Repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages prevents schizophrenia-relevant phenotypes in adult offspring after maternal immune activation: a role of TrkB signaling

Tan, Yunfei; Fujita, Yūkō; Pu, Yaoyu; Chang, Lijia; Qu, Youge; Wang, Xinming; Hashimoto, Kenji

doi:10.1007/s00406-021-01365-6

Cited by 18 publications

(9 citation statements)

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“…Preclinical data suggest that arketamine, but not esketamine, can improve PCP-induced cognitive deficits in rodents [ 104 ]. Furthermore, there is evidence that arketamine can ameliorate cognitive deficits in offspring after MIA through activation of BDNF-TrkB signaling [ 122 ]. Preclinical findings suggest that BDNF-TrkB signaling could play a role in the beneficial effects of arketamine in several animal models [ 36 , 42 – 45 , 66 , 143 – 147 ].…”

Section: Discussionmentioning

confidence: 99%

“…We investigated whether arketamine could prevent the development of psychosis-like phenotypes in adult offspring after MIA. We examined the effects of arketamine (10 mg/kg/day, twice weekly for 4 weeks) during juvenile and adolescent stages (P28–P56) on the development of cognitive deficits, loss of PV-immunoreactivity in the medial PFC (mPFC), and decreased dendritic spine density in the mPFC and hippocampus from adult offspring after prenatal poly(I:C) exposure [ 122 ]. Repeated intermittent administration of arketamine (10 mg/kg/day, twice weekly for 4 weeks) during juvenile and adolescent stages (P28–P56) significantly blocked the development of cognitive deficits, reduced PV-immunoreactivity in the prelimbic (PrL) of mPFC, and decreased dendritic spine density in the PrL of the mPFC, CA3, and dentate gyrus of the hippocampus from adult offspring after MIA.…”

Section: Introductionmentioning

confidence: 99%

“…Repeated intermittent administration of arketamine (10 mg/kg/day, twice weekly for 4 weeks) during juvenile and adolescent stages (P28–P56) significantly blocked the development of cognitive deficits, reduced PV-immunoreactivity in the prelimbic (PrL) of mPFC, and decreased dendritic spine density in the PrL of the mPFC, CA3, and dentate gyrus of the hippocampus from adult offspring after MIA. Furthermore, pretreatment with TrkB inhibitor ANA-12 significantly blocked the beneficial effects of arketamine on cognitive deficits of adult offspring after MIA [ 122 ]. These data suggest that repeated intermittent administration of arketamine during the juvenile and adolescent stages could prevent the development of psychosis in adult offspring after MIA through activation of BDNF-TrkB signaling.…”

Section: Introductionmentioning

confidence: 99%

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Arketamine for cognitive impairment in psychiatric disorders

Hashimoto

2023

Eur Arch Psychiatry Clin Neurosci

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Cognitive impairment has been observed in patients with various psychiatric disorders, including schizophrenia, major depressive disorder (MDD), and bipolar disorder (BD). Although modern therapeutic drugs can improve certain symptoms (i.e., psychosis, depression) in these patients, these drugs have not been found to improve cognitive impairment. The N-methyl-D-aspartate receptor antagonist (R,S)-ketamine has attracted attention as a rapidly acting antidepressant. In addition to its robust antidepressant effects, (R,S)-ketamine has been suggested to improve cognitive impairment in patients with MDD and BD, despite causing cognitive impairment in healthy control subjects. (R,S)-ketamine is a racemic mixture of equal amounts of (R)-ketamine (or arketamine) and (S)-ketamine (or esketamine). Arketamine has been found to have more potent antidepressant-like actions than esketamine in rodents. Interestingly, arketamine, but not esketamine, has been suggested to improve phencyclidine-induced cognitive deficits in mice. Furthermore, arketamine has been suggested to ameliorate cognitive deficits in rodent offspring after maternal immune activation. In the current article, it is proposed that arketamine has therapeutic potential for treating cognitive impairment in patients with psychiatric disorders. Additionally, the potential role of the gut–microbiome–brain axis in cognitive impairment in psychiatric disorders is discussed.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Arketamine for cognitive impairment in psychiatric disorders

Hashimoto

2023

Eur Arch Psychiatry Clin Neurosci

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“…Thus, it is possible that administration of S-ket causes disruption to their function in the prefrontal cortex and hippocampus resulting in cognitive deficits. Interestingly, recent studies report that R-ketamine may in fact ameliorate cognitive deficits induced by maternal immune activation or treatment with PCP and this effect is not seen with S-ketamine (Tan et al, 2020(Tan et al, , 2022.…”

