Role of adult-born granule cells in the hippocampal functions: Focus on the GluN2B-containing NMDA receptors

Doan, Julie; Gardier, Alain M.; Tritschler, Laurent

doi:10.1016/j.euroneuro.2019.07.135

Cited by 12 publications

(8 citation statements)

References 147 publications

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“…7 Although CCI-induced mTBI pathologies primarily affect the cortical regions, the subcortical location of the hippocampus renders it sensitive to the injury. 23,24 The hippocampus's dentate gyrus (DG) granular cell layer harbors a high density of NMDA receptors, 25,26 which hyperactivation by excitatory amino acids leads to excitotoxicity. Homocysteine is a potent NMDA receptor agonist, [27][28][29] suggesting mTBI-induced hippocampal injury may be exacerbated by HHCY.…”

Section: Introductionmentioning

confidence: 99%

Hippocampal vulnerability to hyperhomocysteinemia worsens pathological outcomes of mild traumatic brain injury in rats

Tchantchou

Hsia

Puché

et al. 2023

J Cent Nerv Syst Dis

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Background Mild traumatic brain injury (mTBI) generally resolves within weeks. However, 15-30% of patients present persistent pathological and neurobehavioral sequelae that negatively affect their quality of life. Hyperhomocysteinemia (HHCY) is a neurotoxic condition derived from homocysteine accumulation above 15 μM. HHCY can occur in diverse stressful situations, including those sustained by U.S. active-duty service members on the battlefield or during routine combat practice. Mild-TBI accounts for more than 80% of all TBI cases, and HHCY exists in 5-7% of the general population. We recently reported that moderate HHCY exacerbates mTBI-induced cortical injury pathophysiology, including increased oxidative stress. Several studies have demonstrated hippocampus vulnerability to oxidative stress and its downstream effects on inflammation and cell death. Objective This study aimed to assess the deleterious impact of HHCY on mTBI-associated hippocampal pathological changes. We tested the hypothesis that moderate HHCY aggravates mTBI-induced hippocampal pathological changes. Methods HHCY was induced in adult male Sprague-Dawley rats with a high methionine dose. Rats were then subjected to mTBI by controlled cortical impact under sustained HHCY. Blood plasma was assessed for homocysteine levels and brain tissue for markers of oxidative stress, blood-brain barrier integrity, and cell death. Endothelial cell ultrastructure was assessed by Electron Microscopy and working memory performance using the Y maze test. Results HHCY increased the hippocampal expression of nitrotyrosine in astroglial cells and decreased tight junction protein occludin levels associated with the enlargement of the endothelial cell nucleus. Furthermore, HHCY altered the expression of apoptosis-regulating proteins α-ii spectrin hydrolysis, ERK1/2, and AKT phosphorylation, mirrored by exacerbated mTBI-related hippocampal neuronal loss and working memory deficits. Conclusion Our findings indicate that HHCY is an epigenetic factor that modulates mTBI pathological progression in the hippocampus and represents a putative therapeutic target for mitigating such physiological stressors that increase severity.

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Section: Introductionmentioning

confidence: 99%

Hippocampal vulnerability to hyperhomocysteinemia worsens pathological outcomes of mild traumatic brain injury in rats

Tchantchou

Hsia

Puché

et al. 2023

J Cent Nerv Syst Dis

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“…Alternatively, infantile amnesia may be a result of continuous neurogenesis, which could act to interfere with typical encoding and retrieval processes (Akers et al, 2014;Ramsaran, Schlichting, & Frankland, 2019). The neurogenic hypothesis could still be in line with the proposed ideas of this review, given that new, immature neurons produced during neurogenesis may be able to express niLTD given the higher expression of GluN2B subunits (Doan, Gardier, & Tritschler, 2019). Each of these alternatives, as well as the hypothesis proposed herein, should be experimentally tested in developing animals in vivo.…”

Section: Nonionotropic Nmdar Signaling In Vivo May Act To Limit Infor...mentioning

confidence: 76%

Behind the scenes: Are latent memories supported by calcium independent plasticity?

