 pulses at 100Hz for one second, it causes a large and immediate increase in the evoked response - post-tetanic potentiation for a few mins due to residual Ca2+ in the presynaptic terminals facilitating release (Bliss and Lomo, 1973)

111
Q

Study showing NMDA receptor-dependent long term potentiation- what happens to the tetanized pathway over time following high stimulation frequency

A

The evoked response rapidly decays, but there is a persistent increase in the size of the evoked response that lasts for hours (Bliss and Lomo, 1973)

112
Q

Study showing NMDA receptor-dependent long term potentiation- what is the response of the untetanized pathway over time

A

It does not show any changes in evoked response, showing this form of synaptic plasticity is activity dependent and synapse specific (Bliss and Lomo, 1973)

113
Q

What is behind LTP

A

NMDA receptors acting as a coincidence detector

114
Q

How are NMDA receptors able to detect the high-frequency input and provide an intracellular signal to induce plasticity- 2 mechanisms?

A

NMDARs show voltage-dependent Mg2+ block, Ca2+ permeability

115
Q

What do NMDARs detect a coincidence between in LTP

A

Glutamate release and postsynaptic depolarisation

116
Q

What is the voltage-dependent Mg2+ block shown by NMDA receptors

A

At resting membrane potential, Mg2+ can block ion flow through NMDARs, even if the receptor is activated by glutamate, meaning NMDA contributes little to synaptic transmission
Mg2+ is expelled from the channel when the membrane is depolarised

117
Q

What is the effect of the NMDARs detecting the coincidence of glutamate release and postsynaptic depolarisation

A

Leads to an NMDAR-mediated Ca2+ influx (as Mg2+ is expelled from channel), which provides an intracellular signal for plasticity, driving sustained Ca2+ influx

118
Q

What is the effect of tetanic stimulation on NMDARs

A

Tectanic stimulation initially produces depolarisation of the postsynaptic neuron via AMPA/kainate receptors, but subsequent depolarisation and continued glutamate release recruits NMDAR

119
Q

How can LTP also be induced during low-frequency stimulation

A

By pairing presynaptic release with current-induced depolarisation/spiking

120
Q

What is the effect of applying NMDAR antagonists on LTP

A

Blocks LTP

121
Q

How can the expression of LTP be mediated postsynaptically

A

By an increase in the response to transmitter release- Ca2+ influx through NMDAR activates calcium/CaMKII which increases AMPA currents

122
Q

How does calcium/CaMKII activated by Ca2+ influx through NMDAR increase AMPA currents

A

It phosphorylates AMPA channels increasing their conductance

It favours the insertion/retention of AMPA receptors membrane

123
Q

How does the Morris water maze task support LTP in learning

A

Morris et al (1986)- rat ventricles injected with NMDA antagonist AP5 cannot learn where a submerged platform is, suggesting NMDA receptors are involved in formation of spatial memory in the hippocampus

124
Q

What does it mean that electrical transmission is very fast and nearly failsafe

A

Electrical synapses between sensory and motor neurons in neural pathways mediating escape allow invertebrates like crayfish to quickly respond to danger

125
Q

How does synaptic transmission work in electrical synapses

A

An AP in the presynaptic neuron causes a small amoutn of ionic current to flow across the gap junction channels into the other neuron where it causes a postsynaptic potential (in a bidirectional synape, an AP in the 2nd neuron will in turn induce a PSP in the 1st)

126
Q

What is the size of a PSP generated by a single electrical synapse

A

About 1mV at its peak- may not be enough to trigger an action potential in the postsynaptic cell

127
Q

How do the tiny 1mV PSPs generated by single electrical synapses trigger an AP

A

Synaptic integration- neurons usually form electrical synapses with multple neurons, so multiple PSPs occuring at once may strongly excite a neuron

128
Q

Where are electrical synapses often found

A

Where activity of neighbouring neurons needs to be highly synchronised

129
Q

Example of electrical synapses allowing coordination of neuron activity

A

Neurons in the inferior olive form gap junctions with one another, helping them coordinate and synchronise th activity of inferioir olivary neurons to help control fine timing of motor control

130
Q

Study supporting the importance of gap junctions in allowing synchrony of neurons

A

Long and Connors (2002)- genetic deletion of a critical gap junction protein connexin36 prevents the synchrony of the generation of oscillations and APs between neurons

131
Q

Example of how gap junctinos are especially common early in development

A

Evidence suggests they allow neighbouring cells to share electrical and chemical signals to help coordinate their growth and maturation during brain development

132
Q

Are chemical or elecrical synapses more common in humans?

