title: The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease.
abstract: OBJECTIVE
  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.
authors.affiliation: CNS, Astellas Research Institute of America LLC, Skokie, IL, USA.
authors.forename: Rick
authors.initials: R
authors.lastname: Shin
authors.forename: Katsunori
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Hideo
authors.initials: H
authors.lastname: Hagihara
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Kogan
authors.forename: Shinichi
authors.initials: S
authors.lastname: Miyake
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tajinda
authors.forename: Noah M
authors.initials: NM
authors.lastname: Walton
authors.forename: Adam K
authors.initials: AK
authors.lastname: Gross
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Heusner
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tamura
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyakawa
authors.forename: Mitsuyuki
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D001526:Behavioral Symptoms / Q000378:metabolism / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D001714:Bipolar Disorder / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D064032:Calbindin 2 / Q000378:metabolism*; D018891:Dentate Gyrus / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena; D004827:Epilepsy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D051379:Mice; D018721:Muscarinic Agonists / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D012559:Schizophrenia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D015415:Biomarkers; D064032:Calbindin 2; D018721:Muscarinic Agonists; D010862:Pilocarpine
keywords: bipolar disorder; calbindin; calcium/calmodulin-dependent protein kinase II alpha; calretinin; dentate gyrus; doublecortin; neuronal immaturity; pilocarpine; schizophrenia; seizures
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