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.

Figure 1

Heat map showing behavioral phenotypes of more than 160 strains of genetically engineered mice. Each column represents the mouse strain analyzed in the laboratory of the author's group (unpublished data). Each row represents a behavior category assessed by the comprehensive battery of behavioral tests. Colors represent an increase (red) or decrease (green), compared between wild-type and mutant mice. Adapted from Takao et al. [8].

Figure 2

Mood-change-like behavior and the iDG phenotype in α-CaMKII HKO mice. (a) Pattern of locomotor activity of wild-type and α-CaMKII HKO mice in their home cage. Mutant mice were hyperactive and showed a periodic mood-change-like activity pattern. A.U: arbitrary unit. (b) Among the downregulated genes in the hippocampus of α-CaMKII HKO mice, several genes were expressed selectively in the DG (Allen Brain Atlas [42]. Seattle, WA: Allen Institute for Brain Science. © 2004–2008. Available from: http://www.brain-map.org). Graphs indicate the relative expression levels of each gene in the microarray experiment. (c) In α-CaMKII HKO mice, expression of PSA-NCAM (a late-progenitor and immature-neuron marker) and calretinin (an immature neuron marker) was markedly increased, and expression of calbindin (a mature neuron marker) was decreased. (d) Expression of Arc-dVenus in the DG of α-CaMKII HKO mice after the working memory task (eight-arm radial maze test) was completely abolished. Red: calbindin; green: Arc-dVenus. Adapted from Yamasaki et al. [1] and Matsuo et al. [13].

Figure 3

Impaired working memory performance in Shn-2 KO mice. (a) In the spatial working memory version of the eight-arm radial maze, compared to controls, Shn-2 KO mice performed significantly worse with respect to the number of different arm choices in the first 8 entries (genotype effect: F_1,24 = 62.104, P < 0.0001). (b) Mutants made significantly more revisiting errors than controls (genotype effect: F_1,24 = 45.597, P < 0.0001; genotype × trial block interaction: F_12,228 = 1.470, P = 0.1345). (c) Shn-2 KO mice also showed poor working memory performance in the T-maze forced-alternation task (genotype effect: F_1,21 = 20.497: P = 0.0002; genotype × session interaction: F_7,147 = 3.273: P = 0.0029). (d) Shn-2 KO and wild-type mice were comparable in the left-right discrimination task (genotype effect: F _1,19 = 0.209,  P = 0.6529) and reversal learning (genotype effect: F _1,19 = 5.917,  P = 0.0251). Asterisks indicate statistical significance determined using the Student's t-test with a correction for multiple comparisons in each block (a, b) and each session (c) (*P < 0.05). Adapted from Takao et al. [2].

Figure 4

Maturation abnormalities in DG neurons of Shn-2 KO mice. (a) The hippocampal transcriptome pattern of Shn-2 KO mice is similar to that of α-CaMKII HKO mice, which also demonstrated maturation abnormalities in the DG. Genes showing differential expression between genotypes at P < 0.005 in both experiments were plotted. (b) Normalized gene expression of differentially expressed genes in Shn-2 KO and α-CaMKII HKO mice. The top 10 genes are indicated in the graphs. (c) Expression of the mature neuronal marker calbindin was decreased, and the expression of the immature neuronal marker calretinin was markedly increased in the DG of Shn-2 KO mice. Adapted from Takao et al. [2].

Figure 5

Identification of the iDG phenotype using real-time polymerase chain reaction. iDG is characterized by upregulation of dopamine receptor D1a (Drd1a) and downregulation of both desmoplakin (Dsp) and tryptophan 2,3-dioxygenase (Tdo2) in the hippocampus. Asterisks indicate statistical significance determined using the Student's t-test (**P < 0.01, n = 4–7 per group). Adapted from Yamasaki et al. [1], Takao et al. [2], Kobayashi et al. [5], and Shin et al. [6].

Figure 6

Comparison of gene expression profiles between Shn-2 KO mice and individuals with schizophrenia. (a) Scatter plot of gene expression fold change values in the medial prefrontal cortex (mPFC) of Shn-2 KO mice and Brodmann area (BA) 10 of postmortem schizophrenia brain. (b) Genes differentially expressed in both Shn-2 KO mice and in schizophrenia. Red indicates gene upregulation and blue indicates downregulation in both Shn-2 KO mice and in schizophrenia. The top 40 genes with respect to the fold change values are included. Asterisks indicate inflammation-related genes. (c)–(f) The hippocampal transcriptome pattern of Shn-2 KO mice was similar to the transcriptome data from lipopolysaccharide (LPS) treatment ((c), P = 5.6 × 10⁻⁹), injury ((d), P = 5.7 × 10⁻²⁴), prion infection ((e), P = 1.0 × 10⁻¹⁸), and aging ((f), P = 1.4 × 10⁻²⁶). Adapted from Takao et al. [2].

Figure 7

A schematic representation of the model of involvement of the iDG phenotype in psychiatric disorders. In psychiatric disorders, such as schizophrenia, bipolar disorder, and depression, multiple genetic and environmental factors could induce mild chronic inflammation. This could subsequently result in multiple endophenotypes in the brain, including iDG. Inflammation could induce alterations in neurogenesis [106, 107], mitochondrial dysfunction [108, 109], and oligodendrocyte dysfunction [110, 111]. Involvement of inflammation in induction of a hypoglutamatergic state or hyperdopaminergic state remains unclear. These possible endophenotypes may affect each other, which may, in turn, cause behavioral abnormalities in psychiatric patients. There may not be a single “principal” or “core” mechanism that underlies the behavioral symptom of psychiatric disorders. Indeed, a shared or preserved set of multiple endophenotypes, as a whole, may be the principal mechanisms of these disorders.