Gene Deficiency Triggers Autistic Symptoms in Mice
New findings strongly associate a certain gene with autistic symptoms. Autism is a highly heritable disorder, with up to 90 percent likelihood of both identical twins having the condition.
Mutations in the NRXN2 gene, which makes a protein called alpha-neurexin II, have previously been highlighted in genome-wide studies as potentially contributing to autism spectrum disorder.
Dr. Steven Clapcote and colleagues at Leeds University, U.K., investigated whether a deficiency in the products of NRXN2 would cause autism in animal studies. They used mice with the same defect in NRXN2 as seen in some people with autism.
This did indeed lead to behavioral features similar to autism symptoms, such as a lack of sociability or curiosity about other mice. These mice were also more anxious in “tests of exploratory activity.”
“In other respects, these mice were functioning normally,” said Clapcote. “The gene deficiency mapped closely with certain autism symptoms. This is exciting because we now have an animal model to investigate new treatments for autism.”
The mice did not exhibit stereotyped repetitive behaviors, another core symptom of autism, and showed no impairment in intellectual ability as measured by long-term memory. Findings of the study were published in the journal Translational Psychiatry in November 2104.
“We found that the affected mice had lower levels of a protein called Munc18-1 in the hippocampus area, but not in the frontal cortex,” reported co-author Dr. James Dachtler.
“Munc18-1 usually helps to release neurotransmitter chemicals across synaptic connections in the brain, so neurotransmitter release could be impaired in the affected mice and possibly in some cases of autism.
“As altered Munc18-1 expression is likely just one of many synaptic modifications caused by the loss of alpha-neurexin-II, further work is warranted.”
The team stated, “Recent genetic and genomic studies have implicated a large number of genes in autism, many of which encode synaptic proteins, indicating that synaptic dysfunction may have a critical role in autism. Our findings demonstrate a causal role for the loss of alpha-neurexin-II in the genesis of autism-related behaviors in mice.”
They note that anxiety was significantly raised in these mice in several different tests. “In autism patients,” they write, “it has been noted that anxiety can exacerbate other symptoms, and treatment of anxiety by cognitive behavioral therapy can improve the social skills of patients.”
A further gene, neuroligin-1, has also been implicated in altered synapse signalling in autism. “Not all people with autism will have the alpha-neurexin-II defect, just as not all will have the neuroligin defect, but we are starting to build up a picture of the important role of genes involved in these synapse communications in better understanding autism,” concluded Clapcote.
“We don’t fully understand how the drugs used to treat schizophrenia and some symptoms of autism work,” Clapcote said.
“If we can show they can affect mice with this particular genetic mutation, then it gives us a clue to better understand the illnesses and opens up the possibility of more targeted treatments with fewer side effects.”
He added, “The genetic studies so far are suggesting a common cause for both schizophrenia and autism, which is something our studies will help to establish.
“However, these illnesses are complex, involving not only inheritance, but other factors such as environment and experience. It’s possible the genetic mutation might create a predisposition, making people more likely to develop autism or schizophrenia.”
The specially adapted mice will be tested for many behaviors related to autism and schizophrenia, such as hyperactivity, sensitivity to psychostimulants, attention levels, memory, social interaction, and learning. Their interactions with other mice will also be assessed, and there will be bat recorders to “listen” to their interactions that are too high-pitched for humans to hear.
“Schizophrenia and autism patients both display lower levels of verbal communication and we hope to see this mirrored in the mice we’re working with,” Clapcote said. Initial results from these experiments are due later in 2015.
Dachtler, J. et al. Deletion of a-neurexin II results in autism-related behaviors in mice is published in Translational Biology. Translational Psychiatry, 26 November 2014 doi: 10.1038/TP.2014.123
Collingwood, J. (2015). Gene Deficiency Triggers Autistic Symptoms in Mice. Psych Central. Retrieved on March 24, 2018, from https://psychcentral.com/news/2015/01/20/gene-deficiency-triggers-autism-in-mice/80154.html