Summary:
Researchers at the University of Fukui found that deleting the membrane-fusion protein NSF (N-ethylmaleimide-sensitive factor) specifically from dopamine D2 receptor (D2R)-expressing neurons in mice produces striatal atrophy, severe reduction in striatal dopamine, and pronounced ADHD-like behaviors including hyperactivity and impulsivity. Standard treatment with the stimulant methylphenidate did not correct these behaviors on its own, but combining methylphenidate with a D2R agonist (quinpirole) substantially reduced hyperactivity and impulsive actions, suggesting a potential therapeutic approach for some cases of treatment-resistant ADHD.
Key Facts:
- Cell loss and striatal atrophy: Conditional deletion of NSF from D2R neurons caused increased developmental cell death, fewer D2R-expressing cells, lower striatal dopamine levels, and reduced striatal volume.
- Behavioral impact: Knockout mice showed marked hyperactivity and impulsivity. In an elevated platform test, 86% of the NSF-deficient mice jumped off within seven minutes versus 31% of control animals.
- Synergistic treatment effect: Methylphenidate alone did not normalize activity in the knockout mice, but combining it with the D2R agonist quinpirole reduced impulsive jumping from 78% to 11% and significantly diminished hyperactivity.
Source: University of Fukui
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition marked by persistent inattention, hyperactivity, and impulsivity. Dopamine pathway disruption has long been implicated in ADHD, yet the molecular machinery that supports dopamine-responsive neurons during development has been less clear. This study focuses on the striatum, a brain region central to motor control, reward processing, and executive behavior, and on neurons that express dopamine D2 receptors.
The research team investigated NSF, a protein essential for membrane fusion events that underlie neurotransmitter release and receptor trafficking. Prior work suggested interactions between NSF and D2R and hinted at relevance for neurodevelopmental and psychiatric conditions, but the in vivo role of NSF within D2R-expressing cells had not been established.
Lead investigator Min-Jue Xie, Ph.D., noted that, given the link between ADHD and deficits in striatal dopamine and D2R signaling, they hypothesized NSF is required for the maintenance and function of D2R-expressing neurons. To test this, the team generated mice lacking NSF selectively in D2R-positive cells and examined structural, biochemical, and behavioral consequences.
Molecular Loss Triggers Neurodevelopmental Deficits
Published in Neuropsychopharmacology, the study reports that targeted NSF deletion in D2R-expressing cells produced clear neurodevelopmental damage. During early postnatal maturation the absence of NSF increased apoptotic cell death, which reduced the number and density of D2R-expressing neurons and decreased expression of markers such as preproenkephalin. These cellular losses coincided with measurable striatal atrophy and a pronounced drop in striatal dopamine content.
Additional indicators of dopaminergic impairment included lower expression of the dopamine transporter in the striatum and reduced tyrosine hydroxylase levels in both the striatum and substantia nigra. Behaviorally, NSF-deficient mice displayed elevated locomotor activity and impaired impulse control consistent with ADHD-like phenotypes.
Overcoming Resistance to Standard Stimulants
Because stimulants such as methylphenidate are standard first-line treatments for ADHD, the team evaluated pharmacological responses in their mouse model. Methylphenidate administered alone failed to suppress hyperactivity in NSF-deficient animals. In contrast, adding quinpirole, a selective D2R agonist, to methylphenidate therapy produced robust behavioral rescue: hyperactivity decreased and impulsive jumping on the platform test fell dramatically from 78% to 11%.
The authors stress that animal model results do not directly translate into clinical practice, but the observed synergistic effect points to a biological mechanism where restoring D2R signaling can complement stimulant therapy. This may inform strategies for patients who do not respond adequately to stimulants alone.
“This is foundational research that clarifies how NSF supports D2R-associated striatal neurons and dopaminergic signaling,” said Xie. “While it will not immediately produce a new treatment, it highlights D2R function and striatal dopamine as targets worth exploring, especially for treatment-resistant ADHD.”
Funding information
The work received partial support from KAKENHI grants from Japan’s Ministry of Education, Culture, Sports, Science and Technology (16H05373 to H.M. for study design; 24K02131 to Y.F. for data analysis; 21K06752 to M.-J.X. for data collection and analysis). Internal funding from the University of Fukui and Open Access support from the University of Fukui also contributed to publication.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by editorial staff.
- Additional context was provided by the editorial team.
About this Genetics and Neurology Research:
- Media Contact: Yuuka Kawamoto
- Source: University of Fukui
- Image Credit: Image generated for Neuroscience News
- Original Research (Open Access): Neuropsychopharmacology (September 15, 2026). Title: “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.” Authors: Min-Jue Xie, Koshi Murata, Hiroshi Kuniishi, Yugo Fukazawa, Noriyoshi Usui & Hideo Matsuzaki.
- DOI: 10.1038/s41386-026-02526-8
Abstract
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
NSF is a key regulator of membrane fusion that supports neurotransmitter release and membrane protein trafficking. NSF dysfunction has been associated with neuropsychiatric conditions, and prior in vitro work suggested interactions between NSF and the dopamine D2 receptor (D2R). To determine the in vivo role of NSF within D2R-expressing cells, the authors created D2R-specific NSF conditional knockout (Nsf f/f; D2R-Cre) mice and examined cellular, biochemical, and behavioral outcomes.
Targeted NSF deletion reduced D2R expression and the density of D2R-positive cells, along with decreases in the marker preproenkephalin. These alterations accompanied elevated apoptosis during early postnatal development, reduced striatal volume, and markedly lower striatal dopamine levels. Dopaminergic deficits were further supported by decreased dopamine transporter expression in the striatum and lower tyrosine hydroxylase levels in the striatum and substantia nigra.
Behaviorally, Nsf f/f; D2R-Cre mice displayed ADHD-like features, notably hyperactivity and impulsivity. Combined treatment with methylphenidate and the D2R agonist quinpirole ameliorated these behaviors, pointing to a complementary therapeutic approach. These results underscore the essential role of NSF in maintaining D2R-associated striatal neuronal populations and suggest that disruption of NSF-D2R interactions can produce ADHD-like phenotypes, supporting the translational relevance of this mouse model for studying treatment-resistant ADHD.