Behavioral characterization of mice overexpressing human dysbindin-1
- Norihito Shintani1,
- Yusuke Onaka1,
- Ryota Hashimoto2, 3Email author,
- Hironori Takamura2,
- Tsuyoshi Nagata1,
- Satomi Umeda-Yano4,
- Akihiro Mouri5,
- Takayoshi Mamiya5,
- Ryota Haba1,
- Shinsuke Matsuzaki2, 6, 7,
- Taiichi Katayama6,
- Hidenaga Yamamori2, 4,
- Takanobu Nakazawa8,
- Kazuki Nagayasu8,
- Yukio Ago9,
- Yuki Yagasaki10,
- Toshitaka Nabeshima11,
- Masatoshi Takeda2, 3 and
- Hitoshi Hashimoto1, 2, 8
© Shintani et al.; licensee BioMed Central Ltd. 2014
Received: 6 August 2014
Accepted: 25 September 2014
Published: 9 October 2014
The dysbindin-1 gene (DTNBP1: dystrobrevin binding protein 1) is a promising schizophrenia susceptibility gene, known to localize almost exclusively to neurons in the brain, and participates in the regulation of neurotransmitter release, membrane-surface receptor expression, and synaptic plasticity. Sandy mice, with spontaneous Dtnbp1 deletion, display behavioral abnormalities relevant to symptoms of schizophrenia. However, it remains unknown if dysbindin-1 gain-of-function is beneficial or detrimental.
To answer this question and gain further insight into the pathophysiology and therapeutic potential of dysbindin-1, we developed transgenic mice expressing human DTNBP1 (Dys1A-Tg) and analyzed their behavioral phenotypes. Dys1A-Tg mice were born viable in the expected Mendelian ratios, apparently normal and fertile. Primary screening of behavior and function showed a marginal change in limb grasping in Dys1A-Tg mice. In addition, Dys1A-Tg mice exhibited increased hyperlocomotion after methamphetamine injection. Transcriptomic analysis identified several up- and down-regulated genes, including the immediate-early genes Arc and Egr2, in the prefrontal cortex of Dys1A-Tg mice.
The present findings in Dys1A-Tg mice support the role of dysbindin-1 in psychiatric disorders. The fact that either overexpression (Dys1A-Tg) or underexpression (Sandy) of dysbindin-1 leads to behavioral alterations in mice highlights the functional importance of dysbindin-1 in vivo.
Dysbindin-1 (dystrobrevin binding protein 1) is an evolutionary conserved 40-kDa coiled-coil-containing protein that binds to dystrobrevin and localizes exclusively to neurons in the brain . Dysbindin-1 has been shown to participate in biogenesis of lysosome-related organelles complex 1, which regulates trafficking to lysosome-related organelles , regulation of neurotransmitter release -, membrane surface expression of glutamate NMDA  and dopamine D2 , receptors, and synaptic plasticity ,.
Genetic variations in the human dysbindin-1 gene (DTNBP1) have been shown to be associated with schizophrenia ,, bipolar disorder , and methamphetamine (METH) psychosis , as well as neurocognitive functions in healthy subjects ,. In postmortem brain from schizophrenic patients, decreased dysbindin-1 expression has been demonstrated in the prefrontal cortex , cerebral cortex , and intrinsic glutamatergic terminals of the hippocampal formation .
Sandy mice completely lack dysbindin-1 protein because of spontaneous deletion of introns 5-7 of the Dtnbp1 gene in DBA/2 J mice . These mice display a variety of behavioral abnormalities relevant to symptoms of schizophrenia, including hypoactivity, heightened anxiety-like responses, reduced social interaction , deficits in both long-term  and working memory , and impairments in contextual fear conditioning . As potential mechanisms for these behavioral abnormalities, Sandy mice have been shown to exhibit reduced dopamine transmission in the forebrain  and destabilization of snapin, which binds to SNAP25 and regulates calcium-dependent exocytosis .
The sandy mutation was backcrossed onto a C57BL/6 J background for at least 11 generations to obtain sdy/B6 mice . These mice show schizophrenia-like behaviors including hyperactivity, spatial learning and memory deficits, impaired working memory under challenging conditions, and disruption of dopamine/D2-related mechanisms that regulate cortical function and neuronal excitability ,. sdy/B6 mice also exhibit increased impulsive and compulsive behaviors relevant to psychiatric disorders .
