Wednesday, April 13, 2016

#expbio ASPET Blogging: Chronic Antagonism of p38α MAPK Normalizes Serotonin Clearance, Serotonin Receptor Hypersensitivity and Social Behavior Deficits in a Genetic Murine Model of Autism Spectrum Disorder

Figure 1: Serotonin synapse. (Source)    
Autism is a disorder with a high level of heritability, meaning it is passed down through families genetically. There are hundreds of gene mutations associated with autism. Some of these affect the chemical and neurotransmitter serotonin. Previous work from the Blakely lab has found five genetic variants in the serotonin transporter (SERT) associated with autism. In about 30 percent of autism cases, there is an increase in serotonin in blood platelets. This effect stems from SERT activity on the surface of platelets. Neurons in the brain also contain these transporters and the gene mutations associated with autism pull more serotonin into the cell, similar to the transporters on platelets in the blood. In the brain, this leaves less serotonin in the gap between neurons, called the synapse. Dr. Matthew Robson, a postdoc in Dr. Randy Blakely’s lab at Vanderbilt University, is studying one gene mutation implicated in autism. He is also using a drug that may help relieve some of the symptoms of autism, such as impaired sociability, that are untreatable with current medications.

Figure 2: The mouse tube test for social dominance. 
(Source)
The mouse model Dr. Robson used for his research carried a gene mutation in the SLC6A4 gene (Gly56Ala), which codes for the transporter. Appropriately, the mice are called SERT Ala56 mice. The Gly56Ala mutation is one of the ones found in people with autism so the mouse model is said to have good construct validity. The mutation puts the transporter into a hyperactive state, leading to less serotonin in the synapse. One protein thought to be involved in changing SERT into this hyperactive state is p38α MAPK. Dr. Robson found that a drug that inhibits the activity of p38α MAPK can normalize the activity of SERT in the SERT. In the work he presented at Experimental Biology, he showed that the drug, MW150, improves sociability in a measurement of social dominance in mice. Deficits in sociability is one of the characteristic symptoms in autism that does not yet have a treatment. Being able to improve sociability in people with autism could dramatically improve their quality of life.

To study social dominance in the SERT Ala56 mice, Dr. Robson used the tube test. In this test, two mice are placed into a tube small enough that they cannot “pass” each other so one mouse ends up forcing the other out of their end to get out. The SERT Ala56 mice were often the ones to get pushed out of their end of the tube, indicating impaired social interactions. However, after chronic treatment with MW150 for one week the SERT Ala56 mice were just as likely as the control mice to push the other mouse out of the tube.

They also looked at other characteristics in the SERT Ala56 mice to see if they could be brought to the same level as the non-transgenic mice. These included normalizing a 5-HT1A-agonist-induced decrease in body temperature mediated by one of the serotonin receptors, 5-HT1A, with a drug to activate it. MW150 also blocked a head twitch behavior caused by activation of the 5-HT2A receptor. The levels of SERT activity in the synapse were also brought back to control levels.

Based on Dr. Robson’s research, it seems that MW150 can bring the transporter activity back to control levels AND improve sociability behavior. Additionally, Dr. Robson is using other mouse models of autism to determine if MW150 may be a potential treatment for autism.  He is also working with collaborators to create another mouse model to use in this research. 

Funding for this research was from the National Institutes of Health (link: http://www.nih.gov), the PhRMA Foundation (link: http://www.phrmafoundation.org/), and the Simmons Foundation Autism Research Initiative (SFARI) (link: https://sfari.org/).

1 comment:

  1. Can SSRIs block these hyperactive channels? Are they used to treat autism?

    ReplyDelete