Ryuichi Kimura

A Sensitive Period for GABAergic Interneurons in the Dentate Gyrus in Modulating Sensorimotor Gating

Developmental perturbations during adolescence have been hypothesized to be a risk factor for the onset of several neuropsychiatric diseases. However the physiological alterations that result from such insults are incompletely understood. We investigated whether a defined perturbation during adolescence affected hippocampus-dependent sensorimotor gating functions, a proposed endophenotype in several psychiatric diseases, most notably schizophrenia. The developmental perturbation was induced during adolescence in mice using an antimitotic agent, methylazoxymethanol acetate (MAM), during postnatal weeks (PW) 4–6. MAM-treated mice showed a decrease in hippocampal neurogenesis immediately after treatment, which was restored by PW10 in adulthood. However, the mice treated with MAM during adolescent stages exhibited a persistent sensorimotor gating deficiency and a reduction in prepulse inhibition-related activation of hippocampal and prefrontal neurons in adulthood. Cellular analyses found a reduction of GABAergic inhibitory neurons and abnormal dendritic morphology of immature neurons in the dentate gyrus (DG). Interestingly, bilateral infusion of muscimol, a GABAA receptor agonist, into the DG region reversed the prepulse inhibition abnormality in MAM-treated mice. Furthermore, the behavioral deficits together with the decrease in the number of GABAergic neurons in this MAM model were rescued by exposure to an enriched environment during a defined critical adolescent period. These observations suggest a possible role for GABAergic interneurons in the DG during adolescence. This role may be related to the establishment of neural circuitry required for sensorimotor gating. It is plausible that changes in neurogenesis during this window may affect the survival of GABAergic interneurons, although this link needs to be causally addressed.

Impact of Lipid Nutrition on Neural Stem/Progenitor Cells

The neural system originates from neural stem/progenitor cells (NSPCs). Embryonic NSPCs first proliferate to increase their numbers and then produce neurons and glial cells that compose the complex neural circuits in the brain. New neurons are continually produced even after birth from adult NSPCs in the inner wall of the lateral ventricle and in the hippocampal dentate gyrus. These adult-born neurons are involved in various brain functions, including olfaction-related functions, learning and memory, pattern separation, and mood control. NSPCs are regulated by various intrinsic and extrinsic factors. Diet is one of such important extrinsic factors. Of dietary nutrients, lipids are important because they constitute the cell membrane, are a source of energy, and function as signaling molecules. Metabolites of some lipids can be strong lipid mediators that also regulate various biological activities. Recent findings have revealed that lipids are important regulators of both embryonic and adult NSPCs. We and other groups have shown that lipid signals including fat, fatty acids, their metabolites and intracellular carriers, cholesterol, and vitamins affect proliferation and differentiation of embryonic and adult NSPCs. A better understanding of the NSPCs regulation by lipids may provide important insight into the neural development and brain function.

Paternal Aging Affects Behavior in Pax6 Mutant Mice: A Gene/Environment Interaction in Understanding Neurodevelopmental Disorders.

Neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD) have increased over the last few decades. These neurodevelopmental disorders are characterized by a complex etiology, which involves multiple genes and gene-environmental interactions. Various genes that control specific properties of neural development exert pivotal roles in the occurrence and severity of phenotypes associated with neurodevelopmental disorders. Moreover, paternal aging has been reported as one of the factors that contribute to the risk of ASD and ADHD. Here we report, for the first time, that paternal aging has profound effects on the onset of behavioral abnormalities in mice carrying a mutation of Pax6, a gene with neurodevelopmental regulatory functions. We adopted an in vitro fertilization approach to restrict the influence of additional factors. Comprehensive behavioral analyses were performed in Sey/+ mice (i.e., Pax6 mutant heterozygotes) born from in vitro fertilization of sperm taken from young or aged Sey/+ fathers. No body weight changes were found in the four groups, i.e., Sey/+ and wild type (WT) mice born to young or aged father. However, we found important differences in maternal separation-induced ultrasonic vocalizations of Sey/+ mice born from young father and in the level of hyperactivity of Sey/+ mice born from aged fathers in the open-field test, respectively, compared to WT littermates. Phenotypes of anxiety were observed in both genotypes born from aged fathers compared with those born from young fathers. No significant difference was found in social behavior and sensorimotor gating among the four groups. These results indicate that mice with a single genetic risk factor can develop different phenotypes depending on the paternal age. Our study advocates for serious considerations on the role of paternal aging in breeding strategies for animal studies.

