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Molecules that Mould the Mind

Credit: PhenomArtlover/iStockphoto

Credit: PhenomArtlover/iStockphoto

By Michael Notaras

Molecular psychiatrists are revealing how stress during critical periods in adolescence can influence mental illness later in life.

According to the 2013 report on Mental Health by the Australian Bureau of Statistics, 45% of Australians will experience a mental disorder within their lifetime, of which 76% will do so before the age of 25. This early age of onset means that manifestations of illness can occur during adolescence, a critical period of development that comprises sexual maturation and ongoing changes in the brain.

Decades of research has led to the conclusion that mental illnesses are associated with discrete changes within the brain, including changes in the functioning of the major neurotransmitter systems. In support of this view, antidepressant drugs act principally within the brain and do so via the targeted modulation of specific neurotransmitters such as serotonin and norepinephrine.

But how critical is the chemistry of the brain? Can any one molecule truly change behaviour or impart a risk of mental illness?

My research has focused on how the early experience of stress during development can change adult behaviour. This work is important, as a history of stress, childhood adversity or abuse has been consistently associated with an increased risk of mental illness in adulthood. This suggests that the experience of stress during critical periods may induce long-term changes in the brain that could impart susceptibility to mental illness later in life.

Indeed, early observations from my own experiments have led to the conclusion that the early experience of stress – such as during adolescence – not only can determine adult behaviour but is associated with discrete changes in the chemistry of the brain. The nature of this work has led to a focus on one particular molecule.

Brain-Derived Neurotrophic Factor

Brain-Derived Neurotrophic Factor (BDNF) is a molecule that is centrally expressed within the brain, and is involved in the development, differentiation and plasticity of brain cells during brain maturation. Following adolescent development, BDNF remains heavily expressed in the adult brain in regions involved in memory and emotion, such as the hippocampus, and plays a key role in modulating the release of neurotransmitters and synaptic plasticity within this region.

BDNF has been extensively investigated for its role in mental illness, particularly because stress is able to determine the expression of this molecule within the brain, and is of interest due to its involvement in not just brain development but also its ability to regulate system physiology in adulthood. In this respect, if the expression or activity of BDNF is sequestered at different times during development, divergent effects on brain structure and function may emerge, each of which may influence the risk of mental illness.

Genetic association studies of healthy and psychiatric populations have found that variation within the gene encoding BDNF may be associated with a risk of several mental illnesses, including certain anxiety and mood disorders. However, a limitation of these association studies is deducing what a single genetic change in the BDNF gene may be doing within the brain – an especially difficult task given the wide range of functions of this molecule.

Indeed, even when human brain tissue is available for researchers to use, the potential effects of ageing or suicide may act as confounding factors. Further, protein within the brain degrades relatively quickly, and if tissue is not rapidly preserved the full utility of human brain tissue can be further diminished. Given how precious human tissue is, ensuring that it is preserved and used for only the most definitive of studies is also important.

Using rodents that can be genetically modified to under-, over- or not express BDNF, the causative effects of this molecule on brain structure and function can be evaluated at targeted periods of development without these concerns.

Critically, when the BDNF gene is completely knocked out, rodents have a severely reduced lifespan and also suffer from severe developmental abnormalities within the brain. This highlights the critical importance of BDNF in maintaining normal maturation.

When BDNF expression is reduced by 50% by knocking out one of the two copies of the BDNF gene, the hippocampus is particularly affected. This results in learning and memory deficits, an increase in depressive-like behaviour and, under certain conditions, an anxiety-related phenotype. This indicates that the under-expression of BDNF may result in behavioural abnormalities that are characteristic of mood and anxiety disorders in rodents.

Indeed, BDNF plays a direct role in the development and survival of the serotoninergic neurotransmitter system, which is known for its role in the regulation of mood, and can directly control physiological aspects of serotoninergic cells in the brain. It is not surprising, then, that the efficacy of antidepressant drugs such as selective serotonin reuptake inhibitors are believed to at least partially exert their effects via BDNF. These drugs not only increase BDNF levels within the brains of both mice and humans, specifically in regions associated with the pathophysiology of depression such as the hippocampus, but may also restore circulating BDNF levels within the blood of mood disorder patients to levels that are consistent with controls.

Furthermore, it appears that BDNF is able to exert antidepressant-like effects itself, and can reduce the depressive-like behaviour of rats on a test known as the forced-swim test by as much as 70% when infused directly into the brain.

