Key Receptor for Autism Treatment Identified

Grant of $2.4 million will support further research.

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have uncovered a significant–and potentially treatable–relationship between a chemical that helps transmit signals in the brain and genetic mutations present in a subset of individuals with autism spectrum disorder.

The new research findings, which were published recently in the journal PLoS One, focus on the role that the neurotransmitter serotonin plays in the development of social behavior. Serotonin, together with the serotonin receptors it activates in the brain, plays a significant role in neurological processes, including mood, anxiety, aggression and memory.

The study made use of an animal model of mutations in the gene Pten, a risk factor present in a subgroup of individuals with autism. Treatment of this model with a drug that suppresses the activity of a particular serotonin receptor, 5-HT2cR, can have a dramatic effect.

“Our research shows that targeting one specific serotonin receptor can reverse social deficits in a mouse model of the autism risk gene Pten,” said Julien Séjourné, the first author of the new study. “This discovery is important for understanding the role of this specific subtype of serotonin receptor in autism-relevant behaviors and could lead to new therapeutic strategies.”

“We found a striking contrast between the effects of dialing down the activity of the receptor using a drug, which improved social deficits in the Pten model, versus removing the receptor completely by mutation, which actually impaired social behavior,” added TSRI Assistant Professor Damon Page, who led the study. “Important issues will be uncovering the mechanism by which modulating serotonin receptor activity can influence autism-relevant symptoms and identifying the time window and dose range where targeting serotonin receptors is most effective.”

Child holding a board with Autism written on it.
The study made use of an animal model of mutations in the gene Pten, a risk factor present in a subgroup of individuals with autism. Treatment of this model with a drug that suppresses the activity of a particular serotonin receptor, 5-HT2cR, can have a dramatic effect. Image is for illustrative purposes only.

Page was recently awarded a $2.4 million, five-year grant from the National Institute of Mental Health of The National Institutes of Health (NIH) to further study the relationship between abnormal patterns of brain growth, neurotransmitter signaling and the behavioral and cognitive symptoms in individuals with autism spectrum disorder.

“The new grant will let us expand our research into the relationship between specific risk factors, altered brain development and key neurotransmitter systems, with the ultimate goal of moving toward individualized treatments for particular subgroups of individuals with autism spectrum disorder,” he said.

[divider]About this autism research[/divider]

In addition to Page and Séjourné, other authors of the study, “Social Behavioral Deficits Coincide with the Onset of Seizure Susceptibility in Mice Lacking Serotonin Receptor 2c,” are Danielle Llaneza of TSRI and Orsolya J. Kuti of The Massachusetts Institute of Technology.

Funding: The work was supported by Ms. Nancy Lurie Marks and the National Institutes of Health. The number of the grant is 1R01MH105610.

Source: Eric Sauter – Scripps Research Institute
Image Source: The image is in the public domain
Original Research: Full open access research for “Social Behavioral Deficits Coincide with the Onset of Seizure Susceptibility in Mice Lacking Serotonin Receptor 2c” by Julien Séjourné, Danielle Llaneza, Orsolya J. Kuti, and Damon T. Page in PLOS ONE. Published online August 26 2015 doi:10.1371/journal.pone.0136494


Abstract

Social Behavioral Deficits Coincide with the Onset of Seizure Susceptibility in Mice Lacking Serotonin Receptor 2c

The development of social behavior is strongly influenced by the serotonin system. Serotonin 2c receptor (5-HT2cR) is particularly interesting in this context considering that pharmacological modulation of 5-HT2cR activity alters social interaction in adult rodents. However, the role of 5-HT2cR in the development of social behavior is unexplored. Here we address this using Htr2c knockout mice, which lack 5-HT2cR. We found that these animals exhibit social behavior deficits as adults but not as juveniles. Moreover, we found that the age of onset of these deficits displays similar timing as the onset of susceptibility to spontaneous death and audiogenic-seizures, consistent with the hypothesis that imbalanced excitation and inhibition (E/I) may contribute to social behavioral deficits. Given that autism spectrum disorder (ASD) features social behavioral deficits and is often co-morbid with epilepsy, and given that 5-HT2cR physically interacts with Pten, we tested whether a second site mutation in the ASD risk gene Pten can modify these phenotypes. The age of spontaneous death is accelerated in mice double mutant for Pten and Htr2c relative to single mutants. We hypothesized that pharmacological antagonism of 5-HT2cR activity in adult animals, which does not cause seizures, might modify social behavioral deficits in Pten haploinsufficient mice. SB 242084, a 5-HT2cR selective antagonist, can reverse the social behavior deficits observed in Pten haploinsufficient mice. Together, these results elucidate a role of 5-HT2cR in the modulation of social behavior and seizure susceptibility in the context of normal development and Pten haploinsufficiency.

“Social Behavioral Deficits Coincide with the Onset of Seizure Susceptibility in Mice Lacking Serotonin Receptor 2c” by Julien Séjourné, Danielle Llaneza, Orsolya J. Kuti, and Damon T. Page in PLOS ONE. Published online August 26 2015 doi:10.1371/journal.pone.0136494

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