Glycine <i>N</i>‐methyltransferase expression in the hippocampus and its role in neurogenesis and cognitive performance

Carrasco, Manuel; Rabaneda, Luis G.; Murillo‐Carretero, Maribel; Ortega-Martínez, Sylvia; Martínez‐Chantar, María Luz; Luka, Zigmund; Wagner, Conrad; Lu, Shelly C.; Mato, José M.; Micó, Juan Antonio; Castro, Carmen

doi:10.1002/hipo.22274

Cited by 27 publications

(26 citation statements)

References 48 publications

(71 reference statements)

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“…Immediately after, cells were pretreated with or without 0.5 µM G06850 for 30 minutes, then with or without 5 µM prostratin and, 1.5 hours later, stimulated with or without 10ng/mL bFGF. Western blot was performed as previously described ( Carrasco et al, 2014 ). Antibodies used were mouse anti-cyclin D1, rabbit anti-cyclin E (both at 1:500, Santa Cruz Biotechnologies, Santa Cruz, CA), and mouse anti-β-actin as loading control (1:1000, Sigma-Aldrich, St Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

12-Deoxyphorbols Promote Adult Neurogenesis by Inducing Neural Progenitor Cell Proliferation via PKC Activation

Geribaldi-Doldán

Flores-Giubi

Murillo‐Carretero

et al. 2015

IJNPPY

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Background:Neuropsychiatric and neurological disorders frequently occur after brain insults associated with neuronal loss. Strategies aimed to facilitate neuronal renewal by promoting neurogenesis constitute a promising therapeutic option to treat neuronal death-associated disorders. In the adult brain, generation of new neurons occurs physiologically throughout the entire life controlled by extracellular molecules coupled to intracellular signaling cascades. Proteins participating in these cascades within neurogenic regions constitute potential pharmacological targets to promote neuronal regeneration of injured areas of the central nervous system.Methodology:We have performed in vitro and in vivo approaches to determine neural progenitor cell proliferation to understand whether activation of kinases of the protein kinase C family facilitates neurogenesis in the adult brain.Results:We have demonstrated that protein kinase C activation by phorbol-12-myristate-13-acetate induces neural progenitor cell proliferation in vitro. We also show that the nontumorogenic protein kinase C activator prostratin exerts a proliferative effect on neural progenitor cells in vitro. This effect can be reverted by addition of the protein kinase C inhibitor G06850, demonstrating that the effect of prostratin is mediated by protein kinase C activation. Additionally, we show that prostratin treatment in vivo induces proliferation of neural progenitor cells within the dentate gyrus of the hippocampus and the subventricular zone. Finally, we describe a library of diterpenes with a 12-deoxyphorbol structure similar to that of prostratin that induces a stronger effect than prostratin on neural progenitor cell proliferation both in vitro and in vivo.Conclusions:This work suggests that protein kinase C activation is a promising strategy to expand the endogenous neural progenitor cell population to promote neurogenesis and highlights the potential of 12-deoxyphorbols as pharmaceutical agents to facilitate neuronal renewal.

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Section: Methodsmentioning

confidence: 99%

12-Deoxyphorbols Promote Adult Neurogenesis by Inducing Neural Progenitor Cell Proliferation via PKC Activation

Geribaldi-Doldán

Flores-Giubi

Murillo‐Carretero

et al. 2015

IJNPPY

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“…In general, sample size used in statistical analysis were n = 6 for in vivo experiments and n = 5-9 for in vitro experiments. Sample sizes were chosen based on a previous works related to this one 8,22,29,47 .…”

Section: Discussionmentioning

confidence: 99%

“…The total number of animals used was: 24 2-month old adult mice and 150 7-day old pups. The number of animals used in each experiment was determined based on previous studies 22,29,47 .…”

