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. 1. Introduction The exact mechanisms within the brain that underlie most psychiatric disorders remain largely unknown, and one of the major challenges in psychiatric research is to identify the pathophysiology in the brains of patients with these disorders. This is challenging because psychiatric disorders are diagnosed on the basis of behavioral characteristics and not biological criteria. Therefore, each psychiatric disorder likely consists of multiple biologically heterogeneous populations, which further complicates the search for underlying pathophysiologies. Previously, studies have identified the “immature dentate gyrus (iDG),” a potential brain endophenotype shared by several psychiatric disorders, including schizophrenia and bipolar disorder. The iDG was identified in animal models of psychiatric disorders, which were selected using large-scale behavioral screening of genetically engineered mice [1]. In the iDG phenotype, most of the granule cells or principal neurons in the dentate gyrus (DG) within the hippocampus are arrested at a pseudoimmature status, in which the
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