The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease

Rick Shin, Katsunori Kobayashi, Hideo Hagihara, Jeffrey H. Kogan, Shinichi Miyake, Katsunori Tajinda, Noah M. Walton, Adam K. Gross, Carrie L. Heusner, Qian Chen, Kouichi Tamura, Tsuyoshi Miyakawa, Mitsuyuki Matsumoto

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Objectives: There is accumulating evidence to suggest psychiatric disorders, such as bipolar disorder and schizophrenia, share common etiologies, pathophysiologies, genetics, and drug responses with many of the epilepsies. Here, we explored overlaps in cellular/molecular, electrophysiological, and behavioral phenotypes between putative mouse models of bipolar disorder/schizophrenia and epilepsy. We tested the hypothesis that an immature dentate gyrus (iDG), whose association with psychosis in patients has recently been reported, represents a common phenotype of both diseases. Methods: Behaviors of calcium/calmodulin-dependent protein kinase II alpha (α-CaMKII) heterozygous knock-out (KO) mice, which are a representative bipolar disorder/schizophrenia model displaying iDG, and pilocarpine-treated mice, which are a representative epilepsy model, were tested followed by quantitative polymerase chain reaction (qPCR)/immunohistochemistry for mRNA/protein expression associated with an iDG phenotype. In vitro electrophysiology of dentate gyrus granule cells (DG GCs) was examined in pilocarpine-treated epileptic mice. Results: The two disease models demonstrated similar behavioral deficits, such as hyperactivity, poor working memory performance, and social withdrawal. Significant reductions in mRNA expression and immunoreactivity of the mature neuronal marker calbindin and concomitant increases in mRNA expression and immunoreactivity of the immature neuronal marker calretinin represent iDG signatures that are present in both mice models. Electrophysiologically, we have confirmed that DG GCs from pilocarpine-treated mice represent an immature state. A significant decrease in hippocampal α-CaMKII protein levels was also found in both models. Conclusions: Our data have shown iDG signatures from mouse models of both bipolar disorder/schizophrenia and epilepsy. The evidence suggests that the iDG may, in part, be responsible for the abnormal behavioral phenotype, and that the underlying pathophysiologies in epilepsy and bipolar disorder/schizophrenia are strikingly similar.

Original languageEnglish
Pages (from-to)405-421
Number of pages17
JournalBipolar Disorders
Volume15
Issue number4
DOIs
Publication statusPublished - 01-06-2013

