A new insight into mechanisms of interferon alpha neurotoxicity: Expression of GRIN3A subunit of NMDA receptors and NMDA-evoked exocytosis

Obolenskaya, M. Yu.; Dotsenko, V. A.; Martsenyuk, O.; Ralchenko, Serhii; Krupko, Olga; Pastukhov, Artem; Filimonova, N. B.; Starosila, D. B.; Chernykh, S. I.; Borisova, Тatiana

doi:10.1016/j.pnpbp.2021.110317

Cited by 5 publications

(5 citation statements)

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“…Several transcripts that are key regulators of synaptic signaling were present in modules OUD-1, OUD-2, and OUD-3. These included: GRIN3A [ 50 , 51 ] , SLC6A7 [ 52 ] , KCNJ6 [ 53 , 54 ] , GABRQ [ 55 ], and HPCAL1 [ 56 ] (OUD-1); SEMA5B [ 57 ] and SHISA6 [ 58 ] (OUD-2) PCP4 [ 59 ] and PPP1R1B (DARPP-32) [ 60 ]; (OUD-3). Pathway enrichment analyses of transcripts comprising the networks in the OUD modules further support the connection between rhythmic transcripts in OUD and synaptic function in the NAc, including neurotransmitter receptors and postsynaptic signal transmission, trans-synaptic signaling, positive regulation of excitatory postsynaptic potential, and pathways related to extracellular matrices (ECM) and brain morphology (e.g., ECM glycoproteins, cell-cell adhesion molecules, and axon development) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we found that neuroinflammatory pathways were enriched in differentially expressed transcripts in the NAc from OUD subjects, including interferon (IFN) signaling [ 32 ]. Intriguingly, IFN signaling interacts with GRIN3A, whereby elevated IFN induces NMDA-evoked glutamate release [ 50 ]. Thus, cycles of opioid withdrawal may elevate IFN levels, augmenting excitatory signaling in NAc and inducing opioid-induced synaptic plasticity and behavioral consequences.…”

Section: Discussionmentioning

confidence: 99%

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Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder

et al. 2022

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Severe and persistent disruptions to sleep and circadian rhythms are common in people with opioid use disorder (OUD). Preclinical evidence suggests altered molecular rhythms in the brain modulate opioid reward and relapse. However, whether molecular rhythms are disrupted in the brains of people with OUD remained an open question, critical to understanding the role of circadian rhythms in opioid addiction. Using subjects’ times of death as a marker of time of day, we investigated transcriptional rhythms in the brains of subjects with OUD compared to unaffected comparison subjects. We discovered rhythmic transcripts in both the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), key brain areas involved in OUD, that were largely distinct between OUD and unaffected subjects. Fewer rhythmic transcripts were identified in DLPFC of subjects with OUD compared to unaffected subjects, whereas in the NAc, nearly double the number of rhythmic transcripts was identified in subjects with OUD. In NAc of subjects with OUD, rhythmic transcripts peaked either in the evening or near sunrise, and were associated with an opioid, dopamine, and GABAergic neurotransmission. Associations with altered neurotransmission in NAc were further supported by co-expression network analysis which identified OUD-specific modules enriched for transcripts involved in dopamine, GABA, and glutamatergic synaptic functions. Additionally, rhythmic transcripts in DLPFC and NAc of subjects with OUD were enriched for genomic loci associated with sleep-related GWAS traits, including sleep duration and insomnia. Collectively, our findings connect transcriptional rhythm changes in opioidergic, dopaminergic, GABAergic signaling in the human brain to sleep-related traits in opioid addiction.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder

et al. 2022

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“…Previously, we found that neuroinflammatory pathways were enriched in differentially expressed transcripts in the NAc from OUD subjects, including interferon (IFN) signaling 30 . Intriguingly, IFN signaling interacts with GRIN3A, whereby elevated IFN induces NMDA-evoked glutamate release 48 . Thus, cycles of opioid withdrawal may elevate IFN levels, leading to changes in excitatory signaling in the NAc and other brain regions, involved in opioid-induced synaptic plasticity and behavioral consequences.…”

Section: Discussionmentioning

confidence: 99%

“…Several transcripts that are key regulators of synaptic signaling were present in each of the modules that were significantly enriched for transcripts that were more rhythmic in the NAc of OUD subjects. These transcripts included: GRIN3A 48,49 , SLC6A7 50 , KCNJ6 51,52 , GABRQ 53 , and HPCAL1 54 (brown module); SEMA5B 55 and SHISA6 56 (pink module); and PCP4 57 and PPP1R1B (DARPP-32) 58 (red module). Pathway enrichment analyses of transcripts comprising the networks in brown, pink, and red modules further supported the connection between rhythmic transcripts in OUD and synaptic function in the NAc, including neurotransmitter receptors and postsynaptic signal transmission, trans-synaptic signaling, positive regulation of excitatory postsynaptic potential, and pathways related to extracellular matrices (ECM) and brain morphology (e.g., ECM glycoproteins, cell-cell adhesion molecules, and axon development) (Fig.…”

Section: Gene Module Enrichment Of Synapse-related and Glycoprotein Signaling In Oudmentioning

confidence: 99%

Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder

Xue

Zong

Glausier

et al. 2021

Preprint

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Severe and persistent disruptions to sleep and circadian rhythms are common features of people with opioid use disorder (OUD). Preclinical findings suggest altered molecular rhythms in the brain are involved in opioid reward and dependence. However, whether molecular rhythms are disrupted in brains of people with OUD remained an open question, critical to understanding the role of circadian rhythms in opioid addiction. We previously used subjects' times of death (TOD) as a marker of time of day to investigate transcriptional rhythm alterations in psychiatric disorders. Using TOD and RNA sequencing, we discovered rhythmic transcripts in both the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), key brain areas involved in opioid addiction, were largely distinct between OUD and unaffected comparison subjects. Further, fewer rhythmic transcripts were identified in DLPFC of OUD subjects compared to unaffected subjects, but nearly double the number of rhythmic transcripts were found in the NAc of OUD subjects. In OUD, rhythmic transcripts in the NAc peaked either in the evening or near sunrise, and were associated with dopamine, opioid, and GABAergic neurotransmission. Co-expression network analysis identified several OUD-specific modules in the NAc, enriched for transcripts involved in the modulation of dopamine and GABA synapses, including glutamatergic signaling and extracellular matrices. Integrative analyses with human GWAS revealed that rhythmic transcripts in DLPFC and NAc were enriched for genomic loci associated with sleep duration and insomnia. Overall, our results connect transcriptional rhythm changes in dopamine, opioid, and GABAergic synaptic signaling in human brain to sleep-related phenotypes and OUD.

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“…У пошуках ефективних методів аналізу токсичності частинок планетарного пилу без використання біологічних об'єктів з метою розробки стратегії нейропротекції в умовах довготривалих космічних місій виконавцями проєкту було досліджено вплив помірної та глибокої гіпотермії на синаптичну нейропередачу у центральній нер вовій системі [2,6,64,70,81].…”

Section: рис 1 експериментальна система Expose-r2 із Biomex на борту ...unclassified

Space Biology Projects in Ukraine: Nowadays Trends

Kordyum¹

2023

Kosm. nauka tehnol.

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A new insight into mechanisms of interferon alpha neurotoxicity: Expression of GRIN3A subunit of NMDA receptors and NMDA-evoked exocytosis

Cited by 5 publications

References 68 publications

Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder

Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder

Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder

Space Biology Projects in Ukraine: Nowadays Trends

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