Attention-deficit/hyperactivity disorder (ADHD), marked by excessive activity and impulsivity, is linked to changes in the brain’s dopamine system, though the mechanisms remain unclear. Researchers at the University of Fukui have now found that in genetically modified, conditional knockout mice, loss of a protein called N-ethylmaleimide-sensitive factor (NSF)—which is linked to dopamine receptors—in D2 receptor-expressing cells led to lower dopamine levels and ADHD-like behaviors. Their results also pointed to a potential therapeutic strategy.
The team, headed by assistant professor Min-Jue Xie, PhD, at the Division of Development of Mental Functions, Research Centre for Child Mental Development, suggests that the results offer insight into how brain changes may contribute to ADHD and informing future treatments.
“This is basic research and will not immediately lead to a new treatment,” Xie acknowledged. “However, it provides important clues for understanding how dopaminergic dysfunction may contribute to ADHD. In the future, these findings may help develop new therapeutic strategies targeting D2R function and striatal dopamine signaling, especially for treatment-resistant ADHD.”
Xie is first and corresponding author of the researchers’ published paper in Neuropsychopharmacology, titled “Deletion of N-ethylmaleimide-sensitive factor in dopamine D2 receptor-expressing cells impairs striatal development and dopaminergic function and induces ADHD-like behaviors in mice.”
ADHD is a neurodevelopmental disorder that can affect attention, activity levels, and impulse control, with symptoms often beginning in childhood and sometimes continuing into adulthood. Although the exact causes of ADHD are not fully understood, changes in the brain’s dopamine system have long been linked to the condition. Dopamine is a chemical messenger that helps brain cells communicate and plays an important role in movement, motivation, and behavior.
While dopamine-related changes have been associated with ADHD, it remains unclear how the brain cells that respond to dopamine are maintained and how their disruption may contribute to ADHD-related behaviors. This is particularly relevant to dopamine D2 receptor (D2R)-expressing cells, which are found in the striatum, a brain region involved in movement and behavioral control. Understanding what helps these cells develop and function normally could provide new insights into the biological processes involved in ADHD. “Although D2R has been extensively studied, the upstream mechanisms regulating its function and localization remain unclear,” the authors wrote.
Against this backdrop, a research team from Japan, led by Xie, set out to investigate the role of NSF in these dopamine-related brain cells. NSF regulates membrane fusion, helping brain cells release chemical messengers and move proteins within their membranes. “NSF dysfunction is implicated in neuropsychiatric disorders, with reduced expression in autism spectrum disorder (ASD) and schizophrenia and aggregates in Parkinson’s disease,” the investigators noted.
“The motivation for this study came from previous findings suggesting that NSF may be involved in neurodevelopmental and neuropsychiatric disorders,” Xie explained. “NSF was known to interact with D2R; however, the role of this interaction in vivo remained unclear. Because ADHD is thought to involve reduced striatal dopaminergic function and D2R dysfunction, we hypothesized that NSF may be important for maintaining D2R-expressing neurons and dopaminergic function. This led us to initiate the present study.”
For their study the team created knockout mice in which NSF was removed specifically from D2R-expressing neurons. “… we generated D2R-specific Nsf conditional knockout (Nsf f/f;D2R-Cre) mice to examine NSF function in D2R-expressing cells in vivo,” they explained. They then studied the animals’ brain development, dopamine levels, and behavior. The team also tested whether drugs that affect dopamine signaling could reduce the behavioral changes seen in the modified mice.
The loss of NSF affected the developing brain, resulting in fewer dopamine D2R-expressing cells, increased early developmental cell death, and a smaller striatum. The mice also had markedly lower dopamine levels in this brain region. Together, these findings suggest that NSF helps maintain dopamine-related cells and supports normal development and dopamine function.
The brain changes were accompanied by ADHD-like behaviors. “Nsf f/f;D2R-Cre mice exhibited attention-deficit/hyperactivity disorder (ADHD)-like behaviors, including hyperactivity and impulsivity,” the team reported. The knockout mice were more hyperactive than control mice and showed more impulsive-like behavior in a test that measured how quickly they jumped from an elevated platform. By the end of the seven-minute test, 86% of the experimental group mice had jumped, compared with 31% of the control group mice. “These findings indicate that a reduction in D2R-expressing cells coincides with ADHD-like behaviors, suggesting a link between D2R dysfunction and these abnormalities.”
The researchers then explored whether these behaviors could be reduced by changing dopamine signaling. Methylphenidate, a medicine commonly used to treat ADHD, did not significantly reduce hyperactivity when given alone to the modified mice. However, when it was given together with quinpirole, a drug that activates D2R, the mice became less hyperactive and showed less impulsive-like behavior. During the seven-minute test, the proportion of knockout mice that jumped fell from 78% without treatment to 11% after the two drugs were given together. “Combined administration of methylphenidate and a D2R agonist, quinpirole, alleviated both behaviors, suggesting a potential complementary approach for ADHD treatment,” the investigators wrote.
“This study supports the translational relevance of the Nsf f/f;D2R-Cre model for ADHD and indicates that targeting D2R dysfunction, particularly in treatment-resistant ADHD, may be a promising therapeutic strategy.”
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