Specific Roles of NMDA Receptor Subunits in Mental Disorders

Yamamoto, Hiroyuki; Hagino, Yoko; Kasai, Shinya; Ikeda, Kazutaka

doi:10.2174/1566524015666150330142807

Cited by 40 publications

(21 citation statements)

References 155 publications

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“…Furthermore, genetic variation in SYNJ2, another gene identified in our epigenome-wide analyses, has been linked to corpus callosum abnormalities (Edwards et al, 2014), which are robustly associated with maltreatment (McCrory et al, 2012). Other psychopathology-relevant genes included glutamate and GABA receptors (GRIND2D, GABBR1), which play a key role in excitatory and inhibitory neurotransmission, respectively (Kumar et al, , Yamamoto et al, 2015. Prospective studies will be needed to explicitly test whether the DNAm sites identified in the present study associate with psychopathological outcomes and, if so, whether they may mediate the influence of abuse and neglect on later mental health.…”

Section: The Identified Dna Methylation Markers Support a Molecular Lmentioning

confidence: 94%

Epigenetic signatures of childhood abuse and neglect: Implications for psychiatric vulnerability

Cecil

Smith

Walton

et al. 2016

Journal of Psychiatric Research

105

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Childhood maltreatment is a key risk factor for poor mental and physical health. Recently, variation in epigenetic processes, such as DNA methylation, has emerged as a potential pathway mediating this association; yet, the extent to which different forms of maltreatment may be characterized by unique vs shared epigenetic signatures is currently unknown. In this study, we quantified DNA methylation across the genome in buccal epithelial cell samples from a high-risk sample of inner-city youth (n = 124; age = 16-24; 53% female), 68% of whom reported experiencing at least one form of maltreatment while growing up. Our analyses aimed to identify methylomic variation associated with exposure to five major types of childhood maltreatment. We found that: (i) maltreatment types differ in the extent to which they associate with methylomic variation, with physical exposures showing the strongest associations; (ii) many of the identified loci are annotated to genes previously implicated in stress-related outcomes, including psychiatric and physical disorders (e.g. GABBR1, GRIN2D, CACNA2D4, PSEN2); and (iii) based on gene ontology analyses, maltreatment types not only show unique methylation patterns enriched for specific biological processes (e.g. physical abuse and cardiovascular function), but also share a 'common' epigenetic signature enriched for biological processes related to neural development and organismal growth. A stringent set of sensitivity analyses were also run to identify high-confidence associations. Together, findings lend novel insights into epigenetic signatures of childhood abuse and neglect, point to novel potential biomarkers for future investigation and support a molecular link between maltreatment and poor health outcomes. Nevertheless, it will be important in future to replicate findings, as the use of cross-sectional data and high rates of polyvictimization in our study make it difficult to fully disentangle the shared vs unique epigenetic signatures of maltreatment types. Furthermore, studies will be needed to test the role of potential moderators in the identified associations, including age of onset and chronicity of maltreatment exposure.

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Section: The Identified Dna Methylation Markers Support a Molecular Lmentioning

confidence: 94%

Epigenetic signatures of childhood abuse and neglect: Implications for psychiatric vulnerability

Cecil

Smith

Walton

et al. 2016

Journal of Psychiatric Research

105

View full text Add to dashboard Cite

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“…More differentiated cells expressing AMPAR and NMDAR subunits also expressed CAMK2A , allowing them to be identified using a CAMK2A::GFP reporter gene. This approach allowed the isolation of highly differentiated and synaptically active human patterned induced neurons (hpiNs), underscoring the potential utility of this approach for modeling diseases associated with glutamate receptor dysfunction, including schizophrenia, epilepsy, and autism ( Yamamoto et al, 2015 ; Yuan et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Combining NGN2 Programming with Developmental Patterning Generates Human Excitatory Neurons with NMDAR-Mediated Synaptic Transmission