Fingerprint

Dentate Gyrus
Psychiatry
Epilepsy
Phenotype
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Bipolar Disorder
Schizophrenia
Pilocarpine
Messenger RNA
Calbindin 2
Calbindins
Calcium-Calmodulin-Dependent Protein Kinases
Electrophysiology
Short-Term Memory
Knockout Mice
Psychotic Disorders
Proteins
Immunohistochemistry
Polymerase Chain Reaction
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Shin, Rick ; Kobayashi, Katsunori ; Hagihara, Hideo ; Kogan, Jeffrey H. ; Miyake, Shinichi ; Tajinda, Katsunori ; Walton, Noah M. ; Gross, Adam K. ; Heusner, Carrie L. ; Chen, Qian ; Tamura, Kouichi ; Miyakawa, Tsuyoshi ; Matsumoto, Mitsuyuki. / The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease. In: Bipolar Disorders. 2013 ; Vol. 15, No. 4. pp. 405-421.
@article{7cbe4e6da6ec40429ca4c3301ac078ae,
title = "The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease",
abstract = "Objectives: There is accumulating evidence to suggest psychiatric disorders, such as bipolar disorder and schizophrenia, share common etiologies, pathophysiologies, genetics, and drug responses with many of the epilepsies. Here, we explored overlaps in cellular/molecular, electrophysiological, and behavioral phenotypes between putative mouse models of bipolar disorder/schizophrenia and epilepsy. We tested the hypothesis that an immature dentate gyrus (iDG), whose association with psychosis in patients has recently been reported, represents a common phenotype of both diseases. Methods: Behaviors of calcium/calmodulin-dependent protein kinase II alpha (α-CaMKII) heterozygous knock-out (KO) mice, which are a representative bipolar disorder/schizophrenia model displaying iDG, and pilocarpine-treated mice, which are a representative epilepsy model, were tested followed by quantitative polymerase chain reaction (qPCR)/immunohistochemistry for mRNA/protein expression associated with an iDG phenotype. In vitro electrophysiology of dentate gyrus granule cells (DG GCs) was examined in pilocarpine-treated epileptic mice. Results: The two disease models demonstrated similar behavioral deficits, such as hyperactivity, poor working memory performance, and social withdrawal. Significant reductions in mRNA expression and immunoreactivity of the mature neuronal marker calbindin and concomitant increases in mRNA expression and immunoreactivity of the immature neuronal marker calretinin represent iDG signatures that are present in both mice models. Electrophysiologically, we have confirmed that DG GCs from pilocarpine-treated mice represent an immature state. A significant decrease in hippocampal α-CaMKII protein levels was also found in both models. Conclusions: Our data have shown iDG signatures from mouse models of both bipolar disorder/schizophrenia and epilepsy. The evidence suggests that the iDG may, in part, be responsible for the abnormal behavioral phenotype, and that the underlying pathophysiologies in epilepsy and bipolar disorder/schizophrenia are strikingly similar.",
author = "Rick Shin and Katsunori Kobayashi and Hideo Hagihara and Kogan, {Jeffrey H.} and Shinichi Miyake and Katsunori Tajinda and Walton, {Noah M.} and Gross, {Adam K.} and Heusner, {Carrie L.} and Qian Chen and Kouichi Tamura and Tsuyoshi Miyakawa and Mitsuyuki Matsumoto",
year = "2013",
month = "6",
day = "1",
doi = "10.1111/bdi.12064",
language = "English",
volume = "15",
pages = "405--421",
journal = "Bipolar Disorders",
issn = "1398-5647",
publisher = "Blackwell Munksgaard",
number = "4",

}

Shin, R, Kobayashi, K, Hagihara, H, Kogan, JH, Miyake, S, Tajinda, K, Walton, NM, Gross, AK, Heusner, CL, Chen, Q, Tamura, K, Miyakawa, T & Matsumoto, M 2013, 'The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease', Bipolar Disorders, vol. 15, no. 4, pp. 405-421. https://doi.org/10.1111/bdi.12064

The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease. / Shin, Rick; Kobayashi, Katsunori; Hagihara, Hideo; Kogan, Jeffrey H.; Miyake, Shinichi; Tajinda, Katsunori; Walton, Noah M.; Gross, Adam K.; Heusner, Carrie L.; Chen, Qian; Tamura, Kouichi; Miyakawa, Tsuyoshi; Matsumoto, Mitsuyuki.

In: Bipolar Disorders, Vol. 15, No. 4, 01.06.2013, p. 405-421.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease

AU - Shin, Rick

AU - Kobayashi, Katsunori

AU - Hagihara, Hideo

AU - Kogan, Jeffrey H.

AU - Miyake, Shinichi

AU - Tajinda, Katsunori

AU - Walton, Noah M.

AU - Gross, Adam K.

AU - Heusner, Carrie L.