Section: Animal Subjectsmentioning

confidence: 99%

A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

et al. 2020

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Neural stem cells are activated within neurogenic niches in response to brain injuries. This results in the production of neuroblasts, which unsuccessfully attempt to migrate toward the damaged tissue. Injuries constitute a gliogenic/nonneurogenic niche generated by the presence of anti-neurogenic signals, which impair neuronal differentiation and migration. Kinases of the protein kinase C (PKC) family mediate the release of growth factors that participate in different steps of the neurogenic process, particularly, novel PKC isozymes facilitate the release of the neurogenic growth factor neuregulin. We have demonstrated herein that a plant derived diterpene, (EOF2; CAS number 2230806-06-9), with the capacity to activate PKC facilitates the release of neuregulin 1, and promotes neuroblasts differentiation and survival in cultures of subventricular zone (SVZ) isolated cells in a novel PKC dependent manner. Local infusion of this compound in mechanical cortical injuries induces neuroblast enrichment within the perilesional area, and noninvasive intranasal administration of EOF2 promotes migration of neuroblasts from the SVZ towards the injury, allowing their survival and differentiation into mature neurons, being some of them cholinergic and GABAergic. Our results elucidate the mechanism of EOF2 promoting neurogenesis in injuries and highlight the role of novel PKC isozymes as targets in brain injury regeneration.

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“…The recent discovery of glycine-N-methyltransferase in the hippocampus (Carrasco et al, 2014) suggests that the availability of hippocampal glycine also controls the S-adenosylmethionine (SAM) -dependent transmethylation pathway that provides the substrate for DNA- and histone- methylation. Since epigenetic mechanisms are implicated in epileptogenesis (Kobow and Blumcke, 2011; Kobow et al, 2013; Williams-Karnesky et al, 2013), dysregulation of GlyT1 might influence epilepsy development through an epigenetic mechanism, an exciting possibility that warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Glycine transporter 1 is a target for the treatment of epilepsy

et al. 2015

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Glycine is the major inhibitory neurotransmitter in brainstem and spinal cord, whereas in hippocampus glycine exerts dual modulatory roles on strychnine-sensitive glycine receptors and on the strychnine-insensitive glycineB site of the N-methyl-D-aspartate receptor (NMDAR). In hippocampus, the synaptic availability of glycine is largely under control of glycine transporter 1 (GlyT1). Since epilepsy is a disorder of disrupted network homeostasis affecting the equilibrium of various neurotransmitters and neuromodulators, we hypothesized that changes in hippocampal GlyT1 expression and resulting disruption of glycine homeostasis might be implicated in the pathophysiology of epilepsy. Using two different rodent models of temporal lobe epilepsy (TLE) – the intrahippocampal kainic acid model of TLE in mice, and the rat model of tetanic stimulation-induced TLE – we first demonstrated robust overexpression of GlyT1 in the hippocampal formation, suggesting dysfunctional glycine signaling in epilepsy. Overexpression of GlyT1 in the hippocampal formation was corroborated in human TLE samples by quantitative real time PCR. In support of a role of dysfunctional glycine signaling in the pathophysiology of epilepsy, both the genetic deletion of GlyT1 in hippocampus and the GlyT1 inhibitor LY2365109 increased seizure thresholds in mice. Importantly, chronic seizures in the mouse model of TLE were robustly suppressed by systemic administration of the GlyT1 inhibitor LY2365109. We conclude that GlyT1 overexpression in the epileptic brain constitutes a new target for therapeutic intervention, and that GlyT1 inhibitors constitute a new class of antiictogenic drugs. These findings are of translational value since GlyT1 inhibitors are already in clinical development to treat cognitive symptoms in schizophrenia.

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Glycine N‐methyltransferase expression in the hippocampus and its role in neurogenesis and cognitive performance

Cited by 27 publications

References 48 publications

12-Deoxyphorbols Promote Adult Neurogenesis by Inducing Neural Progenitor Cell Proliferation via PKC Activation

12-Deoxyphorbols Promote Adult Neurogenesis by Inducing Neural Progenitor Cell Proliferation via PKC Activation

A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

Glycine transporter 1 is a target for the treatment of epilepsy

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