The ketamine metabolite (2R,6R)-hydroxynorketamine rescues hippocampal mRNA translation, synaptic plasticity and memory in mouse models of Alzheimer's disease.

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.

Identificación ee factores genéticos en la etiología de la esquizofrenia / Identification of Genetic Factors in the Etiology of Schizophrenia

Esquizofrenia es un trastorno mental que afecta aproximadamente 1% de la población mundial. Está caracterizada por episodios psicóticos, en los cuales los individuos presentan alucinaciones y/o delirios. A su vez, este trastorno involucra un fuerte componente de disfunción social, falta de motivación y deficiencias cognitivas profundas. Las causas de este trastorno se desconocen a ciencia cierta, aunque la evidencia acumulada indica que surge por alteraciones en el desarrollo del sistema nervioso central. Entre los factores que incrementan el riesgo a desarrollar este trastorno se encuentran varios elementos del ambiente incluyendo, infecciones y malnutrición prenatal, así como complicaciones durante el parto. Sin embargo, estudios detallados han corroborado la existencia de factores genéticos involucrados en el desarrollo de esquizofrenia y señalan a estos como los factores más importantes que parecen determinar la aparición de la enfermedad. A pesar de esto, la identificación de genes involucrados en el desarrollo de esta enfermedad ha resultado ser una de las tareas más difíciles que enfrentan la genética y la genómica. El desarrollo de técnicas modernas para el estudio del genoma humano ha permitido estudiar de forma sistemática las variaciones en la secuencia y estructura del genoma que dan lugar a esquizofrenia, permitiendo la identificación de cientos de genes, que pueden estar involucrados en el desarrollo de la enfermedad. Además, se ha sugerido que muchos de estos genes están involucrados en varias enfermedades mentales que en la actualidad se diagnostican como trastornos diferentes, pero cuyo substrato biológico pudiera ser similar.

Schizophrenia is a mental disorder that affects approximately 1% of the worldwide population. It is characterized by psychotic episodes in which individuals have hallucinations or delusions. This disorder also involves a strong element of social dysfunction, lack of motivation and profound cognitive deficits. The causes of this disorder remain largely unknown, but evidence indicates that arises from changes in the development of the central nervous system. Among the identified risk factors for this disorder are several environmental events, including prenatal infections and malnutrition, and complications during childbirth. However, the most important factor seems to be genetics. Despite this, the identification of genes involved in the development of this disorder has emerged as one of the most difficult tasks facing modern genetics and genomics. The development of techniques for studying the human genome has allowed a more systematic approach to determine variations in the genome sequence and structure that area casually involved in schizophrenia. These studies suggest the participation of hundreds of genes in schizophrenia development. In addition, it has been suggested that many of these genes are involved in various mental illnesses that today are diagnosed as separate entities, but whose biological substrate may be shared.