Astrocyte mechanisms in depression

Depression is the most common mental health illness affecting 1 in 4 people in the UK. Common symptoms include feeling numb, pulling away from people and enjoyable activities, insomnia, low energy and poor concentration. It is a leading cause of disability worldwide and significantly increases one's risk for suicide, tragically accounting for more than 6000 deaths per year in the UK.
First line treatments for depression are different classes of antidepressant medications - yet their effectiveness and the extend of adverse side effects varies from patient to patient. Recent research shows that antidepressants improve mood and attention only in about one third of all patients diagnosed with depression. This, and other inconsistencies, demonstrate that our understanding of depression is very much incomplete and that other biological mechanisms are likely to contribute to the evolution of depression. To develop novel antidepressants, particularly for treatment resistant patients, we need to thoroughly and extensively characterise the underlying molecular mechanisms of depression.
Recently non-neuronal brain cells called astrocytes have been associated with depression. Astrocytes control various brain functions such as neuronal energy consumption and the balance of water and ions in the brain. They can also directly communicate with neurons to critically modulate brain functions like memory, sleep and attention. Astrocytes release lactate, a key signalling molecule which has recently been shown to be involved in regulating behaviour related to depression and anxiety in animal models. My own preliminary studies show that (1) decreasing astrocyte lactate worsens the response to stress in mice and (2) two commonly used antidepressants increase brain lactate levels.
Interestingly, antidepressants appear to able to positively modulate lactate levels. My preliminary results show that two commonly prescribed antidepressants can enhance lactate release in mouse brain tissue. Thus, enhancing lactate production might contribute to the therapeutic effect of antidepressants in the brain, yet the precise mechanisms underlying these effects are unknown.
During this project I will use cutting edge measures of molecular and electrical activity of brain cells, combined with genetic modification and behavioural assessment in mice to reveal the relationship between brain lactate and depression/emotional behaviour. I will investigate whether depression is characterised by reduced brain lactate and establish if there is a causal relationship between reduced lactate in the brain and depression. Furthermore, I will investigate whether antidepressants are able to reliably regulate brain lactate and whether this contributes to their therapeutic effects in depression. I will also gather data on other brain processes affected by low brain lactate and how astrocytes are affected by the treatment of antidepressants.
The results will pave the way for the development of new antidepressant treatments with the ultimate aim to reduce the burden to relatives, carers and society and more importantly alleviate everyday suffering in patients.

While depression is the biggest challenge for mental health care, we still know very little about the biological changes driving it. Here, I propose to investigate how non-neuronal brain cells, astrocytes, contribute to the aetiology of depression and to the therapeutic effect of antidepressants.
My preliminary data indicate that reducing lactate specifically in astrocytes in the amygdala augments the stress response in mice. Further preliminary results show that antidepressants fluoxetine and imipramine induce lactate release in vitro.
I hypothesise that lactate, mainly produced by astrocytes in the brain, is an essential regulator of emotional behaviour and crucial for the therapeutic effect of antidepressants.

To test this hypothesis, I will use an unpredictable chronic mild stress model of depression in combination with lactate biosensors, cell type and brain area specific manipulation of astrocyte-derived lactate and astrocyte-specific RNA sequencing to:

1. Determine whether astrocyte-specific reduction of lactate will aggravate depressive phenotype in mice

2. Demonstrate that reducing astrocyte lactate weakens therapeutic effects of antidepressants

3. Identify downstream signalling pathways mediating the effect of lactate on emotional behaviour and define astrocyte-specific genes and pathways affected by antidepressant treatment.

This research will reveal novel molecular mechanisms of depression and will lay the groundwork for the development of a novel class of antidepressant targeting astrocyte signalling pathways.

An MRC Career Development Award would provide me with a unique chance to start pioneering work on the role of lactate signalling controlled by non-neuronal brain cells, astrocytes, in depression. The results of this work will inform the development of novel therapeutic strategies.

This work is of importance to a wide range of scientists, clinicians, patients and the pharmaceutical industry.

The scientific community will benefit from the results of this work as it will
- describe fundamental signalling pathways of neuron-astrocyte communications
- create and characterise in detail novel molecular tools to manipulate lactate signalling that will be of interest especially to researchers studying metabolism and homeostasis
- open new avenues to study astrocyte-neuron interaction via lactate in other neurological and psychiatric disorders including stroke and anxiety
- ensure training of staff in essential in vivo techniques currently identified as an area of skill shortage by the Medical Research Council

Patients, their friends and family and mental health charities will benefit from new knowledge generated on non-neural mechanisms underlying depression. This will improve their understanding of why some patients do not respond to some antidepressants and what scientists are doing to advance treatment strategies. Altogether, it will help patients to understand depression as a complex illness with different underlying biological mechanisms.

Clinicians will find the results are beneficial for their practice as it will broaden their view on depression acknowledging non-neuronal mechanisms. It will improve their communication with patients regarding novel approaches in treatment-resistant depression. This should allow clinicians to make better diagnoses long-term and enable the development of individualised treatment strategies.

The pharmaceutical industry will benefit from the results of this work by having identified novel target pathways for the development of novel treatments in depression. Since many multinational pharmaceutical companies have withdrawn from research into neuropsychiatry, academia has an increased responsibility to keep up research into novel approaches to treatments. This work will identify unexplored astrocyte targets that can be taken forward for further target validation and preclinical testing.