Lectures 9-16: Anatomy and Physiology of Synapse + Synaptic Physiology & Integration Flashcards
Electrical synapses…
Gap junctions (connexons)
Symmetrical bidirectional
very fast (Signals are conveyed cell to cell in <0.3ms)
Ca2+ independent
Temperature insensitive
Large synapse
Allow synchronisation between neighbouring neurones
Usually excitatory
Chemical synapses:
Highly developed structure
Polarised
Pre and post synaptic density
Slow (synaptic delay)
Ca2+ dependent
Temperature sensitive
Excitatory or inhibitory
Specific point to point activity
Molecule that is the main neurotransmitter In excitatory synapses…
Glutamate
Molecule that is the main neurotransmitter In inhibitory synapses…
GABA
The uptake and storage of dopamine in pre synaptic vesicles…
Allows high concentration of transmitter
Allows quantal release of transmitter
Is inhibited by reserpine
Arrival of an action potential at pre synaptic terminal firstly triggers…
Opening of voltage gated calcium channels
Botulinum toxins cause paralysis because they…
Proteolytically cleave SNARE proteins
Inhibit release of acetylcholine at neuromuscular junctions
Acetylcholine:
Binds to ionotropic receptors
Binds to metabotropic receptors
Mediates excitatory transmission in the brain and in the autonomic system
Glutamate:
Binds to ionotropic receptors
Binds to metabotropic receptors
It’s action is terminated by uptake into glial cells
Noradrenaline:
Binds to metabotropic receptors
Mediates excitatory transmission in the brain and in the autonomic system
Can be enzymatically inactivated in pre synaptic terminals
The gap between pre and post synaptic elements at a chemical synapse is about…
50nm
electrical synapses are in…
mammalian retina, spinal cord, bran regions
types of chemical synapse:
axo-dendrite
axo-somatic
axo-axonic
Axo-dendritic=
Between the axon of one Neurone and dendrite of another
Axo-somatic =
Between the axon of one neurone and the soma of another
Axo-axonic=
Between the axon of one neurone and the axon of another
Synapses can be ….
Gray’s type 1 = asymmetrical, excitatory
Gray’s type 2 =
symmetrical, inhibitory
Autonomic nervous system:
Controls voluntary function
Consists of sympathetic and parasympathetic
Sympathetic nervous system:
Fight/flight
Short myelinated preganglionic fibres
Long unmyelinated postganglionic fibres
Postganglionic neurones are noradrenergic = they release noradrenaline which acts on adrenoceptors
Parasympathetic nervous system:
Rest/digest
Long myelinated preganglionic fibres
Short unmyelinated postganglionic fibres
Postganglionic neurones are cholinergic = they release acetylcholine which acts on muscarinic acetylcholine receptors
All preganglionic neurones are …
cholinergic - use acetylcholine as neurotransmitter and act on nicotinic acetylcholine receptors
Nicotinic acetylcholine receptors are…
Ligand gated ion channels
Muscarinic acetylcholine receptors are…
G protein coupled receptors
Stages of chemical synaptic transmission:
1) Neurotransmitter synthesis
2) Neurotransmitter storage into synaptic vesicles
3) Synaptic vesicle cycling, exocytosis and transmitter release
4) transmitter binds to receptor whose identity determines post synaptic response
5) removal of neurotransmitter from synaptic cleft
Vesicles:
Vesicles protect transmitters from degradation by cytoplasmic enzymes and allow regulation
Most transmitters are in 40-50nm vesicles
Neuropeptides (e.g somatostatin) are in larger >100nm dense core vesicles
Vesicle cycling and exocytosis:
Vesicles in the reserve pool are primed to enter readily-releasable pool
Primed vesicles can be induced to fuse with the plasma membrane by sustained depolarisation (elevated Ca2+ in cytoplasm)
Snare zipping is triggered by Ca2+ entering via VOOC
Synaptotagmin =
Is a calcium sensor, it regulates SNARE zipping
SNARE zipping
bridges lipid bilayers and plasma membranes bringing them in proximity and inducing their fusion
Botulinum toxins=
Inhibit vesicle fusion and transmitter release
Quanta -
Corresponds to release of individual synaptic vesicles at the neuromuscular junction
Excitatory post synaptic potential:
Depolarisation
Inward current (Na2, Ca2+)
Increased firing rate (graph increases)
Inhibitory post synaptic potential:
Hyperpolerisation
Inward (Cl-) or outward (k+)
Decreased firing rate (decreased graph)
Amino acid transmitters -
Mediate excitatory (e.g.glutamate) or inhibitory (e.g.GABA or glycine) transmission via ionotropic receptors
Catecholamine and peptide (e.g. enkephalins) transmitters -
modulate transmission via metabotropic receptors by altering the probability of release (of glutamate, GABA, acetylcholine) from presynaptic axon terminals
Acetylcholine -
Mediates excitatory transmission via ionotropic receptors
modulates transmission via metabotropic receptors
Purpose of chemical synapses:
Information transfer between pre synaptic and post synaptic cells
Amplification of signals
Integration of multiple inputs
Plasticity - learning and memory
Neurones are highly complex:
Can generate intrinsic activity or receive inputs from other neurones via synapses
Integrate received synaptic inputs
Encode patterns of activity for output
Distribute outputs to other Nero s via synapses
Ionotropic transmitters:
Open and close to allow ions through a channel by ligand inducing conformational change
Metabotropic transmitters:
Linked to G protein which is activated when ligand binds to receptor which activates a secondary messenger
What makes transmitter excitatory?