Thus, a growing body of evidence implicates dysbindin-1 in psychiatric disorders. However, because of failure to replicate genetic association studies , a lack of causal variants with a notable impact on disease risk that might contribute to schizophrenia , and methodological difficulties in postmortem brain research due to heterogeneity of tissues with respect to biochemical parameters, lifetime history of medications and physiological status at the time of death , it remains unclear how dysbindin-1 functions as a susceptibility gene for these disorders.
A recent study in mice and humans demonstrated an epistatic interaction between catechol-O-methyl transferase (COMT) and dysbindin-1 that modulates prefrontal function, specifically, subjects with reduced function of either COMT or dysbindin-1 show superb physiological performance, whereas those with reductions in both proteins have performance deficits .
As dysbindin-1 has both beneficial and detrimental effects in prefrontal cortical function, we performed a gain-of-function study of dysbindin-1 by developing transgenic mice that express the human dysbindin-1 gene (Dys1A-Tg) and we analyzed their behavioral phenotypes.
Generation of Dys1A-Tg mice
Behavioral characterization of Dys1A-Tg mice under basal conditions
SHIRPA primary screening in Dys1A-Tg mice
Paradigm and examination
Body weight (g)
Behavioral response to acute treatment with METH and phencyclidine in Dys1A-Tg mice
Behavioral response to chronic PCP treatment in Dys1A-Tg mice
Altered gene expression in Dys1A-Tg mouse brain
Genes with significantly altered expression in the brain of Dys1A-Tg mice
Brain region/changes in Dys1A-Tg
Fold change vs. wild-type
TRAF2 and NCK interacting kinase
1.3 ± 0.1
3765 ± 169
4742 ± 195
Kruppel-like factor 10
0.6 ± 0.0
1055 ± 21
621 ± 31
Activity regulated cytoskeletal-associated protein
0.3 ± 0.1
2194 ± 442
644 ± 156
early growth response 2
0.5 ± 0.1
633 ± 76
307 ± 86
RIKEN cDNA 5330406 M23 gene
0.7 ± 0.0
2301 ± 117
1502 ± 86
Myelin transcription factor 1-like
0.6 ± 0.0
1926 ± 154
1224 ± 77
RIKEN cDNA C130075A20 gene
0.5 ± 0.0
643 ± 71
348 ± 21
Integrin beta 1 binding protein 1
0.5 ± 0.0
343 ± 23
172 ± 14
G protein-coupled receptor 178
1.4 ± 0.1
1512 ± 71
2169 ± 76
Chemokine (C-C motif) ligand 21b
1.7 ± 0.1
874 ± 78
1503 ± 65
zinc finger, MYM domain containing 1
0.7 ± 0.0
2050 ± 64
1398 ± 75
TRAF2 and NCK interacting kinase
1.3 ± 0.1
3418 ± 220
4587 ± 232
DNA segment, Chr 4, Wayne State University 53, expressed
0.7 ± 0.1
2878 ± 230
1863 ± 165
Kruppel-like factor 2 (lung)
0.6 ± 0.1
414 ± 62
244 ± 27
We aimed to gain insight into the role of dysbindin-1 in psychiatric disorders. To this end, we first generated Dys1A-Tg mice expressing human DTNBP1 and then analyzed their phenotypes. In order to investigate the function of dysbindin-1 relevant to clinical application, human DTNBP1 was chosen as a transgene. Dys1A-Tg mice were born viable in the expected Mendelian ratios, apparently normal and fertile. Primary screening of behavior and function using the SHIRPA protocol showed a marginal change in limb grasping in Dys1A-Tg mice. They also exhibited increased hyperlocomotion after METH administration. In the brain of Dys1A-Tg mice, transcriptomic analysis identified several up- and down-regulated genes, including the immediate-early genes Arc and Egr2.
Among two lines of Dys1A-Tg mice generated, total levels of dysbindin-1 (human and mouse dysbindin-1) were considered to be significantly higher in line 1 while those in line 2 were only slightly higher than wild-type mice (Figure1C). Therefore, we performed the following behavioral and gene expression experiments in line 1. However, we could not rule out the possibility that the obtained results in the present study might be attributed to the disruption of other genes where the transgene was inserted.
In the social interaction test, which was conducted on day 17 in our test battery, we observed impairments in Dys1A-Tg mice that received vehicle (saline) for 14 days compared with wild-type mice (Figure4D). Although PCP significantly decreased social interaction in wild-type mice, it did not further decrease the behavior in Dys1A-Tg mice. Interpretation of these results is difficult but may be related to detrimental effect in Dys1A-Tg mice caused by repeated vehicle administration for 14 days. As our previous study showed that the FST lasts for only 3 days after the last PCP injection in C57BL6/J mice , and it is necessary to minimize test interactions ,, we designed the present behavioral test battery. However, since we did not use a washout period following chronic PCP treatment, the possibility for residual acute effects of PCP may not be excluded especially in the locomotor test and the FST conducted on day 14 and day 15, respectively, and in the mice treated with PCP at 10 mg/kg.
