Role of NMDA Receptors in Adult Neurogenesis and Normal Development of the Dentate Gyrus

Åmellem, Ingrid; Yovianto, Glen; Chong, Hai Tarng; Nair, Rajeevkumar Raveendran; Cnops, Vanja; Thanawalla, Ayesha; Tashiro, Akimasa

doi:10.1523/eneuro.0566-20.2021

Cited by 11 publications

(6 citation statements)

References 43 publications

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“…Our finding is in accordance with previously published data that have also shown, after MK-801 treatment, a significant decrease in the DCX and NeuN immunoreactive cells’ number in the HIP [ 25 , 26 ] but no change in the BDNF mRNA level [ 27 ]. GD-NR1 KO mice (NR1 is a glycine-binding NMDA receptor subunit) also showed impairment in neurogenesis during postnatal development and adulthood and a significant reduction in the density of DCX positive cells in the GD [ 28 ]. However, we did not observe a significant inhibitory effect of MK-801 on any of the markers studied in the SVZ.…”

Section: Discussionmentioning

confidence: 99%

Effect of Haloperidol and Olanzapine on Hippocampal Cells’ Proliferation in Animal Model of Schizophrenia

Osacka

Kiss

Bačová

et al. 2022

IJMS

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Aberrant neurogenesis in the subventricular zone (SVZ) and hippocampus (HIP) contributes to schizophrenia pathogenesis. Haloperidol (HAL) and olanzapine (OLA), commonly prescribed antipsychotics for schizophrenia treatment, affect neurogenesis too. The effect of HAL and OLA on an mHippoE-2 cell line was studied in vitro where we measured the cell number and projection length. In vivo, we studied the gene expression of DCX, Sox2, BDNF, and NeuN in the SVZ and HIP in an MK-801-induced animal schizophrenia model. Cells were incubated with HAL, OLA, and MK-801 for 24, 48, and 72 h. Animals were injected for 6 days with saline or MK801 (0.5 mg/kg), and from the 7th day with either vehicle HAL (1 mg/kg) or OLA (2 mg/kg), for the next 7 days. In vitro, HAL and OLA dose/time-dependently suppressed cells’ proliferation and shortened their projection length. HAL/OLA co-treatment with MK-801 for 24 h reversed HAL’s/OLA’s inhibitory effect. In vivo, HAL and OLA suppressed DCX and NeuN genes’ expression in the HIP and SVZ. MK-801 decreased DCX and NeuN genes’ expression in the HIP and OLA prevented this effect. The data suggest that subchronic HAL/OLA treatment can inhibit DCX and NeuN expression. In an MK-801 schizophrenia model, OLA reversed the MK-801 inhibitory effect on DCX and NeuN and HAL reversed the effect on DCX expression; however, only in the HIP.

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Section: Discussionmentioning

confidence: 99%

Effect of Haloperidol and Olanzapine on Hippocampal Cells’ Proliferation in Animal Model of Schizophrenia

Osacka

Kiss

Bačová

et al. 2022

IJMS

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“…Despite that all upregulated genes (independently of whether pleiotropic they are or not) are involved in multiple functions, one function is common for these genes: they positively control pathways responsible for the development and maturation of new brain cells. These genes regulate neuritogenesis (S100A8/S100A9) [30], cell proliferation (S100B) [31], neurogenesis and neuroplasticity (TrkB [32], Ngf [33], NmdaR [34], Mapk1 [32,33], Pink1 [35,36]), and decreased inflammation and are associated with neurogenesis (Aqp4 [37], Kcnk2) [38,39]. On the contrary, genes encoding molecules involved in proinflammatory pathways and diminished neurogenesis (NF-kB1, Myd88, Cxcl1, and others) are suppressed (Figure 3 and Table S1).…”

Section: Discussionmentioning

confidence: 99%

Oxidized Cell-Free DNA Rapidly Skews the Transcriptional Profile of Brain Cells toward Boosting Neurogenesis and Neuroplasticity

