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Absence of BRINP1 in mice causes increase of hippocampal neurogenesis and behavioral alterations relevant to human psychiatric disorders.

Kobayashi M, Nakatani T, Koda T, Matsumoto K, Ozaki R, Mochida N, Takao K, Miyakawa T, Matsuoka I - Mol Brain (2014)

Bottom Line: Furthermore, BRINP1-KO mice showed abnormal behaviors with increase in locomotor activity, reduced anxiety-like behavior, poor social interaction, and slight impairment of working memory, all of which resemble symptoms of human psychiatric disorders such as schizophrenia and attention-deficit/hyperactivity disorder (ADHD).Absence of BRINP1 causes deregulation of neurogenesis and impairments of neuronal differentiation in adult hippocampal circuitry.These abnormal behaviors could be caused by alteration of hippocampal circuitry as a consequence of the lack of BRINP1.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Physiological Chemistry, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan. imatsuok@cc.matsuyama-u.ac.jp.

ABSTRACT

Background: We have previously identified BRINP (BMP/RA-inducible neural-specific protein-1, 2, 3) family genes that possess the ability to suppress cell cycle progression in neural stem cells. Of the three family members, BRINP1 is the most highly expressed in various brain regions, including the hippocampus, in adult mice and its expression in dentate gyrus (DG) is markedly induced by neural activity. In the present study, we generated BRINP1-deficient (KO) mice to clarify the physiological functions of BRINP1 in the nervous system.

Results: Neurogenesis in the subgranular zone of dentate gyrus was increased in BRINP1-KO mice creating a more immature neuronal population in granule cell layer. The number of parvalbumin expressing interneuron in hippocampal CA1 subregion was also increased in BRINP1-KO mice. Furthermore, BRINP1-KO mice showed abnormal behaviors with increase in locomotor activity, reduced anxiety-like behavior, poor social interaction, and slight impairment of working memory, all of which resemble symptoms of human psychiatric disorders such as schizophrenia and attention-deficit/hyperactivity disorder (ADHD).

Conclusions: Absence of BRINP1 causes deregulation of neurogenesis and impairments of neuronal differentiation in adult hippocampal circuitry. Abnormal behaviors comparable to those of human psychiatric disorders such as hyperactivity and poor social behavior were observed in BRINP1-KO mice. These abnormal behaviors could be caused by alteration of hippocampal circuitry as a consequence of the lack of BRINP1.

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General health and neurological screening of BRINP1-KO mice. (A) Body weight of BRINP1-KO mice was reduced to about 85% of wild-type mice. (B) Body temperature was measured at rectum. (C) Grip strength of forelimb in Newton. (D) Latency to fall (s) showed in wire hang test. (E) Hot plate test at 55°C. (F) Rotarod test. (wild-type mice, n = 11; BRINP1-KO mice, n = 9) Error bars indicate SEM.
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Figure 2: General health and neurological screening of BRINP1-KO mice. (A) Body weight of BRINP1-KO mice was reduced to about 85% of wild-type mice. (B) Body temperature was measured at rectum. (C) Grip strength of forelimb in Newton. (D) Latency to fall (s) showed in wire hang test. (E) Hot plate test at 55°C. (F) Rotarod test. (wild-type mice, n = 11; BRINP1-KO mice, n = 9) Error bars indicate SEM.

Mentions: BRINP1-KO mice were designed to replace Brinp1 exon8 with neomycin resistant gene (Figure 1A). Homologous recombination of genomic DNA in embryonic stem (ES) cells and F1 mice was confirmed by Southern blot analysis that produced 6.9 kb and 9.6 kb BamHI fragments hybridized with 5’ probe (Figure 1B-C). Northern hybridization with Brinp1 exon8-cRNA probe showed that BRINP1-mRNA was absent in the adult brain of BRINP1-KO mice (Figure 1D). Loss of BRINP1 expression did not alter mRNA levels of BRINP2 or BRINP3, the other members of BRINP family genes, suggesting that there is no compensation of mRNA expression among BRINP family genes in BRINP1-KO mice. BRINP1 homozygous KO mice showed a normal appearance at birth and had normal skeleton. The body weight of BRINP1-KO mice (22.38 ± 0.45 g) was about 85% of wild-type (WT) littermates (26.22 ± 0.38 g) at adult stage (Figure 2A). However, there were no significant differences in the weights of either brain or hippocampus between BRINP1-KO and wild-type mice (i.e. brain weight, WT; 774.4 ± 71.3 mg (n = 5), BRINP1-KO; 697.4 ± 96.4 mg (n = 11), hippocampal weight per mouse, WT; 24.6 ± 2.3 mg (n = 10), BRINP1-KO; 25.8 ± 1.8 mg (n = 12)).


