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. 2025 Jun 6;16(6):690.
doi: 10.3390/genes16060690.

Deficiency in KPNA4, but Not in KPNA3, Causes Attention Deficit/Hyperactivity Disorder like Symptoms in Mice

Affiliations

Deficiency in KPNA4, but Not in KPNA3, Causes Attention Deficit/Hyperactivity Disorder like Symptoms in Mice

Franziska Rother et al. Genes (Basel). .

Abstract

Nucleocytoplasmic transport is crucial for neuronal cell physiology and defects are involved in neurodegenerative diseases like amyotrophic lateral sclerosis and Alzheimer's disease, but also in ageing. Recent studies have suggested, that the classic nuclear import factor adapters KPNA3 (also named importin alpha4) and KPNA4 (also named importin alpha3) could be associated with the development of motor neuron diseases, a condition specifically affecting the neurons projecting from brain to spinal cord or from spinal cord to the muscles. Here we set out to analyze the neuronal function of mice deficient in KPNA3 (Kpna3-KO) or KPNA4 (Kpna4-KO). The motoric abilities and locomotion at different time points in ageing were tested to study the role of these two genes on motor neuron function. While we did not find deficits related to motor neurons in both mouse models, we discovered a hypermotoric phenotype in KPNA4-deficient mice. Attention deficit/hyperactivity disorder (ADHD) is caused by a combination of genetic, environmental and neurobiological factors and a number of genes have been suggested in genome-wide association studies to contribute to ADHD, including KPNA4. Here we provide supportive evidence for KPNA4 as a candidate pathogenic factor in ADHD, by analysing Kpna4-KO mice which show ADHD-like symptoms.

Keywords: ADHD; hyperactivity; importin; karyopherin; motor neuron disease; nucleocytoplasmic transport.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Analysis of neuromuscular function in KPNA3-deficient mice throughout ageing. Female and male Kpna3-KO mice and C57Bl/6 wild-type (WT) mice of different ages (3 months (m): n = 11; 8 m: n = 11; 12 m: n = 10–11; 18 m: n = 8–10) were submitted to rotarod test (A), inverted screen test (B) and tail suspension test (C). n.s.: not significant.
Figure 2
Figure 2
Analysis of neuromuscular function in KPNA4-deficient mice throughout ageing. Female and male Kpna4-KO mice and C57Bl/6 WT mice of different ages (3 months (m): n = 11; 8 m: n = 9–11; 12 m: n = 8–11; 18 m: n = 5–9) were submitted to rotarod test (A), inverted screen test (B) and tail suspension test (C). n.s.: not significant. Significance levels were * p < 0.05, ** p < 0.01.
Figure 3
Figure 3
Spontaneous locomotion in KPNA3- and KPNA4-deficient mice. Female and male Kpna3-KO mice, Kpna4-KO mice and C57Bl/6 WT mice of different ages (3 months (m): n = 11; 8 m: n = 9–11; 12 m: n = 8–11; 18 m: n = 5–11) were submitted to open field experiments for 60 min with a habituation phase of 10 min. Female Kpna4-KO mice but not Kpna3-KO mice clearly show hyperactivity (defined as part of the time when locomotion velocity is >20 cm/s) and increased distance travelled starting at 8 months of age, as well as increased locomotion velocity (A). In male Kpna4-KO mice, enhanced hyperactivity and distance travelled could be found at 8 and 18 months of age, while at 12 months no significant effect was shown (p = 0.09 for hyperactivity; p = 0.07 for distance travelled) with no clear effect on locomotion velocity. The time in the center was significantly increased for several time points in female and male Kpna4-KO mice, but not for Kpna3-KO mice (A,B). n.s.: not significant. Significance levels were * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001.

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