D-serine increases adult hippocampal neurogenesis

2007

The prolonged effects of N-methyl-D-aspartate (NMDA) receptor activation on the proliferation and differentiation of hippocampal neural progenitor cells (NPCs) were studied. Under conditions of mitogen-mediated proliferation, a single NMDA pulse (5 microM) increased the fraction of 5-bromo-2-deoxyuridine (BrdU)-positive (BrdU(+)) cells after a delay of 72 hours. Similarly, a single systemic injection of NMDA (100 mg/kg) increased the number of BrdU(+) cells in the dentate gyrus (DG) after 28 days, but not after 3 days. NMDA receptor activation induced an immediate influx of Ca(2+) into the NPCs and the NPCs expressed and released vascular endothelial growth factor (VEGF) in an NMDA receptor-dependent manner within 72 hours. With repetitive stimulation at the same dose, NMDA stimulated the acquisition of a neuronal phenotype accompanied by an increase in the expression of proneural basic helix-loop-helix (bHLH) factors. Together these findings suggest that neurogenesis in the developing brain is likely to be both directly and indirectly regulated by complex interactions between Ca(2+) influx and excitation-releasable cytokines, even at mild levels of excitation. In addition, our results are the first to show that stimulation of NPCs may lead to either proliferation or neuronal differentiation, depending on the level of NMDA receptor activation.

JIMD Reports, 2012

Preface: Outline of the thesis 11 Chapter 1: D-amino acids in the central nervous system in health and disease 17 D-SerIne anD L-SerIne anaLySIS Chapter 2a: Editorial clinical chemistry: CSF serine enantiomers and glycine in the study of neurologic and psychiatric disorders 45 Chapter 2b: Two mass-spectrometric techniques for quantifying serine enantiomers and glycine in cerebrospinal fluid: potential confounders and age-dependent ranges 51 D-SerIne In Human pHySIoLogy Chapter 3: D-serine in the developing human central nervous system 71 Chapter 4: D-serine in the developing human central nervous system: clinical implications 83 Chapter 5: D-serine influences synaptogenesis in a P19 cell model 105 D-SerIne In Human paTHoLogy Chapter 6: Increased concentrations of both NMDA receptor co-agonists D-serine and glycine in global ischemia: a potential novel treatment target for perinatal asphyxia 119 Chapter 7: Cerebrospinal fluid D-serine and glycine concentrations are unaltered and unaffected by olanzapine therapy in male schizophrenic patients 135 DISCuSSIon Contributors 185 Acknowledgements -Dankwoord 187 Curriculum vitae 191 Publications 193 List of abbreviations 195 Preface 13 Preface ouTLIne oF THe THeSIS As building units of peptides and proteins, amino acids are among the most important molecules for living beings. Most amino acids occur as different enantiomers (an Land a D-form). Although the chemical and physical properties of L-and D-amino acids are almost identical, they differ in their spatial positioning, which plays a major role in structural interactions.

Acta neurobiologiae experimentalis, 2004

It is well documented that in mammals new neurons are generated in the dentate gyrus (DG) and integrated into hippocampal circuits throughout their life. However, functions of these newly generated cells are still hotly debated. One of the important factors that may influence the rate of DG neurogenesis is serotonin. Apart from being a neurotransmitter and neuromodulator it plays many other roles in the central nervous system, including the role of a trophic factor influencing functional state of neurons. In this review I discuss the changing views on adult hippocampal neurogenesis then briefly describe the anatomy and function of the hippocampus, focusing on its serotonergic innervation and receptors. Further, the possible role of serotonin and the newly generated DG neurons in hippocampus-dependent memory is discussed. Finally mechanisms by which serotonin and its receptors influence neurogenesis in the adult DG are summarized and hypotheses linking the decreased rate of DG neurog...