Absence of BRINP1 in mice causes increase of hippocampal neurogenesis and behavioral alterations relevant to human psychiatric disorders.

Kobayashi M, Nakatani T, Koda T, Matsumoto K, Ozaki R, Mochida N, Takao K, Miyakawa T, Matsuoka I - Mol Brain (2014)

General health and neurological screening of BRINP1-KO mice. (A) Body weight of BRINP1-KO mice was reduced to about 85% of wild-type mice. (B) Body temperature was measured at rectum. (C) Grip strength of forelimb in Newton. (D) Latency to fall (s) showed in wire hang test. (E) Hot plate test at 55°C. (F) Rotarod test. (wild-type mice, n = 11; BRINP1-KO mice, n = 9) Error bars indicate SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3928644&req=5

Figure 2: General health and neurological screening of BRINP1-KO mice. (A) Body weight of BRINP1-KO mice was reduced to about 85% of wild-type mice. (B) Body temperature was measured at rectum. (C) Grip strength of forelimb in Newton. (D) Latency to fall (s) showed in wire hang test. (E) Hot plate test at 55°C. (F) Rotarod test. (wild-type mice, n = 11; BRINP1-KO mice, n = 9) Error bars indicate SEM.
Mentions: BRINP1-KO mice were designed to replace Brinp1 exon8 with neomycin resistant gene (Figure 1A). Homologous recombination of genomic DNA in embryonic stem (ES) cells and F1 mice was confirmed by Southern blot analysis that produced 6.9 kb and 9.6 kb BamHI fragments hybridized with 5’ probe (Figure 1B-C). Northern hybridization with Brinp1 exon8-cRNA probe showed that BRINP1-mRNA was absent in the adult brain of BRINP1-KO mice (Figure 1D). Loss of BRINP1 expression did not alter mRNA levels of BRINP2 or BRINP3, the other members of BRINP family genes, suggesting that there is no compensation of mRNA expression among BRINP family genes in BRINP1-KO mice. BRINP1 homozygous KO mice showed a normal appearance at birth and had normal skeleton. The body weight of BRINP1-KO mice (22.38 ± 0.45 g) was about 85% of wild-type (WT) littermates (26.22 ± 0.38 g) at adult stage (Figure 2A). However, there were no significant differences in the weights of either brain or hippocampus between BRINP1-KO and wild-type mice (i.e. brain weight, WT; 774.4 ± 71.3 mg (n = 5), BRINP1-KO; 697.4 ± 96.4 mg (n = 11), hippocampal weight per mouse, WT; 24.6 ± 2.3 mg (n = 10), BRINP1-KO; 25.8 ± 1.8 mg (n = 12)).

Bottom Line: Furthermore, BRINP1-KO mice showed abnormal behaviors with increase in locomotor activity, reduced anxiety-like behavior, poor social interaction, and slight impairment of working memory, all of which resemble symptoms of human psychiatric disorders such as schizophrenia and attention-deficit/hyperactivity disorder (ADHD).Absence of BRINP1 causes deregulation of neurogenesis and impairments of neuronal differentiation in adult hippocampal circuitry.These abnormal behaviors could be caused by alteration of hippocampal circuitry as a consequence of the lack of BRINP1.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Physiological Chemistry, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan. imatsuok@cc.matsuyama-u.ac.jp.

ABSTRACT

Background: We have previously identified BRINP (BMP/RA-inducible neural-specific protein-1, 2, 3) family genes that possess the ability to suppress cell cycle progression in neural stem cells. Of the three family members, BRINP1 is the most highly expressed in various brain regions, including the hippocampus, in adult mice and its expression in dentate gyrus (DG) is markedly induced by neural activity. In the present study, we generated BRINP1-deficient (KO) mice to clarify the physiological functions of BRINP1 in the nervous system.

Results: Neurogenesis in the subgranular zone of dentate gyrus was increased in BRINP1-KO mice creating a more immature neuronal population in granule cell layer. The number of parvalbumin expressing interneuron in hippocampal CA1 subregion was also increased in BRINP1-KO mice. Furthermore, BRINP1-KO mice showed abnormal behaviors with increase in locomotor activity, reduced anxiety-like behavior, poor social interaction, and slight impairment of working memory, all of which resemble symptoms of human psychiatric disorders such as schizophrenia and attention-deficit/hyperactivity disorder (ADHD).

Conclusions: Absence of BRINP1 causes deregulation of neurogenesis and impairments of neuronal differentiation in adult hippocampal circuitry. Abnormal behaviors comparable to those of human psychiatric disorders such as hyperactivity and poor social behavior were observed in BRINP1-KO mice. These abnormal behaviors could be caused by alteration of hippocampal circuitry as a consequence of the lack of BRINP1.

Show MeSH
Related in: MedlinePlus