Filev

Kostyuk

Umriukhin

et al. 2021

CIMB

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Cell-free DNA (cfDNA) is liberated and accumulated in neural tissue due to cell damage. The oxidative and nitrosative stress in the brain that accompanies various pathological conditions has been shown to increase the oxidation of cellular and cell-free DNA. Whether the high concentration of non-oxidized and oxidized cfDNA may affect the transcriptome response of brain cells has not been studied. In the current work, we studied whether cfDNA fragments affect several key pathways, including neurogenesis, at the level of gene expression in brain cells. In the study, primary rat cerebellum cell cultures were used to assess the effects of oxidized and non-oxidized cfDNA on the expression of 91 genes in brain cells. We found that only oxidized cfDNA, not non-oxidized cfDNA, significantly altered the transcription in brain cells in 3 h. The pattern of change included all 10 upregulated genes (S100A8, S100A9, S100b, TrkB, Ngf, Pink1, Aqp4, Nmdar, Kcnk2, Mapk1) belonging to genes associated with neurogenesis and neuroplasticity. The expression of inflammatory and apoptosis genes, which oppose neurogenesis, decreased. The results show that the oxidized form of cfDNA positively regulates early gene expression of neurogenesis and neuroplasticity. At the same time, the question of whether chronic elevation of cfDNA concentration alters brain cells remains unexplored.

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“…The specific role of NMDA receptors in regulating direct and indirect neurogenesis is unclear. Further highlighting the complex role of NMDA receptors in neurogenesis is that they have been proposed to both suppress [23][24][25][26] and promote [27][28][29][30][31] neurogenesis. These differences are presumably due to variations in specific NSPC focus and stages of neurogenesis investigated, each of which differentially contribute to direct and indirect neurogenesis.…”

Section: Introductionmentioning

confidence: 99%

Loss of NMDA receptor function during development results in decreased KCC2 expression and increased neurons in the zebrafish forebrain

Napoli,

Laderwager,

Zoodsma

et al. 2023

Preprint

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Developmental neurogenesis is a tightly regulated spatiotemporal process with its dysfunction implicated in neurodevelopmental disorders. NMDA receptors are glutamate-gated ion channels that are widely expressed and well-studied for their synaptic and activity-dependent function. Nevertheless, they play important roles during development in cell types and stages where there are no synapses or activity-dependence. Numerous mutations in their subunits are associated with neurodevelopmental disorders yet despite this interconnection, the contribution of NMDA receptors to neurogenesis is ambiguous and contradictory in the literature. To rigorously define the role of NMDA receptors in developmental neurogenesis, we capitalized on our mutant zebrafish line (grin1−/−) that lacks all NMDA receptors. Forebrain analysis shows thatgrin1−/−fish have a progressive supernumerary neuron phenotype confined to the telencephalon at the end of embryonic neurogenesis but extended to all forebrain regions during postembryonic neurogenesis. Based on analysis of neural stem and progenitor cells and the ontogenetically-expressed chloride transporter, KCC2, we find that without NMDA receptors, immature neuroblasts acting as transit amplifying cells do not mature into postmitotic neurons in a timely manner. This prolongs their mitotic stage and leads to inappropriate amplification of forebrain neurons. Pharmacological blockade with MK-801 recapitulates this phenotype, indicating that NMDA receptor-mediated maturation of neuroblasts requires ionotropic signaling despite the absence of synapses in these cells. Our results demonstrate that NMDA receptors are required for maturational termination of mitosis in neuroblasts. Disruption of this process results in neuronal overpopulation that can fundamentally change brain circuitry and may be a key factor in neurodevelopmental disorder pathogenesis.SignificanceThe role of NMDA receptors in neurogenesis is ambiguous and complicated by contradictory studies. We show that NMDA receptors are required for the regulation of neurogenesis in neural progenitor cells during the postembryonic period: without NMDA receptors, these mitotically-active neuroblasts do not mature to the post-mitotic phase in a timely manner, causing supernumerary neurons in the forebrain. Dysregulated neurogenesis is a common phenotype in neurodevelopmental disorders and, notably, numerous mutations in NMDA receptor genes are also associated with these disorders. Thus, our work rigorously defines a specific role for NMDA receptors in neurogenesis and post-embryonic brain maturation and offers new perspective on the intersection of developmental neurogenesis, NMDA receptor dysfunction, and neurodevelopmental disorder etiology.

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Role of NMDA Receptors in Adult Neurogenesis and Normal Development of the Dentate Gyrus

Cited by 11 publications

References 43 publications

Effect of Haloperidol and Olanzapine on Hippocampal Cells’ Proliferation in Animal Model of Schizophrenia

Effect of Haloperidol and Olanzapine on Hippocampal Cells’ Proliferation in Animal Model of Schizophrenia

Oxidized Cell-Free DNA Rapidly Skews the Transcriptional Profile of Brain Cells toward Boosting Neurogenesis and Neuroplasticity

Loss of NMDA receptor function during development results in decreased KCC2 expression and increased neurons in the zebrafish forebrain

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