If transmitter opens Na+ or Ca2+ ion channels
- these enter cell because of electrochemical gradient
= membrane potential becomes less negative
=excitatory postsynaptic potential
What makes transmitter inhibitory?
If transmitter opens k+ channels
- k+ exits cell down electrochemical gradient
=membrane potential becomes more negative
=inhibitory postsynaptic potential
If transmitter opens Cl- channels
- Cl- enters cell down electrochemical gradient
=membrane potential becomes more negative
=inhibitory postsynaptic potential
if equilibrium potential of chloride (Ecl) is less than resting membrane potential (Vm) …
net influx of Cl- ions = hyperpolarisation = inhibitory
in adult
if equilibrium potential of chloride (Ecl) is more than resting membrane potential (Vm) …
net efflux of Cl- ions = depolarisation = excitatory
in young
calcium channels…
can be both inhibitory and excitatory
adult = inhibitory young = excitatory
excitatory neurotransmitter:
depolarises excitatory post synaptic potential
requires increase in intracellular positive charge (Na or Ca)
= cation influx causes depolarisation
inhibitory neurotransmitter:
hyperpolarises inhibitory post synaptic potential
requires decrease in intracellular positive charge (Na or Ca)
= cation efflux or anion influx causes hyperpolarisation
cys-loop receptor superfamily:
has both inhibitory and excitatory receptors nACH = excitatory 5-HT3 = excitatory GABAa = inhibitory glycine = inhibitory
- have common molecular structure
mutated glycine receptors..
are cation selective
mutated Ach receptors..
are anion selective
comparison of excitatory post synaptic potential and action potential;
both caused by Na influx…
- excitatory post synaptic potential at ligand gated
cation channel
- action potential at voltage gated sodium channels
excitatory post synaptic potential are smaller than action potentials…
- lower number of synaptic ligand gated cation channels than axonal voltage gated sodium channels
- differences in biophysical properties between these two channels
voltage vs ligand gated :
vlotage = hogh cation selctivity = reversal potential is close to reversal potential for the ligand ligand = less selective between different types of cation = reversal potential is around zero - only slightly more selective for one ion
Spatial synaptic integration =
The integration of inputs that arrive on a dendrite of a neurone at multiple different places at the same time
All cause a small depolarisation that summate to produce a larger effect
Total effect on soma membrane potential is sum of all synaptic potentials
E.g purkinje cells
Temporal synaptic integration:
Integration of signals over time
Series of action potentials arriving and active synapse repeatedly = summation of effects over time
Requires long time constant of excitatory post synaptic potential = post synaptic potentials add up
Why does length constant affect spatial synaptic integration?
Amplitude of synaptic potential change reduces with distance from synapse
Decline in synaptic amplitude with distance from synapse is determined by length constant
Length constant =
Distance taken for excitatory post synaptic potential has declined to 37% of its maximum
What parameters determine the length constant of a dendrite?
Dendritic membrane resistance
Axial resistance of dendrite
Not affected by Myelination as dendrites are not myelinated
What parameter
Influences the time constant of a dendrite?
