Biphasic Npas4 expression promotes inhibitory plasticity and suppression of fear memory consolidation in mice.

Long-term memories are believed to be encoded by unique transcriptional signatures in the brain. The expression of immediate early genes (IEG) promotes structural and molecular changes required for memory consolidation. Recent evidence has shown that the brain is equipped with mechanisms that not only promote, but actively constrict memory formation. However, it remains unknown whether IEG expression may play a role in memory suppression. Here we uncovered a novel function of the IEG neuronal PAS domain protein 4 (Npas4), as an inducible memory suppressor gene of highly salient aversive experiences. Using a contextual fear conditioning paradigm, we found that low stimulus salience leads to monophasic Npas4 expression, while highly salient learning induces a biphasic expression of Npas4 in the hippocampus. The later phase requires N-methyl-D-aspartate (NMDA) receptor activity and is independent of dopaminergic neurotransmission. Our in vivo pharmacological and genetic manipulation experiments suggested that the later phase of Npas4 expression restricts the consolidation of a fear memory and promote behavioral flexibility, by facilitating fear extinction and the contextual specificity of fear responses. Moreover, immunofluorescence and electrophysiological analysis revealed a concomitant increase in synaptic input from cholecystokinin (CCK)-expressing interneurons. Our results demonstrate how salient experiences evoke unique temporal patterns of IEG expression that fine-tune memory consolidation. Moreover, our study provides evidence for inducible gene expression associated with memory suppression as a possible mechanism to balance the consolidation of highly salient memories, and thereby to evade the formation of maladaptive behavior.

Reprogramming iPSCs to study age-related diseases: Models, therapeutics, and clinical trials.

The unprecedented rise in life expectancy observed in the last decades is leading to a global increase in the ageing population, and age-associated diseases became an increasing societal, economic, and medical burden. This has boosted major efforts in the scientific and medical research communities to develop and improve therapies to delay ageing and age-associated functional decline and diseases, and to expand health span. The establishment of induced pluripotent stem cells (iPSCs) by reprogramming human somatic cells has revolutionised the modelling and understanding of human diseases. iPSCs have a major advantage relative to other human pluripotent stem cells as their obtention does not require the destruction of embryos like embryonic stem cells do, and do not have a limited proliferation or differentiation potential as adult stem cells. Besides, iPSCs can be generated from somatic cells from healthy individuals or patients, which makes iPSC technology a promising approach to model and decipher the mechanisms underlying the ageing process and age-associated diseases, study drug effects, and develop new therapeutic approaches. This review discusses the advances made in the last decade using iPSC technology to study the most common age-associated diseases, including age-related macular degeneration (AMD), neurodegenerative and cardiovascular diseases, brain stroke, cancer, diabetes, and osteoarthritis.

Measuring healthy ageing: current and future tools.

Human ageing is a complex, multifactorial process characterised by physiological damage, increased risk of age-related diseases and inevitable functional deterioration. As the population of the world grows older, placing significant strain on social and healthcare resources, there is a growing need to identify reliable and easy-to-employ markers of healthy ageing for early detection of ageing trajectories and disease risk. Such markers would allow for the targeted implementation of strategies or treatments that can lessen suffering, disability, and dependence in old age. In this review, we summarise the healthy ageing scores reported in the literature, with a focus on the past 5 years, and compare and contrast the variables employed. The use of approaches to determine biological age, molecular biomarkers, ageing trajectories, and multi-omics ageing scores are reviewed. We conclude that the ideal healthy ageing score is multisystemic and able to encompass all of the potential alterations associated with ageing. It should also be longitudinal and able to accurately predict ageing complications at an early stage in order to maximize the chances of successful early intervention.

How can we modulate aging through nutrition and physical exercise? An epigenetic approach.

The World Health Organization predicts that by 2050, 2.1 billion people worldwide will be over 60 years old, a drastic increase from only 1 billion in 2019. Considering these numbers, strategies to ensure an extended "healthspan" or healthy longevity are urgently needed. The present study approaches the promotion of healthspan from an epigenetic perspective. Epigenetic phenomena are modifiable in response to an individual's environmental exposures, and therefore link an individual's environment to their gene expression pattern. Epigenetic studies demonstrate that aging is associated with decondensation of the chromatin, leading to an altered heterochromatin structure, which promotes the accumulation of errors. In this review, we describe how aging impacts epigenetics and how nutrition and physical exercise can positively impact the aging process, from an epigenetic point of view. Canonical histones are replaced by histone variants, concomitant with an increase in histone post-translational modifications. A slight increase in DNA methylation at promoters has been observed, which represses transcription of previously active genes, in parallel with global genome hypomethylation. Aging is also associated with deregulation of gene expression - usually provided by non-coding RNAs - leading to both the repression of previously transcribed genes and to the transcription of previously repressed genes. Age-associated epigenetic events are less common in individuals with a healthy lifestyle, including balanced nutrition, caloric restriction and physical exercise. Healthy aging is associated with more tightly condensed chromatin, fewer PTMs and greater regulation by ncRNAs.