Stem Cells and Development, 2017

N-methyl-D-aspartate receptors (NMDARs) are expressed abundantly in the brain and play an important role in the regulation of neuronal development, learning, memory, neurodegenerative diseases, and neurogenesis, all of which is extensively discussed in reviews published elsewhere. While the number of research articles on the developmental and neurological cues that trigger NMDAR localization across a developing neuron and the role of the NMDAR in embryonic and adult stem cell proliferation and differentiation has been growing dramatically over the past few years, there is not a single review on this latter general topic. In the proposed review, we will summarize the current understanding of NMDARs in stem cell biology and their involvement in patho-physiological processes of neuron development, especially during early neuronal development (immature neurons) and differentiation.

Journal of Neuroscience Research, 2008

Neural progenitor cell is a generic term for undifferentiated cell populations composed of neural stem, neuronal progenitor, and glial progenitor cells with abilities for self-renewal and multipotentiality. In this study, we have attempted to evaluate the possible functional expression of N-methyl-D-aspartate (NMDA) receptors by neural progenitor cells prepared from neocortex of 18-day-old embryonic rats. Cells were cultured in the presence of basic fibroblast growth factor (bFGF) for different periods up to 12 days under floating conditions. Reverse transcription-polymerase chain reaction and fluorescence imaging analyses revealed transient expression of functional NMDA receptors in neurospheres formed by clustered progenitors during the culture with bFGF. A similarly potent increase was seen in the fluorescence intensity after brief exposure to NMDA in cells differentiated after the removal of bFGF under adherent conditions, and an NMDA receptor antagonist invariably prevented these increases by NMDA. Moreover, sustained exposure to NMDA not only inhibited the formation of neurospheres when exposed for 10 days from day 2 to day 12 but also promoted spontaneous and induced differentiation of neurospheres to cells immunoreactive for a neuronal marker protein on immunocytochemistry and Western blotting analyses. These results suggest that functional NMDA receptors may be transiently expressed to play a role in mechanisms underlying the modulation of proliferation along with the determination of subsequent differentiation fate toward a neuronal lineage in neural progenitor cells of developing rat neocortex.

Aging Cell, 2006

Age-associated deficits in learning and memory are closely correlated with impairments of synaptic plasticity. Analysis of N -methyl-D-aspartate receptor (NMDAr)dependent long-term potentiation (LTP) in CA1 hippocampal slices indicates that the glial-derived neuromodulator D -serine is required for the induction of synaptic plasticity. During aging, the content of D -serine and the expression of its synthesizing enzyme serine racemase are significantly decreased in the hippocampus. Impaired LTP and NMDAr-mediated synaptic potentials in old rats are rescued by exogenous D -serine. These results highlight the critical role of glial cells and presumably astrocytes, through the availability of D -serine, in the deficits of synaptic mechanisms of learning and memory that occur in the course of aging.

Experimental Neurology, 2005

Neurogenesis is an ongoing process in the hippocampus and olfactory bulb of adult mammals, regulated in part by trophic factors. While glial cell line-derived neurotrophic factor (GDNF) is being directly delivered into the nigrostriatal system of the brain for the treatment of Parkinson's disease in clinical trials, little is known about its effects on cell genesis in the brain. Here, we investigated the effects of GDNF on progenitor cell proliferation and differentiation in two GDNF-responsive areas, the hippocampus and substantia nigra. GDNF (18 Ag/day) was infused in the striatum of 2-month-old Sprague -Dawley rats for 28 days. New cells were identified by the nuclear incorporation of 5bromo-2-deoxyuridine (BrdU) and analyzed by light and electron microscopic immunostaining and quantitative morphometric techniques. GDNF significantly increased cell proliferation in the hippocampus by 78% and in the substantia nigra by 52%. There was no evidence of neurogenesis in the substantia nigra, with new cells displaying glial features and none of the 1549 BrdU-positive cells co-labeled for the dopamine neuronal marker tyrosine hydroxylase (TH). Rather, GDNF upregulated TH in existing neurons, consistent with the restorative actions of this tropic factor. The hippocampus is a site that supports adult neurogenesis and new cells generated here were closely associated with granule cells in the dentate gyrus. Some were double labeled for the neuronal marker NeuN; others had features of astrocytes, the principal source of new adult neurons in the hippocampus. The effects of GDNF on the hippocampus are potentially important in memory and learning processes. D

