Human gene variant produces attention deficit disorder-like problems in
mice
Date:
April 7, 2022
Source:
Florida Atlantic University
Summary:
Mutant mice are providing scientists with a new neurobiological
framework to understand the brain changes observed in distractible
humans who carry a common gene variant whose frequency has been
associated with Attention Deficit Hyperactivity Disorder (ADHD). The
scientists demonstrate that mice that express the variant adopt
an inattentive phenotype similar to that seen in humans.
FULL STORY ========================================================================== Mutant mice are providing scientists with a new neurobiological framework
to understand the brain changes observed in distractible humans who carry
a common gene variant whose frequency has been associated with Attention Deficit Hyperactivity Disorder (ADHD). The scientists demonstrate that
mice that express the variant adopt an inattentive phenotype similar to
that seen in humans.
==========================================================================
The study, led by researchers from the University of Michigan in
collaboration with Florida Atlantic University, Temple University, and
the National Institute on Deafness and Other Communication Disorders,
National Institutes of Health, used genetically engineered mice to
examine the neural and behavioral effects of a choline transporter (CHT) variant. Prior work by the team has shown that the variant associated
with heightened distractibility in humans, though whether the variant
was itself causal for inattention was unclear.
In the new study, researchers made a single change in the gene encoding
the neuronal CHT and then searched for physiological changes in the
brain, focusing on their ability to sustain production and release of the powerful brain chemical acetylcholine, which is synthetized from choline.
In humans, disruption of acetylcholine signaling impairs one's capacity
to filter distractors and to perform focus-demanding tasks. A total
loss of CHT function in mice and people leads to early death due to the
role played by acetylcholine in muscle contraction, particularly the
muscles that control breathing. Lesser reductions in CHT activity allow
for normal growth and movement, but mice with these changes exhibit
premature fatigue when made to run on a treadmill. Work from the new
study reveals that the mice show signs of mental fatigue as well.
Results of the study, published in The Journal of Neuroscience,indicate
that the CHT gene variant known as Val89, reduces the rate of choline
uptake and the capacity to sustain acetylcholine production during attention-demanding conditions, effects that lead to diminished cognitive performance when the mice are faced with attentional challenges. Evidence
from the mouse studies provides direct evidence that Val89 drives
increased vulnerability to distraction and provides a mechanistic basis
for the diminished frontal cortex activation observed in Val89-expressing humans.
"Our mouse studies, along with prior behavioral and brain imaging
studies, indicate that a single copy of the variant is sufficient to
change acetylcholine availability and its resulting cognitive effects,"
said Randy D.
Blakely, Ph.D., co-author, executive director of the FAU Stiles-Nicholson
Brain Institute and professor, FAU Schmidt College of Medicine. "Seeing
effects from a single copy of Val89 suggests that choline transport may be mediated by a pair of CHT proteins such that one poorly functioning copy
can impact the normal function of the other, leading to stronger effects
than expected from simply having one copy compromised." This finding
has been reported before in people with neuromuscular disorder causing
CHT mutations, but this also appears to be the case for brain function.
========================================================================== "Val89 mice lack cognitive flexibility in response to an attentional challenge," said Eryn Donovan, lead author and a graduate student in
the Department of Psychology, University of Michigan. "Our findings
from this mouse model suggest the potential for a more complete
investigation of the effects of the CHT Val89 mutation in the brain
as well as the development of therapeutic strategies for those with
disrupted acetylcholine signaling." According to the United States
Centers for Disease Control and Prevention, the estimated number of
children ever diagnosed with ADHD, according to a 2016 parent survey,
is 6.1 million. This same survey shows that 6 in 10 children with ADHD
had at least one other mental, emotional or behavioral disorder and 62
percent were taking ADHD medication. Although ADHD most often occurs in children, it also can be diagnosed in adulthood.
"We think that the CHT Val89 mouse can be a valuable model to study
heritable risk for cognitive disorders that arise from cholinergic dysfunction," said Blakely. "We now can gain much more insight into
the brain effects of the Val89 variant in ways that cannot be done in
humans and possibly lead to new ways to treat disorders associated with
brain acetylcholine signaling that appear in childhood, such as ADHD,
or during aging, as with Parkinson's disease and Alzheimer's disease."
In addition to new insights into a potential risk factor for psychiatric
and neurological disorders, Martin Sarter, Ph.D., a professor of
psychology and neuroscience at the University of Michigan and the
communicating author of the study says that their findings explain why
healthy humans expressing this genetic variant exhibit robust attentional vulnerabilities.
"As this genetic variant is quite common, occurring in about 9 to 10
percent of humans, we now understand exactly how this variant influences
the brain mechanisms that are essential for paying attention," said
Sarter.
Other study co-authors are Cassandra Avila, a graduate student and Sarah Klausner, an undergraduate student, Department of Psychology, University
of Michigan; Vinay Parikh, Ph.D., an associate professor of psychology
and neuroscience, Temple University; Maria Cristina Fenollar Ferrer,
Ph.D., Laboratory of Molecular Genetics, Section of Human Genetics,
National Institute on Deafness and Other Communication Disorders.
========================================================================== Story Source: Materials provided by Florida_Atlantic_University. Original written by Gisele Galoustian. Note: Content may be edited for style
and length.
========================================================================== Journal Reference:
1. Eryn Donovan, Cassandra Avila, Sarah Klausner, Vinay Parikh,
Cristina
Fenollar-Ferrer, Randy D. Blakely, Martin Sarter. Disrupted
choline clearance and sustained acetylcholine release in vivo by
a common choline transporter coding variant associated with poor
attentional control in humans. The Journal of Neuroscience, 2022;
JN-RM-1334-21 DOI: 10.1523/ JNEUROSCI.1334-21.2022 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/04/220407161941.htm
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