Action potentials are transmitted along axons to specialised regions called synapses, where the axons contact the dendrites of other neurons. These consist of a presynaptic nerve ending, separated by a small gap from the postsynaptic component which is often located on a dendritic spine. The electrical currents responsible for the propagation of the action potential along axons cannot bridge the synaptic gap. Transmission across this gap is accomplished by chemical messengers called neurotransmitters.
Storage and Release
Neurotransmitters are stored in tiny spherical bags called synaptic vesicles in the endings of axons. There are vesicles for storage and vesicles closer to nerve endings that are ready to be released. The arrival of an action potential leads to the opening of ion-channels that let in calcium (Ca++).
This activates enzymes that act on a range of presynaptic proteins given exotic names like “snare”, “tagmin” and “brevin” – really good names for the characters of a recent scientific adventure story.
Neuroscientists have only just discovered that these presynaptic proteins race around tagging and trapping others, causing the releasable synaptic vesicles to fuse with the membrane, burst open, and release the chemical messenger out of the nerve ending.
This messenger then diffuses across the 20 nanometre gap called the synaptic cleft. Synaptic vesicles reform when their membranes are swallowed back up into the nerve ending where they become refilled with neurotransmitter, for subsequent regurgitation in a continuous recycling process. Once it gets to the other side, which happens amazingly quickly – in less than a millisecond – it interacts with specialised molecular structures, called receptors, in the membrane of the next neuron.
Glial cells are also lurking all around the synaptic cleft. Some of these have miniature vacuum cleaners at the ready, called transporters, whose job is to suck up the transmitter in the cleft. This clears the chemical messengers out of the way before the next action potential comes. But nothing is wasted – these glial cells then process the transmitter and send it back to be stored in the storage vesicles of the nerve endings for future use.
Glial-cell housekeeping is not the only means by which neurotransmitters are cleared from the synapse. Sometimes the nerve cells pump the transmitter molecules back directly into their nerve endings. In other cases, the transmitter is broken down by other chemicals in the synaptic cleft.
Messengers that open ion channels
The interaction of neurotransmitters with receptors resembles that of a lock and key. The attachment of the transmitter (the key) to the receptors (the lock) generally causes the opening of an ion channel; these receptors are called ionotropic receptors. If the ion channel allows positive ions (Na+ or Ca++) to enter, the inflow of positive current leads to excitation. This produces a swing in the membrane potential called an excitatory post-synaptic potential (epsp).
Typically, a large number of synapses converge on a neuron and, at any one moment, some are active and some are not. If the sum of these epsps reaches the threshold for firing an impulse, a new action potential is set up and signals are passed down the axon of the receiving neuron.
The main excitatory neurotransmitter in the brain is glutamate. The great precision of nervous activity requires that excitation of some neurons is accompanied by suppression of activity in other neurons. This is brought about by inhibition. At inhibitory synapses, activation of receptors leads to the opening of ion channels that allow the inflow of negatively charged ions giving rise to a change in membrane potential called an inhibitory post-synaptic potential (ipsp). This opposes membrane depolarisation and therefore the initiation of an action potential at the cell body of the receiving neuron. There are two inhibitory neurotransmitters – GABA and glycine.
Synaptic transmission is a very rapid process: the time taken from the arrival of an action potential at a synapse to the generation of an epsp in the next neuron is very rapid 1/1000 of a second. Different neurons have to time their delivery of glutamate on to others within a short window of opportunity if the epsps in the receiving neuron are going to add up to trigger a new impulse; and inhibition also has to operate within the same interval to be effective in shutting things down.
Messengers that modulate
The hunt for the identity of the excitatory and inhibitory neurotransmitters also revealed the existence of a large number of other chemical agents released from neurons. Many of these affect neuronal mechanisms by interacting with a very different set of proteins in the membranes of neurons called metabotropic receptors.
These receptors don’t contain ion channels, are not always localised in the region of the synapse and, most importantly, do not lead to the initiation of action potentials. We now think of these receptors as adjusting or modulating the vast array of chemical processes going on inside neurons, and thus the action of metabotropic receptors is called neuromodulation.
Metabotropic receptors are usually found in complex particles linking the outside of the cell to enzymes inside the cell that affect cell metabolism. When a neurotransmitter is recognised and bound by a metabotropic receptor, bridging molecules called G-proteins, and other membrane-bound enzymes are collectively triggered.
Binding of the transmitter to a metabotropic recognition site can be compared to an ignition key. It doesn’t open a door for ions in the membrane, as ionotropic receptors do, but instead kick-starts intracellular second messengers into action, engaging a sequence of biochemical events.
The metabolic engine of the neuron then revs up and gets going. The effects of neuromodulation include changes in ion channels, receptors, transporters and even the expression of genes. These changes are slower in onset and more long-lasting than those triggered by the excitatory and inhibitory transmitters and their effects extend well beyond the synapse. Although they do not initiate action potentials, they have profound effects on the impulse traffic through neural networks.
Identifying the messengers
Among the many messengers acting on G-protein coupled receptors are acetylcholine, dopamine and noradrenaline. Neurons that release these transmitters not only have a diverse effect on cells, but their anatomical organisation is also remarkable because they are relatively few in number but their axons project widely through the brain.
There are only 1600 noradrenaline neurons in the human brain, but they send axons to all parts of the brain and spinal cord. These neuromodulatory transmitters do not send out precise sensory information, but fine-tune dispersed neuronal assemblies to optimise their performance.
Noradrenaline is released in response to various forms of novelty and stress and helps to organise the complex response of the individual to these challenges. Lots of networks may need to “know” that the organism is under stress. Dopamine makes certain situations rewarding for the animal, by acting on brain centres associated with positive emotional features. Acetylcholine, by contrast, likes to have it both ways. It acts on both ionotropic and metabotropic receptors.
The first neurotransmitter to be discovered, it uses ionic mechanisms to signal across the neuromuscular junction from motor neurons to striated muscle fibres. It can also function as a neuromodulator. It does this, for example, when you want to focus attention on something – fine-tuning neurons in the brain to the task of taking in only relevant information.