Early brain development and heat shock proteins

The brain development of a fetus is really an amazing thing. The first sign of an incipient nervous system emerges during the third week of development; it is simply a thickened layer of tissue called the neural plate. After about 5 more days, the neural plate has formed an indentation called the neural groove, and the sides of the neural groove have curled up and begun to fuse together (see pic to the right). This will form the neural tube, which will eventually become the brain and spinal cord. By around 10 weeks, all of the major structures of the brain are discernible, even if they are not yet fully mature. So, in a matter of two months, the framework for the human brain is built from scratch. If that doesn't put you in awe of nature, nothing will.

Although the process of neural development is amazing, it is also very sensitive. There are indications that a number of environmental exposures during prenatal development may increase the risk of disorders like autism, schizophrenia, and epilepsy. Some of these dangerous environmental exposures are well known (e.g. alcohol consumption during pregnancy increasing the risk of developing fetal alcohol syndrome). However, there are a number of other factors whose detrimental effects on fetal neural development are still debated or have not yet been fully elucidated. For example, the effects on a fetus of substances like phthalates (plasticizers that are likely found in a number of products throughout your home), bisphenol A (another substance used in the production of plastics - found frequently in food and drink containers), and even tobacco smoke, are still being investigated. But a pregnancy free from exposure to any potentially harmful substances doesn't guarantee normal neural development. Even factors that are natural and more difficult to control, like maternal infection during pregnancy, are suspected of being detrimental in some cases.

To complicate the issue even further, it is difficult to predict who will be affected by these environmental insults and who will not. It seems that there may be a genetic susceptibility to neurodevelopmental damage that causes a particular exposure to be detrimental to one fetus, while it may not have a major impact on another with a different genetic makeup. This complication, however, also provides an opportunity to learn more about the etiology of neurodevelopmental disorders. For, if we can learn what mechanism is failing in the fetus who is affected, but functioning in the fetus who is not, then our understanding of the origin of these disorders will be drastically improved.

In a paper published last week in Neuron, Hashimoto-Torii et al. approached the problem from this angle and examined the role of heat shock proteins in neurodevelopmental problems. Heat shock proteins are peptides whose expression is increased during times of stress. They earned their name when it was discovered in the early 1960s that high levels of heat increased their expression in Drosophila (fruit flies). Since, it has been learned that heat shock protein expression is increased during all sorts of stress, including infection, starvation, hypoxia (lack of oxygen), and exposure to toxins like alcohol. Thus, some also refer to heat shock proteins as stress proteins.

To investigate the role of heat shock proteins in neurodevelopmental disorders, Hashimoto-Torii et al. exposed mouse embryos to three different types of environmental insults. They injected pregnant mice with either alcohol, methylmercury, or a seizure-inducing drug. Then, they looked to see how the brains of the embryos reacted. As they hypothesized, they saw a significant increase in the expression of a transcription factor (heat shock factor 1 or HSF1) that promotes the production of heat shock proteins.

When the researchers investigated the effects of prenatal exposure to the insults listed above in mice who lacked an HSF1 gene (HSF1 knockout mice), they saw that the exposed moms had smaller litters than control mice. The mice that were born, however, also displayed malformations consistent with neurodevelopmental damage, greater susceptibility to seizures after birth, and reduced brain size. The reduction in brain volume seemed to be due to decreased neurogenesis after the insult.

To make a clearer connection between heat shock protein activation and human disease, the researchers exposed stem cells derived from schizophrenic patients to methylmercury and alcohol, and compared the response of the "schizophrenic cells" to the response of cells from non-schizophrenic (control) patients. They didn't see an overall difference in heat shock protein expression between the two types of cells, but they did see significant variability in expression among the schizophrenic cells. In other words, both schizophrenic and control cells increased expression of heat shock protein after an insult, but some of the schizophrenic cells appeared to increase expression more or less than others. The control cells all displayed a relatively similar increase in expression. This suggests that there may be an abnormal response involving heat shock proteins in individuals with a certain genetic predisposition; perhaps this abnormal response makes the individual more susceptible to disrupted neurodevelopment.

Thus, the study by Hashimoto-Torii et al. points to heat shock proteins as a potential culprit behind what goes wrong in early brain development to lead to psychiatric disorders like schizophrenia and autism. More research will need to be done, however, to verify this role for heat shock proteins. And, even if future research supports this finding, it is likely that heat shock proteins are still only part of the puzzle. But the puzzle is complex, and so we will need to add many of these little pieces before we can begin to comprehend the whole picture.

Hashimoto-Torii, K., Torii, M., Fujimoto, M., Nakai, A., El Fatimy, R., Mezger, V., Ju, M., Ishii, S., Chao, S., Brennand, K., Gage, F., & Rakic, P. (2014). Roles of Heat Shock Factor 1 in Neuronal Response to Fetal Environmental Risks and Its Relevance to Brain Disorders Neuron DOI: 10.1016/j.neuron.2014.03.002