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what is a synapse
junction between two neurons allowing signals to pass from one to the other
how many neurones does the human brain have
~100 billion
how many neurones does the human brain have
~100 trillion
what is the neurone doctrine theory
the brain is made of separate cells
what is reticular theory
neurones are connected in a continuous network
what theory did golgi believe
reticular theory
what theory did cajal believe
neurone doctrine
what evidence supported neurone doctrine
sherrington (~1900) found differences in reflex timing (due to different no.s of neurones and gaps)
electron microscopy (1950’s) showed synapses
what are the types of synapses
electricl and chemical
what do synapses enable
flexible processing + integration
what are electrical synapses formed of
gap junctions
what is the diameter of a gap junction
~1-2 nm
what happens to action potentials as they pass between gap junctions
passed from one cell to the other but reduced
what are 2 ways of testing if neurones are connected by gap junctions
use a GFP in one cell , then inject small dye that can diffuse between neurones. another cell getting filled with red dye indicates connection by gap junctions
or stimulate one neuron and record it from another, depolarisation and repolarisation should both be passed to the neuron. then delete connexin genes and repeat, if stimulus is blocked from passing GJs are present
what are electrical synapses good for
fast communication + synchronising neurones
what was the first evidence of chemical synapses
Otto Loewi:
stimulated vagus nerve of an isolated frog heart (donor), the heart rate slowed + he took sample of fluid released around the heart
added this fluid to another isolated frog heart (recipient) and found heart rate slowed as well
how wide are chemical synapses
12-20nm
what do motor neurones synapse to
skeletal muscle
what do autonomic neurones synapse to
hormonal gland, smooth muscle, or heart
what are the staged of chemical synaptic transmission
package NTs in vesicles + put at the pre-synaptic terminal
AP arrives → voltage gated Ca2+ channels open
Ca2+ influx → vesicles fuse to membrane + NT released
NTs diffuse across synaptic cleft + activate receptors on post synaptic cell → further signalling
NTs removed from cleft
what are the two vesicles NTs can be packaged into
synaptic vesicles and dense-core secretory granules
how big are synaptic vesicles
40-50nm
how big are dense-core secretory granules
100nm
what do synaptic vesicles carry
small molecule NTs
what do dense-core secretory granules carry
peptide NTs
what fills synaptic vesicles
transporter proteins at the presynaptic terminal
what creates + fills dense-core secretory granules
ER/golgi secretory apparatus
are synaptic vesicles reusable
yes, recycled by endocytosis
are dense-core granules reusable
no
how do vesicles fuse to the membrane
Ca2+ binds to synaptotagmin + causes conformational change, making SNAREs ‘zipper’ together + forcing vesicle to fuse to the plasma membrane
what toxins target SNAREs
botulinum toxin + tetanus toxin
what are the 2 types of post synaptic receptors
ligand gated ion channels + G-protein-coupled receptors
how do ligand gated ion channels cause depolarisation
direct depolarisation
how do G-protein-coupled receptors cause depolarisation
leads to downstream effects which then lead to depolarisation
what are 3 ways NTs are removed from the synaptic cleft
diffuse away
actively taken up by transporters for recycling
destroyed by enzymes
what are similarities between electrical and chemical synapses
plastic (can be modified) + allow summation by post synaptic neurone
compare electrical and chemical signals (direction, speed, etc)
Electrical | Chemical |
Signals pass in both directions | Signals pass in one direction |
Signals are passed directly, can only be attenuated | Signals can be radically transformed (inverted, amplified, modulated...) |
Fast (<0.3 ms) | Slower (0.3–5 ms) |
what NT is used at neuromuscular junctions
acetylcholine
how does the NMJ achieve efficient transmission
one of the largest synapses in the body
large number of active zones in presynaptic neurone
junctional folds in postsynaptic membrane (densely filled with NT receptors)
(active zones + junctional folds precisely aligned)
who discovered that NTs are released by vesicles
Bernard Katz
how do CNS synapses vary
shape adapted to purpose
can be axon-axon, axon-dendrite, or dendrite-dendrite
what is an end plate potential (EPP)
voltage that causes depolarisation of skeletal muscle fibres in the NMJ
what is a miniature end plate potential (MEPP)
small depolarisations caused release of a single vesicle
what is a quantum
1 vesicle full of NT
what 4 criteria must a molecule meet to be a neurotransmitter
should be present in presynaptic terminals
should be released in response to stimulation
should act on the postsynaptic neurone
blocking the neurotransmitter should prevent synaptic transmission
what experimental technique is carried out to determine if a neurotransmitter is present
immunostaining
what experimental technique is carried out to see if a cell expresses enzymes to synthesise NTs or transporter proteins to store it
