22q11欠失症候群モデルマウスの神経発達障害には、マイクロRNAが介在するCxcr4/Cxcl12シグナリングの欠損が寄与する

22q11 deletion syndrome (22q11DS) frequently accompanies psychiatric conditions, some of which are classified as schizophrenia and bipolar disorder in the current diagnostic categorization. However, it remains elusive how the chromosomal microdeletion leads to the mental manifestation at the mechanistic level. Here we show that a 22q11DS mouse model with a deletion of 18 orthologous genes of human 22q11 (Df1/+ mice) has deficits in migration of cortical interneurons and hippocampal dentate precursor cells. Furthermore, Df1/+ mice show functional defects in Chemokine receptor 4/Chemokine ligand 12 (Cxcr4/Cxcl12; Sdf1) signaling, which reportedly underlie interneuron migration. Notably, the defects in interneuron progenitors are rescued by ectopic expression of Dgcr8, one of the genes in 22q11 microdeletion. Furthermore, heterozygous knockout mice for Dgcr8 show similar neurodevelopmental abnormalities as Df1/+ mice. Thus, Dgcr8-mediated regulation of microRNA is likely to underlie Cxcr4/Cxcl12 signaling and associated neurodevelopmental defects. Finally, we observe that expression of CXCL12 is decreased in olfactory neurons from sporadic cases with schizophrenia compared with normal controls. Given the increased risk of 22q11DS in schizophrenia that frequently shows interneuron abnormalities, the overall study suggests that CXCR4/CXCL12 signaling may represent a common downstream mediator in the pathophysiology of schizophrenia and related mental conditions.博士（医学）・乙1331号・平成26年3月17

Adult Neurogenesis Transiently Generates Oxidative Stress

An increasing body of evidence suggests that alterations in neurogenesis and oxidative stress are associated with a wide variety of CNS diseases, including Alzheimer’s disease, schizophrenia and Parkinson’s disease, as well as routine loss of function accompanying aging. Interestingly, the association between neurogenesis and the production of reactive oxidative species (ROS) remains largely unexamined. The adult CNS harbors two regions of persistent lifelong neurogenesis: the subventricular zone and the dentate gyrus (DG). These regions contain populations of quiescent neural stem cells (NSCs) that generate mature progeny via rapidly-dividing progenitor cells. We hypothesized that the energetic demands of highly proliferative progenitors generates localized oxidative stress that contributes to ROS-mediated damage within the neuropoietic microenvironment. In vivo examination of germinal niches in adult rodents revealed increases in oxidized DNA and lipid markers, particularly in the subgranular zone (SGZ) of the dentate gyrus. To further pinpoint the cell types responsible for oxidative stress, we employed an in vitro cell culture model allowing for the synchronous terminal differentiation of primary hippocampal NSCs. Inducing differentiation in primary NSCs resulted in an immediate increase in total mitochondria number and overall ROS production, suggesting oxidative stress is generated during a transient window of elevated neurogenesis accompanying normal neurogenesis. To confirm these findings in vivo, we identified a set of oxidation-responsive genes, which respond to antioxidant administration and are significantly elevated in genetic- and exercise-induced model of hyperactive hippocampal neurogenesis. While no direct evidence exists coupling neurogenesis-associated stress to CNS disease, our data suggest that oxidative stress is produced as a result of routine adult neurogenesis

Hippocampal Pathophysiology: Commonality Shared by Temporal Lobe Epilepsy and Psychiatric Disorders.

Accumulating evidence points to the association of epilepsy, particularly, temporal lobe epilepsy (TLE), with psychiatric disorders, such as schizophrenia. Among these illnesses, the hippocampus is considered the regional focal point of the brain, playing an important role in cognition, psychosis, and seizure activity and potentially suggesting common etiologies and pathophysiology of TLE and schizophrenia. In the present review, we overview abnormal network connectivity between the dentate gyrus (DG) and the Cornus Ammonis area 3 (CA3) subregions of the hippocampus relative to the induction of epilepsy and schizophrenia. In light of our recent finding on the misguidance of hippocampal mossy fiber projection in the rodent model of schizophrenia, we discuss whether ectopic mossy fiber projection is a commonality in order to evoke TLE as well as symptoms related to schizophrenia

Hippocampal Pathophysiology: Commonality Shared by Temporal Lobe Epilepsy and Psychiatric Disorders.