Dendritic Membrane capacitance
When working out Vm, You cannot combine effects of synapses from different distances because…
Activity at one synapse opens ion channels
= change in membrane resistance
= change in length constant
= change in effect on cell soma potential from other synapses
Time constant =
Time it takes for excitatory post synaptic potential to declined to 37% of its maximum
= membrane resistance x membrane capacitance
Effect of greater membrane resistance:
Synaptic current doesn’t leak as rapidly
Postsynaptic potential lasts longer
= longer time constant
Effect of greater membrane capacitance:
More charge resulting from synaptic current flow is stored and discharged after the synaptic current flow has stopped
Postsynaptic potential last longer
=longer time constant
Temporal integrator:
Long time constant
Majority of excitatory postsynaptic potential contribute to activation of action potentials
Precise timing of action potentials is only weakly linked to input pattern
E.g. oculomotor integrator (eye position)
Coincidence detector:
Short time constant
Only few excitatory postsynaptic potentials contribute directly yo activation of action potentials
Timing of action potentials is closely linked to coincident synaptic inputs
E.g. sound localisation between left and right ear and visual processing
Silent postsynaptic inhibition:
Occurs when synaptic reversal potential equals the resting membrane potential
= no current flow
if reversal potential is more positive than membrane potential…
- net inflow of positive charge
- depolarization of the postsynaptic membrane potential
if reversal potential is more negative than membrane potential…
- net outflow of positive charge
- hyperpolarisation of the postsynaptic membrane potential
length constant affects..
spatial summation
time constant affects…
temporal summation
synaptic integration is important because…
neurons receive multiple synaptic inputs and provide multiple synaptic outputs
enables info processing in CNS
integration of synaptic inputs determines nervous system function
parameters that effect synaptic integration:
- complexity of neuritic processes
- distance of synapse to soma
- relative position of synapses to each other
- amplitude of current flow at synapse (multiple synaptic inputs are required to depolarize neuron sufficiently to trigger action potential)
- length constant affects spatial summation
- time constant affects temporal summation
if excitatory and inhibitory synapses are on different dendrites at some distance from soma…
…results in linear summation of currents in soma - smaller depolarization
if inhibitory synapse between excitatory synapse and soma on same dendrite…
…results in current flow that counteracts current flow initiated at excitatory synapse
…results in opening of ion channels lower membrane resistance
- changes length constant of dendrite
- affects spread of EPSP
= both result in non linear summation
= cannot combine effects on soma of EPSP and IPSP
short time constant…
neuron will act as coincidence detector
only EPSPs that arrive nearly simultaneously will summate
long time constant…
Neuron will integrate/summate EPSPs over longer period
precise timing of EPSPs is less important
neuronal activity is more determined by average rate of EPSPs
What happens if synaptic reversal potential equals the resting membrane potential?
= silent postsynaptic inhibition
- neurotransmitter binds to receptor
- opening of postsynaptic ion channels
- change in membrane resistance, but no current flow and no change in membrane potential
when there is only an inhibitory input…
just activates inhibitory synapse
= no current flow
when there is only excitatory input…
more positive than resting potential, ion move into cell
= depolarisaton
when there is excitatory and inhibitory input…
some leakage = less membrane resistance = change in membrane resistance is smaller
= inhibitory ‘shunt’
…(the depolarising current is balanced by the inhibitory current, removing the depolarising effect of the EPSP)
“Silent” Postsynaptic Inhibition in the CNS…
GABA is main inhibitory neuotransmitter in CNS
GABAa receptor = ligand gated chloride channel
GABAb receptor is a (metabotropic) GPCR
chloride reversal potential is -70mV
problems associated with studying integration..
