Researchers hope to boost memory receptors in the brain

Danish brain researchers are hoping to be able to boost receptors in the brain that can help to improve recall in patients with memory dysfunction as a result of a past or current major depression.

The researchers, from the University of Copenhagen, Mental Health Services – Capital Region of Denmark and Rigshospitalet, University of Copenhagen, used brain scans to demonstrate that patients with untreated depression have 7-10 percent fewer well-functioning serotonin 4 receptors in their brain.

These are the signal receptors located in areas such as the hippocampus, and play a major role in how memory works.

‘The study showed a significant difference in the brain of healthy versus mentally ill individuals. The study also indicated that patients with depression, who have a lower level of well-functioning serotonin 4 receptors, basically have poorer recall than patients with higher levels,’ says Vibe Frøkjær, consultant physician and researcher at Mental Health Services – Capital Region of Denmark, the Neurobiology Research Unit at Rigshospitalet, University of Copenhagen and at University of Copenhagen.

This discovery, published in the eminent JAMA Psychiatry journal, means that serotonin 4 receptors are a promising treatment target for helping patients with memory dysfunction if research can find a way of stimulating the receptor.

The serotonin 4 receptor clearly plays a major role in well-functioning memory processes. So, boosting its role inside the receptor might improve memory in such patients,’ Frøkjær explains.

She adds that this hope is based on actual research findings.

‘Studies in animals show that the effect of stimulating these receptors resembles that achieved from prescribing anti-depressants or anxiolytics (tranquilisers), and studies involving healthy human subjects indicate that stimulation can boost cognitive capacity. The hope is naturally that if we can do this in people with conditions that impair memory, that we will be boosting cognitive functions such as recall,’ says Frøkjær.

 

Low level of receptors may be hereditary

There are still many unknowns surrounding serotonin 4 receptors and depression. For example, it has not been firmly established whether depression occurs because the receptor is dysfunctional or, vice versa: that depression makes it dysfunctional.

However, brain scan studies have also shown that the amount of receptors people have may be hereditary, and that the number of well-functioning receptors is lower in people from families susceptible to depression.

Dr Frøkjær brings up an image of three brain scans. All three have two bright kidney-shaped spots on the right and left sides near the centre. But the brightness of the fields in the three brains is very different.

 

‘We can’t see the actual serotonin 4 receptors in the images, but we can see a signal from the bonds they form with our signalling substances. And the image shows that the more close family members you have with depression, the lower your own serotonin 4 receptor bond. There are fewer serotonin 4 receptors to bond with, which is why there is less light in those areas,’ Frøkjær explains.
 

Depression relief and prevention potential

Successfully boosting serotonin 4 receptors might benefit people with depression in several ways. Patients might not only improve their memory and thereby their quality of life.

‘Serotonin 4 receptors might also have a big influence on the brain’s ability to register pleasure and enjoyment, and the desire for food, physical exertion and sex, which in turn activate the brain’s ‘reward system’, where such receptors are densely packed. For many patients, it can be severely disabling to not have access to desire/motivation, and it can have a self-reinforcing effect on depression,’ says Frøkjær.

She believes that stimulating the serotonin 4 receptors might also prevent depression relapse.

‘That could be very significant for the patient’s long-term prognosis, as there is often a high risk of relapse in depression. It might, for example, be difficult to get back to work after a depression, especially if the person has memory problems, and dysfunction in everyday life might be limiting and bring on a new depressive episode. Treating memory impairment may therefore help to prevent relapse,’ Frøkjær explains.

The research team hopes to conduct a study to test the effect of medicinal stimulation of serotonin 4 receptors and to determine whether this could ultimately become a standard treatment for patients with severe memory dysfunction.

The research is supported by the Lundbeck Foundation via a grant made to the Lundbeck Foundation Centre for Integrated Molecular Brain Imaging (CIMBI).