Accumulating evidence points to the association of epilepsy, particularly, temporal lobe epilepsy (TLE), with psychiatric disorders, such as schizophrenia. Among these illnesses, the hippocampus is considered the regional focal point of the brain, playing an important role in cognition, psychosis, and seizure activity and potentially suggesting common etiologies and pathophysiology of TLE and schizophrenia. In the present review, we overview abnormal network connectivity between the dentate gyrus (DG) and the Cornus Ammonis area 3 (CA3) subregions of the hippocampus relative to the induction of epilepsy and schizophrenia. In light of our recent finding on the misguidance of hippocampal mossy fiber projection in the rodent model of schizophrenia, we discuss whether ectopic mossy fiber projection is a commonality in order to evoke TLE as well as symptoms related to schizophrenia

Hippocampal neurogenesis transiently generates oxidative stress.

<p>(a) Total mitochondria and oxidative load were measured in undifferentiated NPCs, early progenitors and postmitotic neurons. (b, c) Total mitochondria prevalence was measured via Mitotracker biological dye (b) while total oxidative load was measured using Mitosox biological indicator dye (measured as–fold change compared to undifferentiated NSCs). Quantifiable fluorescence emission measurements demonstrate a significant increase in maximal mitochondrial abundance and peak oxidative load occurs during the period enriched for early progenitors. p*<0.0001.</p

Markers of oxidative stress accumulate in and around the dentate gyrus of the hippocampus.

<p>(a) Oxidized 8-deoxyguanosine (8OHDG), a marker of oxidized nucleic acid and (c) hydroxynonenal (HNE), a measure of oxidized lipid, both exhibit localized increases in expression throughout the hippocampus. (b, d) Elevated magnification (boxed areas from a, c) indicated that both these markers express highest levels within the SGZ (arrows). Scale bars: 200 µm (a,c), 100 µm (b,d).</p

Inhibition of neurogenesis results in the rapid decline of pathophysiological markers of oxidative stress within the SGZ.

<p>The antimitotic agent Ara-C or saline (vehicle) was infused twice daily for 7 days prior to thymidine analog labeling, resulting in a significant reduction in total cell division as measured by thymidine analog incorporation (a–c). Acute Ara-C treatment disrupts the production of oxidized DNA (8OHDG; d, e) and lipid (HNE; f, g) within the SGZ. Note existing 8OHDG and HNE (+) cells are retained in the outer granular layer (arrows; DG defined in d–g with Mayer’s hematoxylin). Scale bars: 50 µm (a, b), 100 µm (d–g). ***p<0.001.</p

Hippocampal NSCs can be isolated and established as a two-dimensional culture system.

<p>(a–c) Undifferentiated hippocampal NPCs are undifferentiated, expressing insignificant levels of Tuj1 and Doublecortin (DCX). (d–f) Three days following initiation of differentiation, individual progenitor cells become Tuj1 (+) and begin to strongly express DCX. (g, h) Neurogenesis proceeds from focal clusters which expand and contact one another within 7 days of induction of terminal differentiation. (i) Camera lucida of representative of expanding clusters of Tuj1(+) neural progenitors at 12, 24, 48 and 72 hours following differentiation.</p

ORGs exhibit elevated levels of expression in multiple models of enhanced neurogenesis, and respond more dramatically to antioxidant administration than normal controls.

<p>Infusion of the antioxidant Edaravone (3 mg/kg/day) produces an larger magnitude of decrease in OR genes in CaMKIIα hyper-neurogenic mice compared to controls for both individual genes (16/20; a) and as a group (b). Running (14d) significantly increases the expression of 11/20 ORG members (c), with a significant group increase (d). (e) RT-PCR measures of OR expression. p*<0.05.</p