A

Chemical

133
Q

What helps bind the pre/postsynaptic membrane together

A

A matrix of fibrous extracellular protein in the synaptic cleft

134
Q

What are secretory granules

A

Larger synaptic vesicles in the postsynaptic membrane

135
Q

What are active zones

A

Proteins on the intracellular face of the presynaptic membrane jutting into the cytoplasm, and the membrane associated with them

136
Q

What is a synapse whee he postsynaptic membrane is on a dendrite

A

Axodendritic

137
Q

Asymmetric synapses are usually

A

Excitatory

138
Q

Symmetric synapses are usually

A

Inhibitory

139
Q

What are the 3 main types of neurotransmitters

A

Amino acids, amines, peptides

140
Q

What type of molecules are amino acids and amines

A

Small organic molecules containing at least 1 nitrogen atom, stored and released from synaptic vesicles

141
Q

What type of molecules are peptide neurotransmitters

A

Large chains of amino acids, stored in and released from secretory granules

142
Q

What are the fast forms of synaptic transmission mediated by in most CNS synapses

A

Glutamate, GABA or glycine

143
Q

How do vesicles release their contents

A

Exocytosis- their membranes fuse to the presynaptic membrane at the active zone, the fusion pore mouth expands until the vesicle membrane is fully incorporated into the presynaptic membrane, allowing their contents to spill our into the synaptic cleft

144
Q

Evidence for how quickly exocytosis of vesicles occurs

A

Occurs within 0.2msec of Ca2+ influx into the terminal at a giant synapse in the squid nervous system- is faster in mammals as they are generally at higher temperatures

145
Q

Why is exocytosis so quick

A

Ca2+ enters at the active zone precisely where synaptic vesicles are ready to release their content, and there is a higher ca2+ conc in this area around the active zone

146
Q

Where are vesicles mobilised from in periods of prolonged stimulation

A

From a ‘reserve pool’ bound to the axon terminal’s cytoskeleton aka synapsins- their release from the cytoskeleton and docking to the active zone is also triggered by elevated Ca2+

147
Q

What are v-SNAREs and t-SNARES

A

Vesicles have v SNARES and outer membrane has tSNARES- the ends of these complementary SNARE types can bind very tightly, allowing a vesicle to dock very close to a presynaptic membrane and nowhere else

148
Q

What are the 3 stages of 3 protein-coupled receptors acting

A

Neurotransmitter molecules bind to receptor proteins in the postsynaptic membrane, receptor proteins activate G-proteins which are free to move along the intracellular face of the postsynaptic membrane, the G proteins activate ‘effector proteins’

149
Q

What can effector proteins activated by G proteins be

A

G-protein-gated ion channels in the membrane, or enzyems that synthesise 2nd messengers that diffuse away in the cytosolo

150
Q

What can 2nd messengers do once they’ve been activated

A

Can activate ADDITIONAL enzymes in the cytosol that regulate ion channel function and alter cellular metabolism

151
Q

How can ACh have a differet postsynaptic effect when binding to cardiac muscle cells

A

Slows the heart’s rhythmic contractions by causing slow hyperpolarisation of the cardiac muscle cells- a metabotropic ACh receptor is coupled by a G protein to a K+ channel which opens to cause hyperpolarisation, reducing firing rate

152
Q

What are autoreceptors

A

Presynaptic receptors sensitive to the neurotrasmitter released by the presynaptic terminal, typically GPCRs that stimulate second messenger formation

153
Q

What do autoreceptors do

A

Act as a safety valve to reduce release when neurotransmitter conc gets too high, allowing the presyaptic terminal to self-regulate

154
Q

How do dendrites function when carrying EPSPs to the axon hillock

A

Electrically passive cables- as current proceeds down them away from the synapse, the EPSP amplitude diminishes as current leaks through membrane channels
Affected by length constant

155
Q

Are most dendrites in the brain passive or excitable?