AU - Chen, Qian

AU - Tamura, Kouichi

AU - Miyakawa, Tsuyoshi

AU - Matsumoto, Mitsuyuki

PY - 2013/6/1

Y1 - 2013/6/1

N2 - Objectives: There is accumulating evidence to suggest psychiatric disorders, such as bipolar disorder and schizophrenia, share common etiologies, pathophysiologies, genetics, and drug responses with many of the epilepsies. Here, we explored overlaps in cellular/molecular, electrophysiological, and behavioral phenotypes between putative mouse models of bipolar disorder/schizophrenia and epilepsy. We tested the hypothesis that an immature dentate gyrus (iDG), whose association with psychosis in patients has recently been reported, represents a common phenotype of both diseases. Methods: Behaviors of calcium/calmodulin-dependent protein kinase II alpha (α-CaMKII) heterozygous knock-out (KO) mice, which are a representative bipolar disorder/schizophrenia model displaying iDG, and pilocarpine-treated mice, which are a representative epilepsy model, were tested followed by quantitative polymerase chain reaction (qPCR)/immunohistochemistry for mRNA/protein expression associated with an iDG phenotype. In vitro electrophysiology of dentate gyrus granule cells (DG GCs) was examined in pilocarpine-treated epileptic mice. Results: The two disease models demonstrated similar behavioral deficits, such as hyperactivity, poor working memory performance, and social withdrawal. Significant reductions in mRNA expression and immunoreactivity of the mature neuronal marker calbindin and concomitant increases in mRNA expression and immunoreactivity of the immature neuronal marker calretinin represent iDG signatures that are present in both mice models. Electrophysiologically, we have confirmed that DG GCs from pilocarpine-treated mice represent an immature state. A significant decrease in hippocampal α-CaMKII protein levels was also found in both models. Conclusions: Our data have shown iDG signatures from mouse models of both bipolar disorder/schizophrenia and epilepsy. The evidence suggests that the iDG may, in part, be responsible for the abnormal behavioral phenotype, and that the underlying pathophysiologies in epilepsy and bipolar disorder/schizophrenia are strikingly similar.

AB - Objectives: There is accumulating evidence to suggest psychiatric disorders, such as bipolar disorder and schizophrenia, share common etiologies, pathophysiologies, genetics, and drug responses with many of the epilepsies. Here, we explored overlaps in cellular/molecular, electrophysiological, and behavioral phenotypes between putative mouse models of bipolar disorder/schizophrenia and epilepsy. We tested the hypothesis that an immature dentate gyrus (iDG), whose association with psychosis in patients has recently been reported, represents a common phenotype of both diseases. Methods: Behaviors of calcium/calmodulin-dependent protein kinase II alpha (α-CaMKII) heterozygous knock-out (KO) mice, which are a representative bipolar disorder/schizophrenia model displaying iDG, and pilocarpine-treated mice, which are a representative epilepsy model, were tested followed by quantitative polymerase chain reaction (qPCR)/immunohistochemistry for mRNA/protein expression associated with an iDG phenotype. In vitro electrophysiology of dentate gyrus granule cells (DG GCs) was examined in pilocarpine-treated epileptic mice. Results: The two disease models demonstrated similar behavioral deficits, such as hyperactivity, poor working memory performance, and social withdrawal. Significant reductions in mRNA expression and immunoreactivity of the mature neuronal marker calbindin and concomitant increases in mRNA expression and immunoreactivity of the immature neuronal marker calretinin represent iDG signatures that are present in both mice models. Electrophysiologically, we have confirmed that DG GCs from pilocarpine-treated mice represent an immature state. A significant decrease in hippocampal α-CaMKII protein levels was also found in both models. Conclusions: Our data have shown iDG signatures from mouse models of both bipolar disorder/schizophrenia and epilepsy. The evidence suggests that the iDG may, in part, be responsible for the abnormal behavioral phenotype, and that the underlying pathophysiologies in epilepsy and bipolar disorder/schizophrenia are strikingly similar.

UR - http://www.scopus.com/inward/record.url?scp=84878942261&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878942261&partnerID=8YFLogxK

U2 - 10.1111/bdi.12064

DO - 10.1111/bdi.12064

M3 - Article

C2 - 23560889

AN - SCOPUS:84878942261

VL - 15

SP - 405

EP - 421

JO - Bipolar Disorders

JF - Bipolar Disorders

SN - 1398-5647

IS - 4

ER -