The policies and actions that were enacted to colonize Indigenous Peoples in Canada have been described as constituting cultural genocide. When one considers the long-term consequences from the perspective of the social and environmental determinants of health framework, the impacts of such policies on the physical and mental health of Indigenous Peoples go well beyond cultural loss. This paper addresses the impacts of key historical and current Canadian federal policies in relation to the health and well-being of Indigenous Peoples. Far from constituting a mere lesson in history, the connections between colonialist policies and actions on present-day outcomes are evaluated in terms of transgenerational and intergenerational transmission processes, including psychosocial, developmental, environmental, and neurobiological mechanisms and trauma responses. In addition, while colonialist policies have created adverse living conditions for Indigenous Peoples, resilience and the perseverance of many aspects of culture may be maintained through intergenerational processes.
Ketamine has shown antidepressant effects in patients with major depressive disorder (MDD) resistant to first‐line treatments and approved for use in this patient population. Ketamine induces several forms of synaptic plasticity, which are proposed to underlie its antidepressant effects. However, the molecular mechanism of action directly responsible for ketamine's antidepressant effects remains under active investigation. It was recently demonstrated that the effectors of the mammalian target of rapamycin complex 1 (mTORC1) signalling pathway, namely, eukaryotic initiation factor 4E (eIF4E) binding proteins 1 and 2 (4E‐BP1 and 4E‐BP2), are central in mediating ketamine‐induced synaptic plasticity and behavioural antidepressant‐like effect. 4E‐BPs are a family of messenger ribonucleic acid (mRNA) translation repressors inactivated by mTORC1. We observed that their expression in inhibitory interneurons mediates ketamine's effects in the forced swim and novelty suppressed feeding tests and the long‐lasting inhibition of GABAergic neurotransmission in the hippocampus. In addition, another effector pathway that regulates translation elongation downstream of mTORC1, the eukaryotic elongation factor 2 kinase (eEF2K), has been implicated in ketamine's behavioural effects. We will discuss how ketamine's rapid antidepressant effect depends on the activation of neuronal mRNA translation through 4E‐BP1/2 and eEF2K. Furthermore, given that these pathways also regulate cognitive functions, we will discuss the evidence of ketamine's effect on cognitive function in MDD. Overall, the data accrued from pre‐clinical research have implicated the mRNA translation pathways in treating mood symptoms of MDD. However, it is yet unclear whether the pro‐cognitive potential of subanesthetic ketamine in rodents also engages these pathways and whether such an effect is consistently observed in the treatment‐resistant MDD population.
Impaired synaptic plasticity and progressive memory deficits are major hallmarks of Alzheimer's disease (AD). Hippocampal mRNA translation, required for memory consolidation, is defective in AD. Here, we show that genetic reduction of the translational repressors, Fragile X messenger ribonucleoprotein (FMRP) or eukaryotic initiation factor 4E (eIF4E)-binding protein 2 (4E-BP2), ameliorated the inhibition of hippocampal protein synthesis and memory impairment induced by AD-linked amyloid-b; oligomers (AbOs) in mice. Furthermore, systemic treatment with (2R,6R)-hydroxynorketamine (HNK), an active metabolite of the antidepressant ketamine, prevented deficits in hippocampal mRNA translation, long-term potentiation (LTP) and memory induced by AbOs in mice. HNK activated hippocampal signaling by extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 (S6), which promote protein synthesis and synaptic plasticity. S6 phosphorylation instigated by HNK was mediated by mTOR in hippocampal slices, while rescue of hippocampal LTP and memory in HNK-treated AbO-infused mice depended on ERK1/2 and, partially, on mTORC1. Remarkably, treatment with HNK corrected LTP and memory deficits in aged APP/PS1 mice. RNAseq analysis showed that HNK reversed aberrant signaling pathways that are upregulated in APP/PS1 mice, including inflammatory and hormonal responses and programmed cell death. Taken together, our findings demonstrate that upregulation of mRNA translation corrects deficits in hippocampal synaptic plasticity and memory in AD models. The results raise the prospect that HNK could serve as a therapeutic to reverse memory decline in AD.
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