A

Excitable

156
Q

How are most dendrites in the brain excitable

A

Have voltage-gated Na+, Ca2+, and K+ channels- can rarely generate action potentials but open to act as amplifiers of small PSPs generated far out on dendrites, boosting them towards the soma

157
Q

What are inhibitory synapses

A

Those that act to take the membrane potential away from action potential threshold, exert control of a neuron’s output

158
Q

What disease involves defects of inhibitory glycine receptors

A

Startle disease aka hyperekplexia where benign stimuli cause overexaggerated startle response

159
Q

What defect of inhibitory glycine receptors causes startle disease aka hyperekplexia

A

In humans, cased by a mutation in one amino acid in a glycine receptor gene that causes a chlorine channel to open less frequently when exposed to glycine- glycine is less effective at inhibiting neurons

160
Q

What are most transmitter-gated channels of inhibitory synapses permeable to

A

Cl- only

161
Q

How can the synapse act as an electrical shunt

A

If there is an inhibitory synapse on a proximal dendrite segment near the soma that a current must flow past, the membrane potential is approx -65mV (E Cl), so +ve current flows out the neuron here to bring V, to -65mV, preventing it reaching the soma/axon hillock

162
Q

What is the physical basis of shunting inhibition

A

The inward movement of negative charged Cl- ions, equivalent to outward positive current flow

163
Q

How do inhibitory synapses contribute to synaptic integration

A

IPSPs reduce the size of EPSPs, making the postsynaptic neuron less likely to fire action potentials

164
Q

How does shunting inhibition affect lengt constant

A

Reduces it by reducing Rm, allowing positive current to flow across the membrane instead of down the dendrite towards the spike-initiation zone

165
Q

Where are inhibitory synapses located on neurons

A

Spread over the dendrites, as well as found clustered on the soma and near the axon hillock, where they are in a powerful position to influence postsynaptic neuron activity

166
Q

What does the norepinephrine beta receptor (GPCR in the brain) activate

A

The binding of norepinephrine (NE) to the norepinephrine beta receptor triggers a biochemical cascade in the cell- a G protein is activated that activates intracellylar enzyme adenylyl cyclase

167
Q

The norepinephrine beta receptor (GPCR in the brain)- what does the activated enzyme adenylyl cyclase do

A

Adenylyl cyclase catalyses the chemical reaction that converts ATP into cAMP, a second messenger

168
Q

The norepinephrine beta receptor (GPCR in the brain)- what is the effect of cAMP

A

cAMP stimulates protein kinase (another enzyme) that catalyses phosphorylation of eg K+ channels, causing them to change confirmation and close, reducing K+ conductance

169
Q

The norepinephrine beta receptor (GPCR in the brain)- what si the effect of the K+ channels being closed by phosphorylation

A

Increases dendritic membrane resistance, increasing the length constant, meaning distant/weak excitatory syapses become mroe efefctive at depolarising the spike-initiation zone beyond threshold, making the cell more excitable

170
Q

The norepinephrine beta receptor (GPCR in the brain)- what is the overall function of this GPCR

A

Binding of NE to beta receptors greatly increases the response produced by another neurotransmitter at an excitatory synapse

171
Q

What is the rate-limiting step in ACh synthesis

A

Choline transport into the neuron, as choline plus as acetyl gruop makes ACh

172
Q

Study showing the molecules needed to produce ACh

A

Dietary supplements of choline are sometimes prescribed to those with defecits in cholinergic synaptic transmission

173
Q

What are catecholaminergic neurotransmitters

A

Contain a catechol- eg dopamine, norepinephrine, epinephrine

174
Q

What do catecholaminergic neurons regulate

A

Movement, mood, attention and visceral function

175
Q

What limits the rate of production of catecholaminergic neurons

A

The conversion of tyrosine into dopa by the enzyme tyrosine hydroxylase

176
Q

What are the steps of the production of the different catecholaminergic neurotransmitters

A

Dopa -> DA -> NE -> epinephrine

177
Q

What are the stages of 5HT production

A

Tryptophan ->5-HTP -> 5-HT

178
Q

How are catecholamines removed from the synaptic cleft

A

Selective uptake of neurotransmitters back into the acon terminal by Na+ dependent transporters

179
Q

How is 5HT removed from the synaptic cleft

A

Via a specific transporter

180
Q

What is GABA ynthesised from

A

Glutamate

181
Q

What are endocannabinoids

A

Lipid molecules that can be released from postsynaptic neurons and act on presynaptic terminals as retrograde messengers- serve as a feedback system to regulate conventional synaptic transmission

182
Q

Which 2 neurotrasmitters mediate synaptic inhibition in the CNS

A

GABA mediates most synaptic inhibition in the CNS, glycine mediates most of the rest

183
Q

What do structural variations of GPCRs determine

A

Which neurotransmitter, agonists and antagonists bind to the receptors, as well as which G proteins and effector systems are activated in response

184
Q

What is G proteinn short for

A

Guanosine triphosphate (GTP) binding protein

185
Q

What re the 3 subunits of G proteins

A

Alpha, beta and gamma

186
Q

What is the G protein doing in its inactive state

A

The alpha subunit is bound to a GDP molecule and floats around on the inner surface of the membrane