Neuropsychopharmacology, 2017

The functional role of genetic variants in glia in the pathogenesis of psychiatric disorders remains poorly studied. Disrupted-In-Schizophrenia 1 (DISC1), a genetic risk factor implicated in major mental disorders, has been implicated in regulation of astrocyte functions. As both astrocytes and DISC1 influence adult neurogenesis in the dentate gyrus (DG) of the hippocampus, we hypothesized that selective expression of dominant-negative C-terminus-truncated human DISC1 (mutant DISC1) in astrocytes would affect adult hippocampal neurogenesis and hippocampus-dependent behaviors. A series of behavioral tests were performed in mice with or without expression of mutant DISC1 in astrocytes during late postnatal development. In conjunction with behavioral tests, we evaluated adult neurogenesis, including neural progenitor proliferation and dendrite development of newborn neurons in the DG. The ameliorative effects of D-serine on mutant DISC1-associated behaviors and abnormal adult neurogenesis were also examined. Expression of mutant DISC1 in astrocytes decreased neural progenitor proliferation and dendrite growth of newborn neurons, and produced elevated anxiety, attenuated social behaviors, and impaired hippocampus-dependent learning and memory. Chronic treatment with D-serine ameliorated the behavioral alterations and rescued abnormal adult neurogenesis in mutant DISC1 mice. Our findings suggest that psychiatric genetic risk factors expressed in astrocytes could affect adult hippocampal neurogenesis and contribute to aspects of psychiatric disease through abnormal production of D-serine.

AGE, 2012

In the current study, we investigated changes in N-methyl D-aspartate (NMDA) and kainate receptor expression, long-term potentiation (LTP), and neurogenesis in response to neurotoxic stress in long-living Ames dwarf mice. We hypothesized that Ames dwarf mice have enhanced neurogenesis that enables retention of spatial learning and memory with age and promotes neurogenesis in response to injury. Levels of the NMDA receptors (NR)1, NR2A, NR2B, and the kainate receptor (KAR)2 were increased in Ames dwarf mice, relative to wild-type littermates. Quantitative assessment of the excitatory postsynaptic potential in Schaffer collaterals in hippocampal slices from Ames dwarf mice showed an increased response in high-frequency induced LTP over time compared with wild type. Kainic acid (KA) injection was used to promote neurotoxic stress-induced neurogenesis. KA mildly increased the number of doublecortinpositive neurons in wild-type mice, but the response was significantly enhanced in the Ames dwarf mice. Collectively, these data support our hypothesis that the enhanced learning and memory associated with the Ames dwarf mouse may be due to elevated levels of NMDA and KA receptors in hippocampus and their ability to continue producing new neurons in response to neuronal damage.

2014

Cumulative studies indicated that adult hippocampal neurogenesis might be involved in the action mechanism of antidepressant drugs and/or the pathophysiology of depression. Dopamine (DA) is involved in the regulation of motivation, volition, interest/pleasure, and attention/concentration, all of which are likely to be impaired in depressed patients. Several previous reports suggest that depression may often be accompanied by a relative hypodopaminergic state, and some DA receptor agonists are beneficial effects in the treatment for refractory and bipolar depression. In the present study, to clarify the direct effect of DA on neural progenitor cells, we examined the effect of DA on the proliferation of adult rat dentate gyrus-derived neural precursor cells (ADPs). In addition, we examined the effect of DA receptor agonists on adult rat hippocampal neurogenesis in vivo. Results showed that DA promoted the increase of ADPs via D1-like receptor and D1-like receptor agonist promoted the survival of newborn cells in the adult hippocampus. On the contrary, D2-like receptor agonist did not affect both proliferation and survival. These results suggested that DA might play, at least in part, a role in adult hippocampal neurogenesis via D1-like receptor and the activation of D1-like receptor has a therapeutic potential for depression.