As discussed above, there is a growing body of evidence implicating dysbindin-1 in psychiatric disorders -,-, nevertheless it remains unclear how dysbindin-1 increases susceptibility to these disorders -. Dysbindin-1-deficient mutant Sandy mice (spontaneous mutant in a DBA/2 J mouse strain) display a variety of behavioral abnormalities relevant to symptoms of schizophrenia ,-, as well as reduced dopamine transmission in the forebrain . sdy/B6 mice (Sandy mutant mice on a C57BL/6 J background) show schizophrenia-like behaviors including hyperactivity, learning and memory deficits, and disruption of dopamine/D2-related mechanisms that regulate cortical function and neuronal excitability ,. These mice also exhibit increased impulsive and compulsive behaviors relevant to psychiatric disorders . The present observations that Dys1A-Tg mice are essentially normal under basal conditions (except for increased limb grasping behavior) and exhibit altered behavioral responses to METH, indicate that dysbindin-1 overexpression does not cause strong detrimental effects under basal conditions but may induce vulnerability toward psychotomimetics. The fact that either overexpression (Dys1A-Tg) or underexpression (Sandy both on DBA/2 J and C57BL/6 J backgrounds) of dysbindin-1 leads to behavioral alterations in mice highlights the functional importance of this protein and the molecular networks in which dysbindin-1 is involved.
Dysbindin-1 is expressed ubiquitously in the body and brain , and has been postulated to be implicated not only in psychiatric disorders such as schizophrenia, bipolar disorder, and METH psychosis ,-,-, but also peripheral diseases such as type 7 Hermansky-Pudlak syndrome, which is accompanied with oculocutaneous albinism, prolonged bleeding, and pulmonary fibrosis due to abnormal vesicle trafficking to lysosomes and related organelles . Thus, Dys1A-Tg mice may serve as a model for various diseases and complement dysbindin-1-null Sandy mice.
DTNBP1 variants (including e.g., protective and risk haplotypes) are reported to affect susceptibility to substance-induced psychosis , and dysbindin-1 is involved in regulation of synaptic plasticity ,, neurotransmitter release -, and membrane surface expression of NMDA and D2 receptors -. Altogether, it is suggested that dysbindin-1 plays significant roles in neurobehavioral control and psychiatric disorders.
In summary, we have generated Dys1A-Tg mice expressing human DTNBP1. Dys1A-Tg mice are apparently normal and fertile without abnormalities in their coat color, but with a marginal change in limb grasping, slightly exaggerated behavioral response to acutely administered METH. In the brain of Dys1A-Tg mice, expression levels of several genes are altered, including the immediate-early genes, Arc and Egr2. Our results in Dys1A-Tg mice further suggest a critical role for dysbindin-1 in psychiatric disorders.
All animal care and handling procedures were performed according to the Guidelines for the Care and Use of Laboratory Animals approved by the Japanese Pharmacological Society, and were approved by the Animal Care and Use Committee of the Graduate School of Pharmaceutical Sciences, Osaka University. All efforts were made to minimize the number of animals used.
Generation of Dys1A-Tg mice expressing human dysbindin-1
hDTNBP1-GFP consists of Homo sapiens dysbindin-1 isoform A (accession no. NP_115498, 351 amino acids), green fluorescent protein (GFP), and a termination codon. A 1,773-bp fragment encoding 591 amino acids of hDTNBP1-GFP was inserted into the Hap I site of the pCA-pA vector containing the CA promoter , and the transgene construct confirmed by DNA sequencing. Next, a 3.7-kb fragment including hDTNBP1-GFP cDNA was excised by Bam HI-Xho I digestion, and used to generate Dys1A-Tg mice by pronuclear injections into fertilized C57BL/6 mouse eggs.
Genotypes were determined by PCR using genomic DNA extracted from tail biopsies in extraction buffer (5 mM EDTA, 100 mM Tris HCl, pH 8.5, 200 mM NaCl, 0.2% SDS, and 200μ g/mL proteinase K). Genotyping was performed on genomic DNA (40 ng) using AmpliTaqGold DNA Polymerase (Applied Biosystems, Foster City, CA, USA) and the following primers located in different exons of the human DTNBP1 gene (5 -GAC TAA GAA TCC ATG ACA GCA AAT C-3 and 5 -TTA ATT CTG AGG GAT TTG GAA CCT-3 ; product size, 547 bp). The PCR reaction consisted of 40 cycles of denaturation at 94°Cfor 30 s, annealing at 55°Cfor 30 s, and elongation at 72°Cfor 1 min.