connected neurons frequently form multiple contacts with each other
= even stimulating a single neuron usually activates multiple synaptic sites
experimental approaches for studying integration…
computational models
- useful
- only as good as underlying assumptions
photolysis of caged neurotransmitter to mimics synaptic transmitter release
(photo release of caged glutamate to simulate effect of glutamate release at individual synapses
photolysis of caged neurotransmitter:
- brain slice is bathed in solution of ‘caged’ neurotransmitter (inactive)
- exposure to UV light releases active transmitter – mimics synaptic release
- neuron is filled with fluorescent dye to visualise processes
- UV light is focussed on small spots along dendrites and briefly turned on = release of small amount of glutamate
EPSP and IPSP summate, but summation is only linear when…
…when synapses are on different dendrites so that changes in membrane resistance do not affect spread of EPSP or IPSP
“Silent” postsynaptic inhibition:
Inhibitory synapses can affect EPSPs, even if they do not cause a change in membrane potential
Homosynaptic short-term synaptic plasticity:
amplitude of synaptic potentials/synaptic currents can vary strongly depending on preceding activity
= activity dependent short-term plasticity
synaptic facilitation -
‘paired-pulse’ facilitation:
- first action potential
- Ca2+ influx = release of transmitter from some vesicles = priming of other vesicles - increased number of primed vesicles
- second action potential
- Ca2+ influx = more transmitter release
synaptotagmin 7 =
= calcium sensors that control synaptic vesicle release, essential for synaptic facilitation
spike broadening during synaptic facilitation:
repetitive firing can lead to spike broadening
- longer presynaptic depolarisation
- more presynaptic Ca++ influx
- more transmitter release
- increased synaptic response
synaptic depression:
at some synapses repeated firing of presynaptic neuron leads to progressively weaker postsynaptic responses
- first action potential
- Ca2+ influx, releae of docked vesicles - causes depletion of docked vesicles
- second action potential
- Ca2+ influx, few docked vesicles ready to release
Heterosynaptic modulation of synapse function…
Postsynaptic modulation:
Modulatory input alters sensitivity of postsynaptic membrane to presynaptic transmitter release
Heterosynaptic modulation of synapse function…
Presynaptic modulation:
Modulatory input alters presynaptic transmitter release
Two examples:
- Presynaptic inhibition
- Presynaptic facilitation
Postsynaptic modulation – Example 1 : GABAa receptor modulation by phosphorylation
- activation of G-protein coupled receptor (e.g. serotonin receptor)
- activation of protein kinase (e.g. protein kinase A)
- phosphorylation of GABAA receptor
- alters GABAA receptor function – can either enhance or suppress receptor function depending on phosphorylation site and subunit composition of GABAA receptor
Postsynaptic modulation – Example 2 : Altering the number of postsynaptic receptors
- GABAA receptors are assembled in endoplasmatic reticulum and packaged into vesicles in Golgi apparatus
- Insulin promotes the insertion of GABAA receptors into the postsynaptic membrane = increase in postsynaptic receptor number
- BNDF (brain-derived neurotrophic factor) promotes removal of GABAA receptors = decrease in postsynaptic receptor number
Presynaptic inhibition – a presynaptic mechanism of heterosynaptic modulation
Inhibitory + Excitatory Input
= Reduced presynaptic Ca++ influx
= Reduced transmitter release
= Reduced receptor activation
= Reduced EPSP
Heterosynaptic facilitation – a presynaptic mechanism for synapse strengthening
Example: Sensitisation of gill withdrawal reflex in sea hare Aplysia californica
- Touch of siphon alone produces weak gill withdrawal response
- Touch of siphon briefly after electrical shock of tail enhances gill withdrawal response, i.e. touch response has been sensitised
- Sensitisation is due to heterosynaptic facilitation of sensory to motoneuron synapse
Heterosynaptic facilitation –How does it work?
1) 5-HT activates metabotropic 5-HT receptor
2) 5-HT receptor activates adenylate cyclase
3) Increase in intracellular cAMP concentration
4) cAMP activates protein kinase A
5) PKA phosphorylates voltage-gated K+ channel = reduction in K+ current during action potential = broadening of AP
6) Voltage-gated Ca++ channels are open longer = more Ca++ influx
7) Higher Ca++ concentration = more transmitter release
Mechanisms of synaptic modulation:
Presynaptic:
- altered vesicle release
- altered Ca++ entry
- altered vesicle recycling
Postsynaptic:
- altered receptor function
- altered receptor number
long term synaptic plasticity
- long term potentiation in hippocampus is important for learning
Synapses with low release probability….
are more likely to show synaptic facilitation
synapses with high release probability….
more likely to show synaptic depression
Heterosynaptic modulation of synapse function:
- Altering sensitivity of postsynaptic neuron to presynaptic transmitter release – can lead to facilitation or depression of synapse
- Altering presynaptic transmitter release by modulation of presynaptic calcium influx – can lead to facilitation or depression of synapse
short term synaptic plasticity:
- Synaptic facilitation
- Synaptic depression