Similarly, exercise is also associated with a reduced risk of depression, and this also increases BDNF levels within the hippocampus, providing further evidence for the antidepressant properties of BDNF within the brain.

On the contrary, chronic stress, a risk factor for depression and anxiety disorders, reduces the expression of BDNF in the hippocampus of rodents and can exacerbate behavioural phenotypes associated with reduced levels of BDNF in the brain. In particular, I have observed that mice carrying a BDNF gene variant called Val66Met have altered depression and anxiety-related behaviours in adulthood, but that the experience of adolescent stress critically determines susceptibility to this.

While informative, rodent studies have been criticised for their translational value within psychiatry, with critics often arguing that rodent models are too simplistic. That said, animal models of altered BDNF gene function do appear to have at least some translational value.

First, the BDNF gene is highly conserved between species and shows a high degree of similarity between mice and humans, which suggests a conserved role of BDNF across species.

Second, mice that have been genetically modified to express 50% less BDNF – a severe genetic modification that is not representative of changes seen in humans – show an expression pattern in the brain that is similar to reductions seen in some post mortem brain studies of patients with mental illness, particularly schizophrenia.

Nevertheless, humans rarely carry just one functional copy of the BDNF gene, and it seems more likely that epigenetic modifications or small genetic variants termed single nucleotide polymorphisms are likely to mediate a genomic effect of BDNF.

In fact, some of the most convincing evidence for a conserved role for BDNF between species comes from studies that have assessed a genetic variant of the BDNF gene. The Val66Met polymorphism is carried by approximately 30% of Caucasians and 50% of Asians. It arises from the substitution of just one nucleotide in the BDNF gene, but occurs at a position in the gene that mediates the efficacy of BDNF secretion. In this respect, BDNF can be synthesised in the brain but is not efficiently secreted under activity-dependent processing, such as a memory task.

Not surprisingly, then, the Val66Met polymorphism affects the morphology and function of the hippocampus, and may be associated with disorders such as post-traumatic stress disorder and major depressive disorder.

Critically, however, mice that have been genetically modified to carry the Val66Met polymorphism of the BDNF gene have displayed many of the principle phenotypes observed among human carriers of this genetic variant, including memory deficits, depressive-like behaviour and anxiety-related traits.

Therapeutic Limitations of BDNF

Given the association of BDNF with mental illness as well as related behaviour in genetically modified rodents, the question then becomes whether BDNF can be targeted to treat specific disorders. While chemical compounds that mimic the effects of BDNF have been developed, their use in the treatment of mental illness is far from a reality.

According to Dr Rachel Hill, Head of the Psychoneuro­endocrinology Laboratory at the Florey Institute of Neuroscience and Mental Health and an expert on the molecular biology of BDNF, even if a drug was developed to target this molecule it is unlikely to be a universal solution to mental illness. “I think this could work for some patients but not others,” she says. “Mental disorders are very heterogeneous, with several probable causes leading to a variety of symptoms. Consequently, in some patients depression may have resulted from low levels of BDNF, while in others it may be something else”.

Likewise Prof Maarten van den Buuse, who has spent much of the past decade examining how BDNF contributes to psychosis-related behaviour, notes that “the ubiquitous nature of BDNF’s action in the brain means that new treatments targeting this system are likely to have major side-effects”.

While it may be the case that certain subgroups or individuals carrying genetic variants that modify the function of BDNF may benefit from a drug that targets this molecule, the widespread but locally controlled expression of BDNF in the brain means that side-effects may be particularly devastating – especially given that BDNF plays a role in important functions such as energy homeostasis.

Prof van den Buuse says that a potential solution to this may involve the development of “localised treatments that only modulate BDNF action in certain parts of the brain or in certain types of brain cells may reduce the severity of side-effects”. While not technically impossible, this type of targeted delivery of drugs within the brain is likely to be invasive and is some way from being feasible in humans. In this respect BDNF is unlikely to be a panacea for mental illness, but as Dr Hill quipped may be a promising adjunctive target.

Conclusion

While the rise of molecular psychiatry has provided insights into the possible role of single molecules in the mediation of behaviour and mental illness, this young but ever-growing field faces challenges that must be resolved if it is to discern the mechanisms underlying mental illness. These challenges not only include taking a factorial approach that integrates how the brain responds to biological and environmental insults, but also how novel experimental results can be translated into feasible clinical treatments.

Mike Notaras is a PhD candidate in the Behavioural Neuroscience Laboratory at The Florey Institute of Neuroscience and Mental Health.