Dys1A-Tg mice were backcrossed with female C57BL/6 J mice (Charles River, Osaka, Japan) for at least 10 generations. Wild-type female mice were mated with male Dys1A-Tg mice and 8 20-week-old male offspring were used for experiments. Mice were group housed under a 12-h light dark cycle (lights on at 8:30 a.m.) with free access to food and water.
RT-PCR and western blot analyses
RT-PCR was performed as described previously, but with some modifications . Briefly, total RNA was reverse transcribed and cDNA from three mice mixed and subjected to semi-quantitative RT-PCR analysis using Gotaq Hot Start Green Master Mix (Promega, Tokyo, Japan) and the following primers corresponding to different exons of the mouse Dtnbp1 gene (5 -GAA CCA TTT GCT GCA CCT GGA C-3 and 5 -GGC CTT CTG TGT GTG CTC TGT ATC G-3 ; product size, 157 bp), the human DTNBP1 gene (5 -GCA GCT CCC AGC TTT AAT CGC AG-3 and 5 -TGG GCG TGC TCT GCA TCT AGT-3 ; product size, 232 bp), and the mouse GAPDH gene, which served as an internal control (5 -GTG TTC CCT ACC CCC AAT GTG-3 and 5 -TAC CAG GAA ATG AGC TTG AC-3 ; product size, 241 bp). To confirm validity of genomic DNA amplification, the mouse Dtnbp1 gene was amplified using intron 6-specific primers (5 -GCA CTC AGG AGA CCA TGA CA-3 and 5 -GGT TGA CAC TCT TGC GGA AT-3 ; product size, 305 bp). Quantitative real-time RT-PCR was also performed in the same way as mentioned above.
Western blot analysis was performed as described , using mouse monoclonal anti-dysbindin antibody, which was produced in our laboratory against glutatione S-transferase-fused human dysbindin-1 . Briefly, 20μ g of protein from precipitated brain homogenates were separated on SDS-PAGE and electrotransferred onto Immobilon-P Transfer Membranes (Millipore, Billerica, MA, USA), and then probed with primary antibodies: mouse monoclonal anti-dysbindin antibody (1:1,000; Cell Signaling Technology, Danvers, MA, USA) and mouse anti-GAPDH antibody (1:10,000; Millipore), followed by anti-mouse horseradish peroxidase-conjugated antibody (1:2,000; GE Healthcare, Piscataway, NJ, USA). The intensity of the bands was quantitated with Image J software (National Institutes of Health, MD, USA).
Drugs and experimental design for behavioral analyses
Drug solutions were administered to mice in a volume of 0.1 mL/10μ body weight. METH and PCP dissolved in saline were acutely injected intraperitoneally or subcutaneously, respectively. Each behavioral study was performed using separate cohorts of mice, except for the novel object investigation test.
In the chronic PCP administration model , 6-week-old mice were chronically administered with PCP for 14 consecutive days, and then subjected to a battery of four different behavioral tests: locomotor analysis on day 14 (30 min after the last PCP dose), FST on day 15, social interaction test on day 17, and novel object recognition test on days 20 (training session) and 21 (retention test session). The sequence of this behavioral test battery was fundamentally designed to minimize test interactions, by arranging the least stressful tasks first and more stressful tasks last ,, with the exception that the FST was performed the day after the last PCP injection as it has been shown that chronic PCP-increased immobility in the FST lasts for only 3 days in C57BL/6 J mice .
Initial behavioral screening
The open-field test was performed using the infrared Actimeter system (Panlab, Barcelona, Spain), and distance traveled, vertical rearing activity, and time spent in the center area were measured using Acti-Track software (Panlab), as described previously ,. In the PCP study, locomotor activity was measured using a digital counter system with an infrared sensor (Supermex; Muromachi Kikai Co., Tokyo, Japan), as described previously .
PPI of the acoustic startle response
PPI of the acoustic startle response was measured in a startle chamber (SR-LAB; San Diego Instruments, San Diego, CA, USA), essentially as described previously . PPI was calculated as percentage score for each pre-pulse trial type using the following equation: pre-pulse inhibition (%) = [1 (startle response for pulse with pre-pulse)/(startle response for pulse alone)] 100.
