Lecture 9 - synapses & neurotransmitter Flashcards
What should a neurotransmitter be?
- be present in the presynaptic terminals
- be released in response to stimulation
- act on the postsynaptic neuron
- blocking the neurotransmitter should prevent synaptic transmission
How do we experimentally determine if a molecule acts a neurotransmitter?
- IS IT THERE? –> immunostaining
- does the cell express enzymes to synthesise it, or immunostaining, in situ hybridisation
- IS IT RELEASED? –> collect fluid around the neurons after stimulating them (this might be difficult) - remember Loewi’s 1921 experiment
DOES IT AFFECT THE POSTSYNAPTIC CELL? –> test if the molecule mimics the effect of stimulating the presynaptic cell
BLOCK THE NEUROTRANSMITTER? –> apply drugs; delete genes encoding enzymes/transports/receptors
What are 3 types of neurotransmitters?
- amino acids
- amines
- peptides
Describe the features of amino acids & amines
- small molecules (100-200 Da)
- stored in synaptic vesicles
- can bind to ligand-gated ion channels or G-protein coupled receptors
Describe the features of peptides
- large molecules (1000-3000 Da)
- stored in secretory granules
- only bind to G-protein coupled receptors
How many kinds of neurotransmitters do neurons usually release?
one kind of neurotransmitter, but some can release more than one
What do peptide-releasing neurons also release?
a small molecule transmitter, called a ‘co-transmitter’
Describe different types of neurotransmitter receptors
- Ligand-gated ion channels (ionotropic receptors) –> directly depolarise or hyperpolarisation and the post synaptic cell
- G-protein- coupled receptors (metabotropic receptors) –> more complex effects (multiple possible second messengers, which allow amplification)
How does convergence & divergence allow flexibility?
- each transmitter can activate multiple different receptors
- each receptor can activate different downstream effectors
- different transmitters or receptors can activate the same downstream effector
Describe the features of glutamate
- most common excitatory transmitter in CNS
- amino acid, therefore found in all neurones
- 3 ionotropic glutamate receptor subtypes based on the drugs which act as selective agonists
- action is terminated by selective uptake into the presynaptic terminals & glia
What are the 3 types of receptors affected by Glutamate?
- AMPA
- NMDA
- Kainate
Describe features of Glutamate - AMPA receptors
- AMPA receptors mediate fast excitatory transmission
- Glutamate binding to AMPA receptors trigger Na+ & K+ currents resulting in an EPSP (excitatory post synaptic potential)
- opening of the receptors is going to depolarise the cell, as the cell is already negative - leading to positive current flowing into the cell
Describe the features of a Glutamate - NMDA receptors
- NMDA receptors often co-exist with AMPA receptors
- NMDA receptors have a voltage-dependent Mg+ block
- so, NMDA receptors only open when the neurons is already depolarised
- NMDA receptors let Ca+ in –> leads to downstream signalling
- NMDA receptors function as a coincidence detector: when a neuron is activated right after it was already activated
What else do glutamate activate?
metabotropic glutamate receptors (mGluRs)
Describe ionotropic receptors
- 4 subunits forming a gated ion channel
- Examples - AMPAR NMDAR
- works by opening ion channel
- FAST (msec)
Describe metabotropic receptors
- G-protein coupled receptor
- Examples - mGluR1, mGluR2
- works by activating G-protein, which triggers downstream singalling cascade
- SLOW (sec-min)
What do mGluRs allow?
mGluRs allow glutamate to sometimes be inhibitory (e.g. in the retina)
What is GABA (Y-amino butyric acid)?
- not an amino acid used to synthesise protein
- synthesised from glutamate by enzyme glutamic acid decarboxylase (glutamate without carboxyl group)
- action is terminated by selective uptake into presynaptic & glia
Is GABA normally an inhibitory neurotransmitter?
YES
- most common inhibitory transmitter in the CNS
- produces IPSPs (inhibitory postsynaptic potential) via GABA-gated chloride channels (GABAa receptors), if the membrane potential is above chloride’s Nerst potential
What happens if there isn’t the right amount of inhibition via GABA?
- too much –> coma or loss of consciousness
- too little –> seizures
Describe what occurs during the modulation of GABAa receptors
- other chemicals can bind to the GABAa receptor and modulate the response to GABA binding
- these chemicals have no effects without GABA binding (allosteric drug)
- Benzodiazepines e.g. diazepam, used to treat anxiety
- barbiturates are sedatives & anti-convulsants
- neurosteriods are metabolites of steroid hormones e.g. progesterone (possible natural regulators)
How does GABA act?
via metabotropic GABAab receptors
Describe how GABA acts via metabotropic GABAb receptor
- like the mGluRs, GABAb receptors are GPCPs
- they act in diverse ways in different cells, but might:
- open K+
- close Ca2+ channels
- trigger other second messengers like cAMP
- often presynaptic or autoinhibitory
What is glycine?
- inhibits neurones via glycine-gated chloride channel (glycine receptor)
- but it also binds to NMDA glutamate receptors
What is dendritic integration?
- each individual EPSP is not enough by itself to trigger an action potential (a few millivolts) - multiple EPSP (either from different parts of the neuron or in quick succession) to depolarise the cell enough to fire an action potential
- when the postsynaptic neuron is depolarised, the voltage rises, but when the glutamate leaves, the postsynaptic neuron DOESNT FALL BACK DOWN STRAIGHT AWAY - few milliseconds in between - this create a window in which, if another EPSP arrives, it will raise cells voltage from a higher starting point (or baseline)
- depolarisation at various parts of the dendritic tree (positive currents) - these currents diffuses and propagates passively till it reaches the part of the neuron with has a high concentration of voltage-gated sodium channels - usually the axon segment (axon pollick)
The axon pillock is where there may be enough voltage-gated sodium channels, that if a wave of depolarisation from the dendrites arrives, this will lead to a rise in membrane potential past the threshold, triggering the sodium channels
Does it matter how excitatory & inhibitory synapses are arranged spatially?
YES
- an inhibitory synapse can block the propagation of an EPSP towards the soma
- GABAa receptors don’t always produce an IPSP, e.g. if Vm is near chloride’s Nernst potential
- in this can they act by SHUNTING INHIBITION
- opening chloride conductance decreases the membrane resistance –> current leaks out the membrane
- location/geometry of the synapses are important - e.g. inhibitory synaose must be after excitatory synapse otherwise there would be no point of the inhibitory synapse
Explain how inhibition often occurs pre-synaptically?
- an action potential arises at the axon terminal, which opens voltage gated calcium channels - triggering synaptic release. HOWEVER, the release of GABA on the first neuron - activating GABAb receptors - triggering a downstream signalling cascade - e.g. deactivation of calcium channels - this will prevent the release of the presynaptic release of neurotransmitters
What is inhibition for?
- inhibitory neurons control/sculpt the activity of excitatory neurons
- inhibitory neurons can gate signals and shut down pathways
What is glutamate?
the major excitatory neurotransmitter
What is GABA?
the major inhibitory neurotransmitter