Section: Discussionmentioning

confidence: 99%

Understanding the role of the NMDA receptor subunit, GluN2D, in mediating NMDA receptor antagonist‐induced behavioral disruptions in male and female mice

Vinnakota,

Schroeder,

et al. 2023

J of Neuroscience Research

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Noncompetitive NMDA receptor (NMDAR) antagonists like phencyclidine (PCP) and ketamine cause psychosis‐like symptoms in healthy humans, exacerbate schizophrenia symptoms in people with the disorder, and disrupt a range of schizophrenia‐relevant behaviors in rodents, including hyperlocomotion. This is negated in mice lacking the GluN2D subunit of the NMDAR, suggesting the GluN2D subunit mediates the hyperlocomotor effects of these drugs. However, the role of GluN2D in mediating other schizophrenia‐relevant NMDAR antagonist‐induced behavioral disturbances, and in both sexes, is unclear. This study aimed to investigate the role of the GluN2D subunit in mediating schizophrenia‐relevant behaviors induced by a range of NMDA receptor antagonists. Using both male and female GluN2D knockout (KO) mice, we examined the effects of the NMDAR antagonist's PCP, the S‐ketamine enantiomer (S‐ket), and the ketamine metabolite R‐norketamine (R‐norket) on locomotor activity, anxiety‐related behavior, and recognition and short‐term spatial memory. GluN2D‐KO mice showed a blunted locomotor response to R‐norket, S‐ket, and PCP, a phenotype present in both sexes. GluN2D‐KO mice of both sexes showed an anxious phenotype and S‐ket, R‐norket, and PCP showed anxiolytic effects that were dependent on sex and genotype. S‐ket disrupted spatial recognition memory in females and novel object recognition memory in both sexes, independent of genotype. This datum identifies a role for the GluN2D subunit in sex‐specific effects of NMDAR antagonists and on the differential effects of the R‐ and S‐ket enantiomers.

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“…Activating TrkB receptors by small-molecule agonists (e.g., 7,8-dihydroxy avone, 7,8-DHF) improves cognition in normal rodents and animal models of cognitive de cits such as Alzheimer's disease 26,31−33 . The BDNF-TrkB pathway has also been reported to mediate cognitionenhancing effects of some drugs, e.g., (R)-ketamine 34,35 , memantine 36 , melatonin 37,38 . The therapeutic effects targeting at the BDNF-TrkB pathway in neurodevelopmental animal models have been seldom studied 39 .…”

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confidence: 99%

The causal involvement of the BDNF-TrkB pathway in dentate gyrus in early-life stress-induced cognitive deficits

Sun²,

et al. 2022

Preprint

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Cognitive dysfunction is a signiﬁcant, untreated clinical need in patients with psychiatric disorders, for which preclinical studies are needed to understand the underlying mechanisms and to identify potential therapeutic targets. Early-life stress (ELS) leads to long-lasting deficits of hippocampus-dependent learning and memory in adult mice, which may be associated with the hypofunction of the brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB). In this study, we carried out eight experiments to examine the causal involvement of the BDNF-TrkB pathway in dentate gyrus (DG) and the therapeutic effects of the TrkB agonist (7,8-DHF) in ELS-induced cognitive deficits. Adopting the limited nesting and beding material paradigm, we first demonstrated that ELS impaired spatial memory, suppressed BDNF expression and neurogenesis in DG in adult mice. Down-regulating BDNF expression (conditional BDNF knockdown) or inhibition of the TrkB receptor (using its anatognist ANA-12) in the DG mimicked the cognitive deficits of ELS. Acute up-regulation of BDNF (exogenous human recombinant BDNF microinjection) levels or activation of TrkB receptor (using its agonist, 7,8-DHF) in the DG restored ELS-induced spatial memory loss. Finally, acute and subchronic systemic administration of 7,8-DHF successfully restored spatial memory loss in stressed mice. Subchronic 7,8-DHF treatment also reversed ELS-induced neurogenesis reduction. Our findings highlight BDNF-TrkB system as the molecular target of ELS-induced spatial memory deficits and provide translational evidence for the intervention at this system in the treatment of cognitive deficits in stress-related psychiatric disorders, such as major depressive disorder.

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Repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages prevents schizophrenia-relevant phenotypes in adult offspring after maternal immune activation: a role of TrkB signaling

Cited by 18 publications

References 67 publications

Arketamine for cognitive impairment in psychiatric disorders

Arketamine for cognitive impairment in psychiatric disorders

Understanding the role of the NMDA receptor subunit, GluN2D, in mediating NMDA receptor antagonist‐induced behavioral disruptions in male and female mice

The causal involvement of the BDNF-TrkB pathway in dentate gyrus in early-life stress-induced cognitive deficits

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