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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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Neuronal differentiation marker expression in dentate gyrus. (A,B) Doublecortin, (C,D) Calretinin, (E,F) Calbindin expression in 7-week-old mouse dentate gyrus. (A,C,E) Wild-type mice, (B,D,F) BRINP1-KO mice. Scale bar; 50 μm.
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Figure 8: Neuronal differentiation marker expression in dentate gyrus. (A,B) Doublecortin, (C,D) Calretinin, (E,F) Calbindin expression in 7-week-old mouse dentate gyrus. (A,C,E) Wild-type mice, (B,D,F) BRINP1-KO mice. Scale bar; 50 μm.

Mentions: To assess the level of adult neurogenesis in SGZ, we examined the number of 5-bromo-2’-deoxyuridine (BrdU)-positive neurons in SGZ after an intraperitoneal injection of BrdU as well as the number of Ki-67-positive neurons in 7 to 10-week-old mice. As a result, the immunoreactivities of both incorporated-BrdU and Ki-67 were noticeably increased in SGZ of 8-week-old BRINP1-KO mice compared to wild-type mice (Figure 7A-D). At 7 and 8-weeks, the average number of BrdU-positive cells per section in BRINP1-KO mice was 1.65- and 1.94-fold greater than those in wild-type mice, respectively (Figure 7E). The number of Ki-67-positive cells in SGZ was also increased in the BRINP1-KO mice in a similar manner to the BrdU-positive cells. On the other hand, in SGZ of 10-week-old mice, there were no obvious differences in the numbers of BrdU- and Ki-67-positive cells between BRINP1-KO mice and wild-type mice (data not shown). These results suggest that BRINP1 function in the hippocampus of normal animals is to suppress neurogenesis in SGZ. Developing dentate granule neurons as well as adult born dentate neurons express several marker proteins depending on their levels of maturation. In the dentate gyrus of 7-week-old BRINP1-KO mice, staining of doublecortin (DCX), a marker for neuroblast and immature neurons [16,17], was stronger than that in wild-type mice (Figure 8A-B). In contrast, expressions of both calretinin, a marker of postmitotic immature neurons and calbindin, a marker of mature neurons in BRINP1-KO mice were similar to those in wild-type mice (Figure 8C-F).


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)

Neuronal differentiation marker expression in dentate gyrus. (A,B) Doublecortin, (C,D) Calretinin, (E,F) Calbindin expression in 7-week-old mouse dentate gyrus. (A,C,E) Wild-type mice, (B,D,F) BRINP1-KO mice. Scale bar; 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Neuronal differentiation marker expression in dentate gyrus. (A,B) Doublecortin, (C,D) Calretinin, (E,F) Calbindin expression in 7-week-old mouse dentate gyrus. (A,C,E) Wild-type mice, (B,D,F) BRINP1-KO mice. Scale bar; 50 μm.
Mentions: To assess the level of adult neurogenesis in SGZ, we examined the number of 5-bromo-2’-deoxyuridine (BrdU)-positive neurons in SGZ after an intraperitoneal injection of BrdU as well as the number of Ki-67-positive neurons in 7 to 10-week-old mice. As a result, the immunoreactivities of both incorporated-BrdU and Ki-67 were noticeably increased in SGZ of 8-week-old BRINP1-KO mice compared to wild-type mice (Figure 7A-D). At 7 and 8-weeks, the average number of BrdU-positive cells per section in BRINP1-KO mice was 1.65- and 1.94-fold greater than those in wild-type mice, respectively (Figure 7E). The number of Ki-67-positive cells in SGZ was also increased in the BRINP1-KO mice in a similar manner to the BrdU-positive cells. On the other hand, in SGZ of 10-week-old mice, there were no obvious differences in the numbers of BrdU- and Ki-67-positive cells between BRINP1-KO mice and wild-type mice (data not shown). These results suggest that BRINP1 function in the hippocampus of normal animals is to suppress neurogenesis in SGZ. Developing dentate granule neurons as well as adult born dentate neurons express several marker proteins depending on their levels of maturation. In the dentate gyrus of 7-week-old BRINP1-KO mice, staining of doublecortin (DCX), a marker for neuroblast and immature neurons [16,17], was stronger than that in wild-type mice (Figure 8A-B). In contrast, expressions of both calretinin, a marker of postmitotic immature neurons and calbindin, a marker of mature neurons in BRINP1-KO mice were similar to those in wild-type mice (Figure 8C-F).

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