Emergence of d-aspartic acid in the differentiating neurons of the rat central nervous system

Sakai, Kumiko; Homma, Hiroshi; Lee, Jen Ai; Fukushima, Takeshi; Santa, Tomofumi; Tashiro, Kensuke; Iwatsubo, Takeshi; Imai, Kazuhiro

doi:10.1016/s0006-8993(98)00599-x

Cited by 76 publications

(56 citation statements)

References 28 publications

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“…Rat testis revealed immunoreactivity in the cytoplasm of germ cells and interstitial cells, and in the nuclei of the spermatogonia (Sakai et al 1998a).At least two broad mechanisms for the function of free -Asp in the nucleus could be proposed: -Asp could directly interact with DNA and/or -Asp could act on nuclear proteins to maintain the structure and/or active/inactive state of genes in order to control the regulation of proliferation and differentiation. Further studies are necessary to clarify the mechanism of action of -Asp in the mitogen activity of the testis.…”

Section: Discussionmentioning

confidence: 99%

“…An extremely high content of -Asp was detected in human brain (Fisher et al 1991) as well as in the cerebrospinal fluid (Fisher et al 1994). In addition, -Asp may participate in brain development, differentiation and functioning (Hashimoto et al 1993, Hashimoto & Oka, 1997, Sakai et al 1998a or may be a novel messenger in neuronal and neuroendocrine organs (Schell et al 1997. Most recent investigations have examined the endocrine system of mammals where -Asp is well represented in the pineal gland (Imai et al 1995, Lee et al 1997, Takigawa et al 1998, hypothalamus (Fisher et al 1994, Wang et al 2002, pituitary (D'Aniello et al 2000a,b), adrenals (Hamase et al 1997, Lee et al 2001 and gonads (D'Aniello et al 1996, Sakai et al 1998b.…”

Section: Introductionmentioning

confidence: 99%

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Endocrine roles of d-aspartic acid in the testis of lizard Podarcis s. sicula

Raucci¹,

D’Aniello²,

Fiore³

2005

Journal of Endocrinology

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In the lizard Podarcis s. sicula, a substantial amount of -aspartate (-Asp) is endogenous to the testis and shows cyclic changes of activity connected with sex hormone profiles during the annual reproductive phases. Testicular -Asp content shows a direct correlation with testosterone titres and a reverse correlation with 17 -estradiol titres.In vivo experiments, consisting of i.p. injections of 2·0 µmol/g body weight of -Asp or other amino acids, in lizards collected during the three main phases of the reproductive cycle (pre-reproductive, reproductive and post-reproductive period), revealed that the testis can specifically take up and accumulate -Asp alone. Moreover, this amino acid influences the synthesis of testosterone and 17 -estradiol in all phases of the cycle. This phenomenon is particularly evident during the pre-and post-reproductive period, when endogenous testosterone levels observed in both testis and plasma were the lowest and 17 -estradiol concentrations were the highest. -Asp rapidly induces a fall in 17 -estradiol and a rise in testosterone at 3 h post-injection in the testis and at 6 h post-injection in the blood. In vitro experiments show that testicular tissue converted -Asp into -Asp through an aspartate racemase. -Asp synthesis was measured in all phases of the cycle, but was significantly higher during the reproductive period with a peak at pH 6·0. The exogenous -Asp also induces a significant increase in the mitotic activity of the testis at 3 h (P<0·05) and at 6 h (P<0·01). Induction of spermatogenesis by -Asp is recognized by an intense immunoreactivity of the germinal epithelium (spermatogonia and spermatids) for proliferation cell nuclear antigen (PCNA). The effects of -Asp on the testis appear to be specific since they were not seen in lizards injected with other -or -forms of amino acids with known excitatory effects on neurosecretion. Our results suggest a regulatory role for -Asp in the steroidogenesis and spermatogenesis of the testis of the lizard Podarcis s. sicula.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Endocrine roles of d-aspartic acid in the testis of lizard Podarcis s. sicula

Raucci¹,

D’Aniello²,

Fiore³

2005

Journal of Endocrinology

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“…Consistent with a neurodevelopmental hypothesis of SCZ, 12,61 a putative precocious downregulation of D-Asp levels, associated to abnormal metabolism of this molecule, may have a much greater impact during critical phases of brain development, when D-Asp levels are physiologically high. 13,14,16 Future studies in mouse models permitting controlled exposure of D-Asp levels during neurodevelopment are warranted to investigate this basic issue.…”

Section: Discussionmentioning

confidence: 99%

A Role for D-aspartate Oxidase in Schizophrenia and in Schizophrenia-related Symptoms Induced by Phencyclidine in Mice.

