Immature Dentate Gyrus: An Endophenotype of Neuropsychiatric Disorders

Abstract

Adequate maturation of neurons and their integration into the hippocampal circuit is crucial for normal cognitive function and emotional behavior, and disruption of this process could cause disturbances in mental health. Previous reports have shown that mice heterozygous for a null mutation in α-CaMKII, which encodes a key synaptic plasticity molecule, display abnormal behaviors related to schizophrenia and other psychiatric disorders. In these mutants, almost all neurons in the dentate gyrus are arrested at a pseudoimmature state at the molecular and electrophysiological levels, a phenomenon defined as “immature dentate gyrus (iDG).” To date, the iDG phenotype and shared behavioral abnormalities (including working memory deficit and hyperlocomotor activity) have been discovered in Schnurri-2 knockout, mutant SNAP-25 knock-in, and forebrain-specific calcineurin knockout mice. In addition, both chronic fluoxetine treatment and pilocarpine-induced seizures reverse the neuronal maturation, resulting in the iDG phenotype in wild-type mice. Importantly, an iDG-like phenomenon was observed in post-mortem analysis of brains from patients with schizophrenia/bipolar disorder. Based on these observations, we proposed that the iDG is a potential endophenotype shared by certain types of neuropsychiatric disorders. This review summarizes recent data describing this phenotype and discusses the data's potential implication in elucidating the pathophysiology of neuropsychiatric disorders.

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).…”

Type 2 diabetes mellitus, drug addiction, bipolar disorder and epilepsy display overlapping aetiopathogenic mechanisms: Implication for prevention and pharmacotherapy

“…The immature dentate gyrus may be an endophenotype of bipolar disorder and epilepsy (Hagihara et al, 2013), mediated partly by hyperdopaminergic signalling which dysregulates GSK-3 signalling, and metformin may upregulate neurogenesis in the dentate gyrus after dematuration by high-fat diet (Yoo et al, 2011).…”

Ectopic Mossy Fiber Pathfinding in the Hippocampus Caused the Abnormal Neuronal Transmission in the Mouse Models of Psychiatric Disease

“…During postnatal development, MFs extend to both the stratum lucidum (SL) and the stratum oriens (SO), forming supra-pyramidal bundles (SPB) and infra-pyramidal bundles (IPB), respectively. The formation of IPB, however, is transient and undergoes pruning during development, leaving mostly SPB upon maturation.2) It is of note that some pathological conditions such as temporal lobe epilepsy result in ectopic formation of IPB.3) The CaMKIIα heterozygous knockout (CaMKIIα-hKO) mouse is considered one of the psychiatric model mice as they showed hyper locomotor activity, the deficits of working memory and social interaction, 4,5) which also have the ectopic MF projection in SO. 6) In the present study, we investigated the electrophysiological properties in the MF-CA3 connection in CaMKIIα-hKO mice to characterize the functional abnormalities of the ectopic MF distribution.…”

“…3) The CaMKIIα heterozygous knockout (CaMKIIα-hKO) mouse is considered one of the psychiatric model mice as they showed hyper locomotor activity, the deficits of working memory and social interaction, 4,5) which also have the ectopic MF projection in SO. 6) In the present study, we investigated the electrophysiological properties in the MF-CA3 connection in CaMKIIα-hKO mice to characterize the functional abnormalities of the ectopic MF distribution.…”