RESUMO
INTRODUCTION: Impaired brain protein synthesis, synaptic plasticity, and memory are major hallmarks of Alzheimer's disease (AD). The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has been shown to modulate protein synthesis, but its effects on memory in AD models remain elusive. METHODS: We investigated the effects of HNK on hippocampal protein synthesis, long-term potentiation (LTP), and memory in AD mouse models. RESULTS: HNK activated extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 signaling pathways. Treatment with HNK rescued hippocampal LTP and memory deficits in amyloid-ß oligomers (AßO)-infused mice in an ERK1/2-dependent manner. Treatment with HNK further corrected aberrant transcription, LTP and memory in aged APP/PS1 mice. DISCUSSION: Our findings demonstrate that HNK induces signaling and transcriptional responses that correct synaptic and memory deficits in AD mice. These results raise the prospect that HNK could serve as a therapeutic approach in AD. HIGHLIGHTS: The ketamine metabolite HNK activates hippocampal ERK/mTOR/S6 signaling pathways. HNK corrects hippocampal synaptic and memory defects in two mouse models of AD. Rescue of synaptic and memory impairments by HNK depends on ERK signaling. HNK corrects aberrant transcriptional signatures in APP/PS1 mice.
Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Hipocampo , Ketamina , Camundongos Transgênicos , Plasticidade Neuronal , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Ketamina/análogos & derivados , Ketamina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Camundongos , Potenciação de Longa Duração/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , RNA Mensageiro/metabolismo , Memória/efeitos dos fármacos , Masculino , Transtornos da Memória/tratamento farmacológico , Camundongos Endogâmicos C57BL , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Presenilina-1/genética , HumanosRESUMO
Hippocampus is hypothesized to play a temporary role in the retrieval of context memories. Similarly, previous studies have reported that the expression of context memories becomes more generalized as memory ages. We report, first, that contextual fear memory expression changes from being sensitive to dorsal hippocampus inactivation by muscimol at 2 days post-conditioning, to insensitive at 28 days, and second, that over the same period rats lose their ability to discriminate between a novel and conditioned context. Furthermore, we show that repeated brief memory reactivation sessions prevent memory from becoming both hippocampus-independent and generalized.