2.2 Depression: the vital role of serotonin

Anti-depressant pills don’t always work. A young woman in one discussion group, whose friend had had to undergo ECT (electro convulsive therapy) for just this reason, wondered how the pills are supposed to work. It took a visit to a cell biology lab for the group to find out. Talking to the researcher it soon became clear that the feeling of wellbeing that we rely on for everyday functioning is affected by specific chemicals in the brain.  The signalling between one nerve cell and the next can break down.  In cases of depression the chemical serotonin, which is present in the gaps between nerve cells in the brain, seems to be less abundant than usual.

In the lab the group were able to see the effects of this directly, by looking at a collection of nematode worms through a microscope. Extraordinary as it may seem, the nerve signalling system in these tiny creatures – a mere millimetre in length – has important features in common with our human one.

Diagram of a nematode worm

Happy nematodes wriggle around hectically as though there is no tomorrow; unhappy ones barely move at all; and it’s serotonin that makes the difference. For scientific researchers, a colony of millimetre worms offers a valuable sample for experiments to investigate the way messages are communicated in our nervous system.

Signals are transmitted in our brains (and other parts of the body) through nerve cells. These neurons, as they are called, are just one of the many different kinds of cell of which our bodies are made. They are unusual amongst cells in that they are extended enormously in one particular direction, creating a long thin thread, almost like a piece of wire.

Diagram of a neuron

In this diagram, the long thin thread (called the axon) carries the signal along. The twig-like branches (called dendrites) receive signals from neighbouring cells. The main body of the nerve cell contains the nucleus (where the cell’s DNA is kept).

Signals pass from one neuron to the next from the axon terminal. By connecting up in this way, groups of neurons form networks or ‘circuits’. The myelin sheath (in yellow) acts as a kind of insulation material which increases the speed of the electrical signal as it passes along the neuron.

Pulses of electricity are able to pass through these long filaments (axons), enabling signals to pass from one part of the body to another. In some places these neurons can be very long indeed – centimetres or even meters in the case of nerves leading to the remote muscles in the foot, for example. Within the brain, distance is not so much of an issue, but complexity most certainly is. As in any complex communication system there need to be many possible pathways for signals to pass along, and consequently many junctions along the way. In the case of the human brain “many” is quite an understatement” – there are perhaps 100 billion nerve cells and 100 trillion junctions between them. It is this sheer quantity that helps explain how we human beings are capable of such extraordinary feats of memory, learning and emotion. 

The key question, given this complexity is how one nerve cell connects with its neighbouring ones. How does the signal transmitted down one axon communicate itself to the next cell? What are we to imagine – a switch to allow electrical impulses to pass? A kind of telephone exchange that connects wires to one another? A spark that leaps from cell to cell? As it turns out the answer is stranger than any of these conjectures. This particular aspect of brain functioning – bridging the gap from one nerve cell to the next – seems to be central to brain disorders such as depression.

At the “head end” of a nerve cell there are literally hundreds of threads leading into the body of the cell (dendrites) and at the tail end there are also many “exits”. So, a single nerve cell may be connected to hundreds, or even thousands of neighbouring nerve cells. In this way, any given nerve cell is connected to many others, forming the so-called “circuits” (or networks) which underlie the extreme complexity of the brain.

Now, back to the junctions ….. the places where the tail end of one nerve cell connects with a dendrite (twig-like branch) at the head end of another. The extraordinary thing is that these two ends don’t actually touch each other – it’s not like two electrical wires touching. In fact the passage of the electrical impulses in the body is quite unlike electricity as we know it from everyday life. There are no wires, no metallic conductors, no switches; in their place is a set of fascinating biological processes that carry out the same function – conducting electrical impulses – but in a wholly different way. And these processes are at the core of research in neuroscience today.

The junction between two nerve endings is called a synapse. When an electrical pulse has passed down the long axon of one cell it reaches its end point where it finds a number of containers (called vesicles) filled with a particular chemical. These chemicals are the neurotransmitters, the vital substances that communicate the pulse from one nerve to the next

Diagram of a synapse

These containers (tiny biological sacks) attach themselves to the wall of the first cell, then open themselves up to the external space and release their contents into the area surrounding the nerve ending. Here the chemicals diffuse across the short distance to the neighbouring nerve cell and are received by large molecules embedded in its outer walls (appropriately called receptors). These large receptor molecules are sensitive to the much smaller molecules that have diffused across the gap (called neurotransmitters), because hollows in their outer surface exactly fit round the diffusing molecules. When the neurotransmitter and the receptor come into contact, a kind of click occurs which slightly alters the shape of the receptor molecule. This tiny change is felt right inside the second nerve cell, because the receptor molecule runs right through the wall, jutting into the interior of it. This change of shape is sufficient to trigger off a new electrical pulse within the second cell; you could almost say, by loose analogy, it flicks a switch in the second cell. The signal that passed through one cell has now been safely transmitted to a neighbouring one where it will rush on once again – a beacon lit in one place has been picked up by another nearby.

You can see an animation of this process on the science museum website: synapse

This highly complex process, involving the molecules that cross the gap and the ones that “click” in response, is breathtaking in its intricacy. It is also remarkably quick – the delay between a pulse arriving at the junction and a new pulse being triggered is measured in milliseconds (thousands of a second). That’s why it takes but a “split second” to establish whether a face is friendly or otherwise – our very existence hangs on the speedy transmission of nerve signals.

However, intricate mechanisms are, as we know from practical experience, also open to failure; nerve transmission is no exception. Problems with the transmitter chemicals at the nerve cell junctions can disrupt the functioning of the brain, and this was the problem for the unhappy nematode worms we met at the beginning of this story.

Research showed that one of the chemicals that transmits the signal, known as serotonin (see diagram), was simply too scarce in the synapses (the gaps between the cells). Its scarcity meant nerve signals were failing to jump from cell to cell as required. A pulse transmitted successfully through one nerve cell was simply failing to pass across the gap to the next cell, stopping the signal in its tracks.

Model of a serotonin molecule

The researchers studying nematode worms in their happy and miserable moods were tackling this very problem: how the level of serotonin in the synaptic gaps affects the sense of wellbeing.

Discoveries to date reveal that the supply of serotonin is dependent on interactions between a set of large protein molecules at the tip of the nerve cell. As you can imagine, given the enormous suffering inflicted by depressive illness, a major research effort is now directed at defects in the supply chain of serotonin. The hope is that ways will be found to compensate for these defects, to restore normal levels of serotonin to the synapses.

Before leaving the topic it’s important to point out that the causes of depression are complex and not  fully understood. If they were, fully effective treatments would be more readily available. This story about serotonin by no means gives the full picture.  As the NHS website says:

It would be too simplistic to say that depression and related mental health conditions are caused by low serotonin levels, but a rise in serotonin levels can improve symptoms and make people more responsive to other types of treatment, such as CBT.

The purpose of this story has been to illustrate, in a particular case, the general process by which messages pass through the nervous system.  Perhaps what is most surprising in all this intricacy is that what goes for tiny worms appears to go for humans too. Over the course of evolution this particular biological process – the serotonin pathway – appears to have changed little. Fortunately for us, this conservative tendency offers hope for the future treatment of depression.  There are many, many pitfalls on the path to successful drug therapies, but basic research about the nature of nerve transmission might one day lead to a pharmaceutical remedy for this most widespread and damaging of disorders.   

© Andrew Morris 4th April 2019