2021

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N‐methyl‐D‐aspartate receptors (NMDARs) can be considered to be the de facto “plasticity” receptors in the brain due to their central role in the activity‐dependent modification of neuronal morphology and synaptic transmission. Since the 1980s, research on NMDARs has focused on the second messenger properties of calcium and the downstream signaling pathways that mediate alterations in neural form and function. Recently, NMDARs were shown to drive activity‐dependent synaptic plasticity without calcium influx. How this “nonionotropic” plasticity occurs in vitro is becoming clearer, but research on its involvement in behavior and cognition is in its infancy. There is a partial overlap in the downstream signaling molecules that are involved in ionotropic and nonionotropic NMDAR‐dependent plasticity. Given this, and prior studies of the cognitive impacts of ionotropic NMDAR plasticity, a preliminary model explaining how NMDAR nonionotropic plasticity affects learning and memory can be established. We hypothesize that nonionotropic NMDAR plasticity takes part in latent memory encoding in immature rodents through nonassociative depression of synaptic efficacy, and possibly shrinking of dendritic spines. Further, the late postnatal alteration in NMDAR composition in the hippocampus appears to reduce nonionotropic signaling and remove a restriction on memory retrieval. This framework substantially alters the canonical model of NMDAR involvement in spatial cognition and hippocampal maturation and provides novel and exciting inroads for future studies.

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“…It has higher levels than other subunits in the early postnatal brain and has been linked with neurotoxicity in the immature brain . The GluN2B subunit is thought to be responsible for memory formation; thus, high levels in the immature brain appear appropriate given the degree of learning that occurs during early life.…”

Section: Importance Of Balanced Inhibitory and Excitatory Actionmentioning

confidence: 99%

Perinatal compromise contributes to programming of GABAergic and glutamatergic systems leading to long‐term effects on offspring behaviour

Shaw

Crombie

Zakár

et al. 2019

J Neuroendocrinology

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Extensive evidence now shows that adversity during the perinatal period is a significant risk factor for the development of neurodevelopmental disorders long after the causative event. Despite stemming from a variety of causes, perinatal compromise appears to have similar effects on the developing brain, thereby resulting in behavioural disorders of a similar nature. These behavioural disorders occur in a sex‐dependent manner, with males affected more by externalising behaviours such as attention deficit hyperactivity disorder (ADHD) and females by internalising behaviours such as anxiety. Regardless of the causative event or the sex of the offspring, these disorders may begin in childhood or adolescence but extend into adulthood. A mechanism by which adverse events in the perinatal period impact later in life behaviour has been shown to be the changing epigenetic landscape. Methylation of the GAD1/GAD67 gene, which encodes the key glutamate‐to‐GABA‐synthesising enzyme glutamate decarboxylase 1, resulting in increased levels of glutamate, is one epigenetic mechanism that may account for a tendency towards excitation in disorders such as ADHD. Exposure of the fetus or the neonate to high levels of cortisol may be the mediator between perinatal compromise and poor behavioural outcomes because evidence suggests that increased glucocorticoid exposure triggers widespread changes in the epigenetic landscape. This review summarises the current evidence and recent literature about the impact of various perinatal insults on the epigenome and the common mechanisms that may explain the similarity of behavioural outcomes occurring following diverse perinatal compromise.

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Role of adult-born granule cells in the hippocampal functions: Focus on the GluN2B-containing NMDA receptors

Cited by 12 publications

References 147 publications

Hippocampal vulnerability to hyperhomocysteinemia worsens pathological outcomes of mild traumatic brain injury in rats

Hippocampal vulnerability to hyperhomocysteinemia worsens pathological outcomes of mild traumatic brain injury in rats

Behind the scenes: Are latent memories supported by calcium independent plasticity?

Perinatal compromise contributes to programming of GABAergic and glutamatergic systems leading to long‐term effects on offspring behaviour

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