Squillace

Errico

D’Argenio

et al. 2015

European Psychiatry

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Increasing evidence points to a role for dysfunctional glutamate N-methyl-D-aspartate receptor (NMDAR) neurotransmission in schizophrenia. D-aspartate is an atypical amino acid that activates NMDARs through binding to the glutamate site on GluN2 subunits. D-aspartate is present in high amounts in the embryonic brain of mammals and rapidly decreases after birth, due to the activity of the enzyme D-aspartate oxidase (DDO). The agonistic activity exerted by D-aspartate on NMDARs and its neurodevelopmental occurrence make this D-amino acid a potential mediator for some of the NMDAR-related alterations observed in schizophrenia. Consistently, substantial reductions of D-aspartate and NMDA were recently observed in the postmortem prefrontal cortex of schizophrenic patients. Here we show that DDO mRNA expression is increased in prefrontal samples of schizophrenic patients, thus suggesting a plausible molecular event responsible for the D-aspartate imbalance previously described. To investigate whether altered D-aspartate levels can modulate schizophrenia-relevant circuits and behaviors, we also measured the psychotomimetic effects produced by the NMDAR antagonist, phencyclidine, in Ddo knockout mice (Ddo −/ − ), an animal model characterized by tonically increased D-aspartate levels since perinatal life. We show that Ddo − / − mice display a significant reduction in motor hyperactivity and prepulse inhibition deficit induced by phencyclidine, compared with controls. Furthermore, we reveal that increased levels of D-aspartate in Ddo − / − animals can significantly inhibit functional circuits activated by phencyclidine, and affect the development of cortico-hippocampal connectivity networks potentially involved in schizophrenia. Collectively, the present results suggest that altered D-aspartate levels can influence neurodevelopmental brain processes relevant to schizophrenia.

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“…Levels of this unique amino acid are transiently increased during tissue development [1,2]. We recently demonstrated that D-Asp is localized in specific cell types in developing tissues [3][4][5] and changes its localization within the organs as well as its intracellular distribution during development [6]. Our recent study also indicated that D-Asp is actually synthesized in mammalian cells [7].…”

Section: Introductionmentioning

confidence: 89%

“…D-Asp is mainly localized in the cytoplasm of elongate spermatids, the most mature of the germ cells, and is assumed to regulate steroidogenesis as a paracrine factor in the testis [3]. D-Asp is also present in other steroidogenic tissues such as the ovary, adrenal cortex and brain [1,28], where the levels of D-Asp are developmentally and spatially regulated [1,3,6]. Our results indicate that D-Asp may regulate steroid production through modulation of StAR gene expression in these steroidogenic tissues.…”

Section: D-a~t Effect On Star Gene Expression In Rat Leydig Cellsmentioning

confidence: 99%

Stimulation of steroidogenic acute regulatory protein (STAR) geneexpression by D‐aspartate in rat Leydig cells

et al. 1999

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n-aspartate and human ehorionic gonadotropin act synergistically to increase testosterone production in purified rat Leydig cells, and n-aspartate stimulates testosterone synthesis even in the absence of human chorionic gonadotropin stimulation. In addition, D-aspartate enhances steady-state cellular mRNA and protein levels of steroidogenic acute regulatory protein, which is a key regulatory factor in gonadal and adrenal steroidogenesis, n-aspartate therefore appears to increase testosterone production in rat Leydig cells by stimulating steroidogenic acute regulatory protein gene expression. To our knowledge, this is the first report demonstrating a direct effect of D-aspartate on gene expression in mammalian cells.

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Emergence of d-aspartic acid in the differentiating neurons of the rat central nervous system

Cited by 76 publications

References 28 publications

Endocrine roles of d-aspartic acid in the testis of lizard Podarcis s. sicula

Endocrine roles of d-aspartic acid in the testis of lizard Podarcis s. sicula

A Role for D-aspartate Oxidase in Schizophrenia and in Schizophrenia-related Symptoms Induced by Phencyclidine in Mice.

Stimulation of steroidogenic acute regulatory protein (STAR) geneexpression by D‐aspartate in rat Leydig cells

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