A mouse hippocampus expressing green fluorescence. Source: Wikimedia Commons http://upload.wikimedia.org/wikipedia/commons/ 6/61/Transgeni c_mouse_hippocamus.jpg
On February 26, 2014, Bryan Luikart, a professor of neurobiology at the Geisel School of Medicine, gave a presentation on his research into the effects of PTEN mutations on autism spectrum disorder (ASD). He was able to discover that the symptoms of a specific form of autism was likely caused by a form of “sensory overload” in autistic children, caused by abnormalities in their neurons due to partial loss of PTEN function.
ASD is a group of developmental disorders characterized by an avoidance of social interaction, delayed language development, abnormal response to sensory stimuli, and/or restricted patterns of behavior (1). In ASD caused by PTEN mutation, patients also develop enlarged heads, downward-slanting eyes, and noncancerous growths on the body.
PTEN is a gene coding for a critical protein that is necessary for many intracellular signaling pathways. It stands for phosphatase and tensin homolog and is mainly involved in the regulation of the cell cycle and division. Without it, humans die shortly after conception, and when individual cells lose PTEN function, they generally become cancerous. Luikart and his team set out to answer how mutated PTEN affects neurons, since they generally do not divide.
In order to model inactive PTEN in humans, he used mice since their neurons share enough characteristics with our own to act as a model. Because PTEN deficiency is fatal when the entire body lacks it, he obtained conditional knockout mice, which allow genes to be permanently deactivated in tissues when a specific enzyme is added.
He then bred these mice, and delivered a virus to each of their hippocampi that exposed those cells to the deactivating enzyme. The hippocampi were then removed and cut into slices for imaging. The enzyme also expressed green fluorescence protein (GFP), allowing Luikart to visualize which neurons had their PTEN disabled.
When looking at the cells under a microscope, he was able to see that the cell bodies of the mutant cells were much larger, had more dendrites branching off of them, and were more disorganized than the wild-type cells.
Another experiment was performed where another virus, which caused neurons to flash whenever they fired, was delivered to mouse hippocampi. These neurons were then stimulated with electrodes that delivered electrical shocks of known voltages, allowing the group to determine if neurons fired, at what frequency, and in response to how much voltage.
When PTEN-mutant neurons were compared to wild-type neurons, a number of phenomena were observed. The PTEN-mutant neurons stored much less electricity (electricity can dissipate easier as surface area increases), but overall, a higher amount of electricity was required from them to fire, most likely because the mutant neurons were larger. The mutants could also fire much more frequently than the wild-type neurons, probably because the cells can store less electricity.
Overall, these mutations cause neurons to form more branching dendrites, which leads to the formation of more connections between neurons, and fire more frequently than wild-type neurons when stimulated. These findings lead to an interesting possible mechanism for the manifestation of ASD symptoms: they could be a form of sensory overload. When neurons in PTEN-mutant patients are stimulated, they could fire more often and with more neurons, causing an even greater change in the degree of stimulation. This could lead to sensory information having a much greater effect than usual. Because social interaction requires a great amount of attention to sensory input, this overload could affect how autistic people interact. For them, it can be hard to adapt to the degree of sensory stimulation in the environment, leading to avoidance.
While there may be no direct clinical implications of this research just yet, in order to treat any disease it must be understood as best as possible. Luikart’s research may eventually lead to a focused treatment for people afflicted with this specific form of autism.
References:
1. DSM-5 Diagnostic Criteria (2013). Available at http://www.autismspeaks.org/what-autism/diagnosis/dsm-5-diagnostic-criteria (28 February 2014).