187
Q

What happens when a GDP bound G protein bumps into the correct GPCR with a transmitter bound to it

A

The GDP is exchanged for GTP- the activated protein splits and the G alpha (GTP) subunit and Gbetagamma subunit become available to actiavet effector proteins

188
Q

What is the process of a G protein stopping working

A

The Galpha subunit is an enzyme that eventually breaks down GTP to GDP, terminating its own activity
The Galpha subunit and Gbetagamma subunit come back together, allowing the cycle to begin again

189
Q

What is the shortcut pathway for G proteins

A

Receptor -> G protein -> Ion channel eg GABAb receptors

The fastest GPC system

190
Q

How is the shortcut pathway for G proteins limited

A

Very localised compared with other effector systems- G protein cannot diffuse very far down the membrane so only nearby channels can be affected

191
Q

What enzymes act to counteract phosphrylation by protein kinases in second messenger cascades

A

Protein phosphatases rapidly remove phosphate gruops from eg ion channels

192
Q

What are protein kinases

A

Downstream enzymes often activated by second messenger cascades by GPCRs, that transfer phosphate from ATP to proteins (phosphorylation) to change their shape and biological activity

193
Q

What are the benefits of second messenger cascades activated by GPCRs

A

A single bound neurotransmitter molecule can activate 10-20 G proteins
Small messengers that can difuse quickly eg cAMP allows signalling over a wide stretch of membrane
Signal cascades provide many sites for further regulation and interaction between cascades

194
Q

What is divergence

A

The ability of a transmitter to activate more than one type of receptor and cause more than one type of postsynaptic response

195
Q

What is convergence

A

Refers to how multiple transmitters, each activating their own receptor type can converge to influence the same effector system- can occur at the level of the G protein, secnod messenger cascade or type of ion channel

196
Q

Evidence for the synaptic delay in chemical synapses vs electrical synapses

A

Synaptic delay of usually 1-5ms in chemical synapses, with virtually none in electrical synspases (Furshpan and Potter, 1957)

197
Q

Study showing how electrical coupling can allow gruops of neurons to trigger firing explosively in an all-or-nothing manner

A

When seriously perturbed, the marine snail Aplysia releases a massive amount of purple ink as a protective screen, mediated by synchronous firing of 3 electrically coupled high-threshold motor cells that innervate the ink gland (Carew and Kandel, 1976)

198
Q

How can gap-junction channel conductance be modulated

A

Most close in response to lowered cytoplasmic pH or elevated cytoplasmic Ca2+, some are sensitive to voltage, some can be phosphorylated by protein kinases

199
Q

Study showing it is Ca2+ that triggers release of transmitter

A

When Na+ and K+ channels are blocked, graded depolarisation of the terminals activates a graded inward Ca2+ current, which results in a graded release of transmitter (Llinas and Heuser, 1977)

200
Q

Study showing where the Ca2+ influx occurs in the postsynaptic neuron

A

Ca2+ influx is 10x greater at the active zone region than anywhere else in the terminal, voltage-gated Ca2+ channels much mroe abundant in the axon terminal (Katz and Miledi, 1967)

201
Q

What suggests the role of external Ca2+ in affecting release of quanta

A

Alterations in external Ca2+ don’t affect the amplitude of the synaptic potential but the number of failures decreases and incidences of higher-amplitude responses increases- suggests external Ca2+ affects probability a quanta is released rather than the quanta size (Katz and Miledi, 1967)

202
Q

What are freeze fracture techniques

A

Involve breaking open frozen tissue under a high vaccuum, used to create sections containing vesicles to view under TEM

203
Q

What technique can be used to view vesicles undergoing exocytosis

A

Quick freezing tissue with liquid helium after the nerve has been stimulated (Alberts et al, 1989)

204
Q

What is presynaptic inhibition

A

When a neuron contacts the axon terminal of another cell, it can reduce the amount of neurotransmitter that will be released by the 2nd cell onto a 3rd cell

205
Q

What is presynaptic facilitation

A

Increases the amount of transmitter released by the presynaptic cell

206
Q

What 3 mechanisms for presynaptic inhibition have been identified in mechanoreceptor neurons of vertebrates

A

Simultanoeus closure of Ca2+ channels and opening of voltage-gated K+ channels, increased Cl- conductance, direct inhibition of transmitter release machinery

Neurophysiology (23 decks)

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