et al. 2018

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SUMMARYTranscription factor programming of pluripotent stem cells (PSCs) has emerged as an approach to generate human neurons for disease modeling. However, programming schemes produce a variety of cell types, and those neurons that are made often retain an immature phenotype, which limits their utility in modeling neuronal processes, including synaptic transmission. We report that combining NGN2 programming with SMAD and WNT inhibition generates human patterned induced neurons (hpiNs). Single-cell analyses showed that hpiN cultures contained cells along a developmental continuum, ranging from poorly differentiated neuronal progenitors to well-differentiated, excitatory glutamatergic neurons. The most differentiated neurons could be identified using a CAMK2A::GFP reporter gene and exhibited greater functionality, including NMDAR-mediated synaptic transmission. We conclude that utilizing single-cell and reporter gene approaches for selecting successfully programmed cells for study will greatly enhance the utility of hpiNs and other programmed neuronal populations in the modeling of nervous system disorders.

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“…For example, McOmish et al [25] demonstrated that environmental enrichment rescued loss of muscarinic cholinergic receptors in the neocortex and hippocampus of the PLC-β 1 knockout model in the mouse, but there were limited effects of enrichment on behavioral outcomes in this model, with no effect of environmental enrichment on prepulse inhibition, exploratory behavior, or cognitive deficits in the Morris water maze. Koseki et al [26] found that environmental enrichment potentiated the hyperlocomotor behavioral response to acute treatment with phencyclidine, an antagonist to glutamatergic NMDA receptors which has relevance to the NMDA receptor hypofunction known to exist in schizophrenia [51]. Environmental enrichment also prevented chronic phencyclidine treatment-induced impairments of social behavior and recognition memory in the social interaction and novel object recognition tests, but neither sensitization nor associative effects of phencyclidine were analyzed in this study.…”

Section: Discussionmentioning

confidence: 52%

Effects of Environmental Enrichment on Nicotine Sensitization in Rats Neonatally Treated with Quinpirole: Analyses of Glial Cell Line-Derived Neurotrophic Factor and Implications towards Schizophrenia

et al. 2018

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The current study analyzed the effects of environmental enrichment versus isolation housing on the behavioral sensitization to nicotine in the neonatal quinpirole (NQ; dopamine D₂-like agonist) model of dopamine D₂ receptor supersensitivity, a rodent model of schizophrenia. NQ treatment in rats increases dopamine D₂ receptor sensitivity throughout the animal’s lifetime, consistent with schizophrenia. Animals were administered NQ (1 mg/kg) or saline (NS) from postnatal day (P)1 to P21, weaned, and immediately placed into enriched housing or isolated in wire cages throughout the experiment. Rats were behaviorally sensitized to nicotine (0.5 mg/kg base) or saline every consecutive day from P38 to P45, and brain tissue was harvested at P46. Results revealed that neither housing condition reduced nicotine sensitization in NQ rats, whereas enrichment reduced sensitization to nicotine in NS-treated animals. The nucleus accumbens (NAcc) was analyzed for glial cell line-derived neurotrophic factor (GDNF), a neurotrophin important in dopamine plasticity. Results were complex, and revealed that NAcc GDNF was increased in animals given nicotine, regardless of housing condition. Further, enrichment increased GDNF in NQ rats regardless of adolescent drug treatment and in NS-treated rats given nicotine, but did not increase GDNF in NS-treated controls compared to the isolated housing condition. This study demonstrates that environmental experience has a prominent impact on the behavioral and the neural plasticity NAcc response to nicotine in adolescence.

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Specific Roles of NMDA Receptor Subunits in Mental Disorders

Cited by 40 publications

References 155 publications

Epigenetic signatures of childhood abuse and neglect: Implications for psychiatric vulnerability

Epigenetic signatures of childhood abuse and neglect: Implications for psychiatric vulnerability

Combining NGN2 Programming with Developmental Patterning Generates Human Excitatory Neurons with NMDAR-Mediated Synaptic Transmission

Effects of Environmental Enrichment on Nicotine Sensitization in Rats Neonatally Treated with Quinpirole: Analyses of Glial Cell Line-Derived Neurotrophic Factor and Implications towards Schizophrenia

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