immunostaining or in situ hybridisation
how do you determine if a NT is released
collect fluid around neurones after stimulating them
how do you determine if a NTs affects the postsynaptic cell
testing if the molecule mimics the effects of stimulating the presynaptic cell
how do you block a NT
apply drugs or delete genes encoding enzymes, transporters, or receptors
what are the 3 types of neurotransmitters
amino acids
amines
peptides
compare aa, amines, and peptides
Amino acids and amines | Peptides |
Small molecules (100-200 Da) | Large molecules (1000-3000 Da) |
Stored in synaptic vesicles | Stored in secretory granules |
Can bind to ligand-gated ion channels or G-protein coupled receptors | Only bind to G-protein coupled receptorsglutamate |
what are the major excitatory NTs
glutamate
what type of NT is glutamate
amino acid
what are the ionotropic glutamate receptors
AMPA, NMDA, kainate
what are the metabotropic glutamate receptors
mGluR1 mGluR2
what is the mechanism for activating ionotropic receptors
opening ion channel
what is the mechanism for activating metabotropic receptors
activating G-protein to trigger downstream signalling cascade
how is glutamate + GABA action terminated
selective uptake into presynaptic terminals + glia
what do AMPA receptors mediate
fast excitatory transmission
how are AMPA receptors activated
glutamate binds, triggering Na+ and K+ currents and resulting in an EPSP
how do NMDA receptors function
often coexist with AMPA receptors, act as a coincidence detector
how are NMDA receptors activated
only opne when the neurone is already depolarised due to voltage dependent MG2+ block. let Ca2+ in which leads to downstream signalling
what are the major inhibitory NTs
GABA (γ-amino butyric acid)
glycine
how is GABA made
synthesised from glutamate by glutamic acid decarboxylase
what are GABAA receptors
GABA-gated chloride channels
what are GABAB receptors
G-protein coupled receptors that can open K+ channels, close Ca2+ channels, or trigger other seconds messengers like cAMP
(often presynaptic or autoinhibitory)
what does glycine act on
glycine gated chloride channels + NMDA glutamate receptors
what are the major modulatory NTs + what do they act on
allosteric drugs: ethanol, benzodiazepine, barbiturates, neurosteroids: bind to GABAA + modulate response to GABA binding
how does inhibition occur presynaptically
GABA inactivated Ca2+ channels so when an AP arrives, less Ca2+ enters, less NT is released, + there is a reduced effect on the postsynaptic membrane
how is ACh created
combining choline + Acetyl CoA by ChAT (choline acetyltransferase)
how is ACh broken down in the synaptic cleft
converted to acetic acid + choline by acetylcholinesterase
what is a marker for cholinergic neurones
ChAT
where is Acetyl CoA produced
cellular respiration in mitochondria
what are nicotinic/ionotropic receptors (nAChRs)
ACh gated Na+/Ca2+ channel found at the NMJ + CNS
what are muscarinic/metabotropic receptors (mAChRs)
5 types of GPCRs found in the CNS + ANS
how many more mAChRs are there than nAChRs in the brain
~10-100x
what are the 5 types of mAChRs
M1,3,5: excitatory via Gq
M2,4: inhibitory via Gi/o
what drugs block release of ACh
botulinum toxin + black widow spider venom
what drugs block AChE
nerve gas + organophosphate pesticides + alzheimer’s treatments
what drugs activate ACh receptors
nicotine + muscarine + neonicotinoid pesticides
what drugs block ACh receptors
nicotinic: curare + a-bungarotoxin
muscarinic: atropine
what is used to treat nerve gas poisning
atropine
what are monoamines synthesised from
amino acids
what are the catecholamines
tyrosine → L-dopa → dopamine → noradrenaline → adrenaline
what is the rate limiting step in catecholamines
tyrosine → L-dopa by tyrosine hydroxylase (TH)
how is serotonin produced
tryptophan → 5-HTP → serotonin/5-HT
what is the rate limiting step of serotonin production
tryptophan
how are monoamines stored
packaged into vesicles by vesicular monoamine transporters (VMAT)
how are monoamines destroyed
by monoamine oxidase (MAO) in presynaptic cell
how are catecholamines destroyed
by monoamine oxidase (MAO) in presynaptic cell
catechol-O-methyltransferase (COMT) on postsynaptic cell
what are most monoamine receptors
GPCRs, serotonin is the exception
what are the dopamine receptors
D1-like: D1,D5
D2-like: D2, D3, D4
what are the adrenaline + noradrenaline receptors
alpha + beta adrenergic receptors
what are the serotonin receptors
7 receptors: 1 is ligand gated Na+/K+ channel
what are the 2 major functions of dopamine
motor control + ‘reward’
how do dopaminergic neurones control motor control
dopaminergic neurones in the substantia nigra project to the striatum (nigrostriatal pathway)
this facilitates initiation of voluntary movement
what causes parkinson’s disease
dopiminergic receptors in nigrostriatal pathway die → motor dysfunction
how is parkinsons treated
treated with L-dopa
(TH is limiting factor so dont add tyrosine + dopamine doesnt cross blood brain barrier)
monoamineoxidase inhibitors also used
how does dopamine control ‘reward’
dopaminergic neurones in the ventral tegmental area (VTA) project to the cortex + limbic system (mesolimbic pathway)
mediated reward/motivation