Dynamic expression patterns of Pax6 during spermatogenesis in the mouse.

Spermatogenesis is a series of complex processes to generate mature sperm, and various molecules play crucial roles in regulating these processes. Previous studies imply a possibility that a transcriptional factor Pax6, a key player of brain and sensory organ development, could be involved in spermatogenesis, but neither expression nor function of Pax6 in the adult testis has been examined yet. In the present study, we described for the first time Pax6 expression dynamics in the adult mouse testis. Using cell‐type‐specific markers, the expression of Pax6 was detected in 67.0% of promyelocytic leukemia zinc finger (Plzf)‐positive type A spermatogonia. The expression of Pax6 was also observed in p63‐positive spermatocytes and round spermatids. We did not detect any expression of Pax6 in Sox9‐positive Sertoli cells or in elongated spermatids and mature sperm. High‐resolution analyses revealed that Pax6 formed a single dot‐like structure during mid‐phase of the pachytene spermatocyte. This dot‐like structure co‐localized with γH2A.X demarcating XY body, a domain in which X and Y chromosomes are silenced and compartmentalized. These results may suggest a novel role of Pax6 in spermatogenesis.

Preservation of cochlear function in Fabp3 (H-Fabp) knockout mice

Fatty acid-binding protein 3 (Fabp3) is an intracellular lipid trafficking protein that mediates energy metabolism and long-chain fatty acid-related signaling. Fabp3 is expressed in the spiral ganglion neurons and supporting cells of the organ of Corti. However, it is unclear what role Fabp3 plays in the cochlea. Here, we demonstrated that the ABR thresholds of young and aged Fabp3 knockout mice were unchanged compared with those of wild-type mice. Compared with the wild-type mice, the adult mutant mice demonstrated no differences in their vulnerability to acoustic overexposure. These results suggest that Fabp3 deficiency alone does not adversely affect hearing function.

Risk of Neurodevelopmental Disease by Paternal Aging: A Possible Influence of Epigenetic Alteration in Sperm

Sincethe theory of DOHaD has been thrown in the spotlight, most attention has focused on environmental effects of the uterus on developing embryos/fetuses. However, the ontogenesis traces back to gametogenesis. Compared to oogenesis, spermatogenesis goes through far more cell divisions and is therefore more prone to genetic variation and epigenetic alterations. This article will mainly discuss recent findings about the effects of the advanced paternal age on the next generation, in relation to the onset of psychiatric disorders such as autism spectrum disorder. We would like to advocate for further exploration on the DOHaD theory in a wider view.

Correction: Early postnatal vocalizations predict sociability and spatial memory in C57BL/6J mice: Individual differences in behavioral traits emerge early in development

[This corrects the article DOI: 10.1371/journal.pone.0186798.].

Fabp7, a brain specific fatty acid binding protein, regulates proliferation of oligodendrocyte precursor cells

reduced by administration of the intracellular Ca2+ store depletor, thapsigargin or IP3 receptor antagonist, 2-APB. Therefore, these Ca2+ rhythms were not induced by action potential, and mainly due to Ca2+ release from an intracellular Ca2+ store (i.e. endoplasmic reticulum) via IP3 receptor.Activation of some kind of metabotropic receptors induces the Ca2+ release from an intracellular Ca2+ store. It was reported that metabotropic glutamate receptor type 5 (mGluR5) was one of therapeutic targets for Parkinson’s disease. Thus, we investigated effects of mGluR5 on the spontaneous Ca2+ rhythms. Antagonist of mGluR5, MPEP, suppressed the spontaneous Ca2+ rhythms. Thus, mGluR5PLC-IP3 signal cascade might be concerned with the Ca2+ rhythms. This result suggested that mGluR5 might contribute to the information processing in striatum by means of regulating intracellular Ca2+ concentration. Research fund: JST, CREST.