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

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. The immature dentate gyrus represents a sharedphenotype of mouse models of epilepsy and psychiatric disease.Bipolar Disord 2013: 15: 405–421. © 2013 John Wiley & Sons A/S.Published by John Wiley & Sons Ltd.Objectives: There is accumulating evidence to suggest psychiatricdisorders, such as bipolar disorder and schizophrenia, share commonetiologies, pathophysiologies, genetics, and drug responses with many ofthe epilepsies. Here, we explored overlaps in cellular/molecular,electrophysiological, and behavioral phenotypes between putative mousemodels of bipolar disorder/schizophrenia and epilepsy. We tested thehypothesis that an immature dentate gyrus (iDG), whose associationwith psychosis in patients has recently been reported, represents acommon phenotype of both diseases.Methods: Behaviors of calcium/calmodulin-dependent protein kinase IIalpha (a-CaMKII) heterozygous knock-out (KO) mice, which are arepresentative bipolar disorder/schizophrenia model displaying iDG, andpilocarpine-treated mice, which are a representative epilepsy model, weretested followed by quantitative polymerase chain reaction (qPCR)/immunohistochemistry for mRNA/protein expression associated with aniDG 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 behavioraldeficits, such as hyperactivity, poor working memory performance, andsocial withdrawal. Significant reductions in mRNA expression andimmunoreactivity of the mature neuronal marker calbindin andconcomitant increases in mRNA expression and immunoreactivity of theimmature neuronal marker calretinin represent iDG signatures that arepresent in both mice models. Electrophysiologically, we have confirmedthat DG GCs from pilocarpine-treated mice represent an immature state.A significant decrease in hippocampal a-CaMKII protein levels was alsofound in both models.Conclusions: Our data have shown iDG signatures from mouse modelsof both bipolar disorder/schizophrenia and epilepsy. The evidencesuggests that the iDG may, in part, be responsible for the abnormalbehavioral phenotype, and that the underlying pathophysiologies inepilepsy and bipolar disorder/schizophrenia are strikingly similar.