An accelerating rotarod treadmill (Acceler Rota-Rod 7650; Ugo Basile, Varese, Italy) was used to evaluate motor coordination and learning. Mice were first trained repeatedly at a fixed speed (12 rpm) until the mice were able to stay on the rod for at least 300 s. One day after training, performance on the accelerating (12 30 rpm) rotarod was examined for a maximum recording time of 600 s. Tests were performed once for 3 consecutive days.
Novel object investigation test
Exploratory behavior towards a novel object was evaluated as described . After 15 min habituation under dim light (40 lx) in an observation cage (28 cm length 20 cm width 12 cm height), mice were presented with a novel object (a wooden ball; diameter 5 cm), which was placed in the center of the cage. Duration of object exploratory behavior (sniffing or licking the wooden ball) was measured for 5 min from recordings by trained blinded observers. The test was performed just after locomotor analysis in the same mice treated with acute PCP.
The FST was performed as described previously . Briefly, behavior of mice in a glass cylinder (19 cm diameter 25 cm height) containing water (25 1 ± °C) to a depth of 13 cm was videotaped for 6 min, and duration of immobility (making only minimal movements to keep floating) was measured by trained blinded observers. After the test, mice were dried thoroughly with a towel and returned to their home cage.
Social interaction test
In chronic PCP-treated mice, social interaction between adult mice was evaluated as described , with slight modifications. Mice were individually habituated to the observation apparatus (35 cm length 25 cm width 25 cm height) for 10 min for 2 consecutive days. Next, two unfamiliar test mice of the same genotype and treatment were placed in the apparatus, and social interaction behavior videotaped for 5 min. Time spent in active social interaction such as sniffing and following the partner, mounting, and crawling under/over the partner was measured by trained blinded observers.
Novel object recognition memory test
Novel object recognition memory was evaluated as described ,, with slight modifications . Mice were individually habituated to the observation box (30 cm length 20 cm width 20 cm height) for 10 min for 3 consecutive days. Next, a training session was performed, and mice were allowed to explore the observation box containing two different objects for 10 min. After 24 H, the retention test session was conducted, and each mouse was placed back in the observation box with a familiar object (presented in the training session) and a novel object. Behavior of the mice was videotaped and evaluated by trained blinded observers. Preference indices were calculated as the ratio of time spent exploring the novel object vs. the total time spent exploring both familiar and novel objects, and used as a dependent measure of recognition memory.
Prefrontal cortex, hippocampus, and striatum were manually dissected from the brains of nine each Dys1A-Tg and wild-type mice. Three samples were pooled and subjected to GeneChip mouse genome 430 2.0 arrays (Affymetrix, Tokyo, Japan) which is one of the most comprehensive whole mouse genome expression array. A total of 18 hybridization experiments were performed according to the manufacturer s instructions, and data analyzed using GeneChip Operating Software (GCOS) v1.1.1. GCOS was used to calculate the signal intensity and percent present calls on hybridized chips. Fold change of individual genes between Dys1A-Tg and wild-type mice are presented as the ratio of normalized gene expression values in Dys1A-Tg vs. wild-type mice.
Statistical analysis was performed using StatView (SAS Institute Japan Ltd., Tokyo, Japan). Significant differences were determined by the Student s t-test, Mann Whitney U test, x2 test or two- or three-way, factorial or repeated-measures ANOVA with genotype, drug, and time as factors of variation. Tukey Kramer post-hoc tests were also performed after significant main effects for genotype, drug, or interaction between genotype drug were observed. The threshold for statistical significance was defined as P < 0.05.
RHas, TK, TNab, MT, and HH conceived the study. NS, RHas, HT, AM, TM, SM, TK, TNab, MT, and HH designed the experiments. NS, RHas, and HH wrote the manuscript. NS, YO, HT, TNag, SU, AM, TM, RHab, and YA performed the behavioral experiments, and NS, YO, HT, YA and HH analyzed the data. RHas, HT, SU, SM, TK, HY, and YY generated Dys1A-Tg mice. RHas, SU, SM, TK, HY, TNak, and KN performed the gene expression analysis and analyzed the data. All authors read and approved the final manuscript.
We are grateful to Dr. Takayoshi Inoue at the National Center of Neurology and Psychiatry for help and advice on constructing the hDTNBP1-GFP construct. This work was supported in part by the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research, KAKENHI (Grant Nos. 23790086 (NS); 22390225, 23659565, and 25293250 (RHas); 26293020 and 26670122 (HH)), Research Fellowships for Young Scientists (YO), the Funding Program for Next Generation World-Leading Researchers (Grant No. LS081 (HH)), and grants for research from the Uehara Memorial Foundation, Japan (HH).
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