Adequate maturation of neurons is crucial for normal cognitive functions and emotional behaviors, with disruptions of this process likely to result in mental health perturbation. Previously, we reported that mice heterozygous for a null mutation of alpha-CaMKII, a key molecule in synaptic plasticity, have profoundly dysregulated behaviors, including hyper-locomotor activity and a severe working memory deficit, which are endophenotypes of schizophrenia and other psychiatric disorders. Almost all the neurons in the dentate gyrus (DG) of these mutant mice fail to mature at molecular, morphological and electrophysiological levels. We named this phenotype " immature dentate gyrus (iDG) ".
By analyzing gene expression patterns in the DG of the mice showing analogous behavioral phenotypes, we identified several other strains of mutant mice that have a phenotype strikingly similar to iDG, including forebrain-specific calcineurin knockout mice, mice lacking the transcription factor Schnurri-2 (Shn-2), and mice with a point mutation in the SNAP-25 gene. We also found that chronic fluoxetine treatment or a single pilocarpine administration induced " de-maturation ", resulting in an iDG-like phenotype in wild-type mice. Importantly, optogenetic stimulation of DG induced an iDG-like gene expression pattern, suggesting that excitation of neurons may cause de-maturation.
Most of the strains of the mice with iDG phenotype have decreased parvalbumin, GAD67 and oligodendrocyte markers. Moreover, gene- and protein expression patterns in the brains of these mice were similar to those found in the post-mortem brains of the patients of psychiatric disorders, including schizophrenia and bipolar disorder. The brains of iDG mice show mild chronic inflammation, distinct from typical acute inflammation, which is characterized by increase of C1q family genes and a lack of large changes of typical inflammatory cytokines, such as TNF-alpha and IL1-beta.
Thus, genetic, molecular and neuronal events regulating excitations of neurons seem to be involved in the bidirectional change of maturation status of cells in the brain. The potential implication of these findings in elucidating the pathophysiology of those neuropsychiatric disorders will be discussed.