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

Abstract

ObjectivesThere 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.MethodsBehaviors 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.ResultsThe 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.ConclusionsOur 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.

Mossy fiber mis-pathfinding and semaphorin reduction in the hippocampus of α-CaMKII hKO mice

“…As these findings are similar to ours, it supports a common theme, that ectopic mossy fiber projection may contribute to seizure generation by inducing hyperactivity in hippocampus. This hypothesis is supported by previous findings that identify decreased seizure threshold in ␣-CaMKII hKO mice [15]. Further, mossy fibers undergo continuous turnover, even in adulthood [23], and some studies have suggested that the newly-generated granule cells play an important role in pattern separation task [24], which is often disturbed in psychiatric patients [25].…”

“…Previously-described ␣-CaMKII hKO mice, licensed from Massachusetts Institute of Technology [14,15], were maintained on a C57BL/6 background at Hilltop Labs (Scottdale, PA, USA). Adult mice (3-9 months old C57BL/6 wild type (WT) and ␣-CaMKII hKO littermates) were maintained on a 12 h on, 12 h off light cycle.…”

How to make a hippocampal dentate gyrus granule neuron

“…Several studies have recently identified the 'immature dentate gyrus' (iDG) as a conserved pathophysiological alteration that is found in neuropsychiatric disorders, including schizophrenia and bipolar disorder (Reif et al, 2006;Yamasaki et al, 2008;Walton et al, 2012;Hagihara et al, 2013;Shin et al, 2013). The observation of iDG was first reported in mice with a heterozygous mutation in the α-calcium/calmodulindependent protein kinase II (Camk2a) gene.…”

“…Finally, hippocampal neurogenesis deficits have been linked to cognitive defects characteristic of depression (Patricio et al, 2013), impairment in early Alzheimer's disease pathology (Demars et al, 2010;Faure et al, 2011;Mu and Gage, 2011;Rodriguez et al, 2011), bipolar disorder (Valvezan and Klein, 2012;Walton et al, 2012) and schizophrenia (SCZD) (Tamminga et al, 2010;Walton et al, 2012;Hagihara et al, 2013). More specifically, alterations in DG granule neuron maturation have been implicated in the etiology and pathogenesis of schizophrenia and bipolar disorder (see Box 1; Reif et al, 2006;Yamasaki et al, 2008;Walton et al, 2012;Hagihara et al, 2013;Shin et al, 2013).…”

Benzodiazepines induce sequelae in immature mice with inflammation-induced status epilepticus

“…Number of entries to the arm were measured and taken to reflect the level of anxiety. The alternation rate was attributed to working memory [18].…”