The stress granule protein G3BP1 alleviates spinocerebellar ataxia-associated deficits.

Polyglutamine diseases are a group of neurodegenerative disorders caused by an abnormal expansion of CAG repeat tracts in the codifying regions of nine, otherwise unrelated, genes. While the protein products of these genes are suggested to play diverse cellular roles, the pathogenic mutant proteins bearing an expanded polyglutamine sequence share a tendency to self-assemble, aggregate and engage in abnormal molecular interactions. Understanding the shared paths that link polyglutamine protein expansion to the nervous system dysfunction and the degeneration that takes place in these disorders is instrumental to the identification of targets for therapeutic intervention. Among polyglutamine diseases, spinocerebellar ataxias (SCAs) share many common aspects, including the fact that they involve dysfunction of the cerebellum, resulting in ataxia. Our work aimed at exploring a putative new therapeutic target for the two forms of SCA with higher worldwide prevalence, SCA type 2 (SCA2) and type 3 (SCA3), which are caused by expanded forms of ataxin-2 (ATXN2) and ataxin-3 (ATXN3), respectively. The pathophysiology of polyglutamine diseases has been described to involve an inability to properly respond to cell stress. We evaluated the ability of GTPase-activating protein-binding protein 1 (G3BP1), an RNA-binding protein involved in RNA metabolism regulation and stress responses, to counteract SCA2 and SCA3 pathology, using both in vitro and in vivo disease models. Our results indicate that G3BP1 overexpression in cell models leads to a reduction of ATXN2 and ATXN3 aggregation, associated with a decrease in protein expression. This protective effect of G3BP1 against polyglutamine protein aggregation was reinforced by the fact that silencing G3bp1 in the mouse brain increases human expanded ATXN2 and ATXN3 aggregation. Moreover, a decrease of G3BP1 levels was detected in cells derived from patients with SCA2 and SCA3, suggesting that G3BP1 function is compromised in the context of these diseases. In lentiviral mouse models of SCA2 and SCA3, G3BP1 overexpression not only decreased protein aggregation but also contributed to the preservation of neuronal cells. Finally, in an SCA3 transgenic mouse model with a severe ataxic phenotype, G3BP1 lentiviral delivery to the cerebellum led to amelioration of several motor behavioural deficits. Overall, our results indicate that a decrease in G3BP1 levels may be a contributing factor to SCA2 and SCA3 pathophysiology, and that administration of this protein through viral vector-mediated delivery may constitute a putative approach to therapy for these diseases, and possibly other polyglutamine disorders.

Regulation of neuronal plasticity by the DNA repair associated Gadd45 proteins.

Neurons respond rapidly to extracellular stimuli by activating signaling pathways that modulate the function of already synthetized proteins. Alternatively, signal transduction to the cell nucleus induces de novo synthesis of proteins required for long-lasting adaptations. These complementary strategies are necessary for neuronal plasticity processes that underlie, among other functions, the formation of memories. Nonetheless, it is still not fully understood how the coupling between different stimuli and the activity of constitutively and/or de novo expressed proteins gate neuronal plasticity. Here, we discuss the molecular functions of the Growth Arrest and DNA Damage 45 (Gadd45) family of proteins in neuronal adaptation. We highlight recent findings that indicate that Gadd45 family members regulate this function through multiple cellular processes (e.g., DNA demethylation, gene expression, RNA stability, MAPK signaling). We then summarize the regulation of Gadd45 expression in neurons and put forward the hypothesis that the constitutive and neuronal activity-induced pools of Gadd45 proteins have distinct and complementary roles in modulating neuronal plasticity. Therefore, we propose that Gadd45 proteins are essential for brain function and their dysfunction might underlie pathophysiological conditions such as neuropsychiatric disorders.

Does the white coat influence satisfaction, trust and empathy in the doctor-patient relationship in the General and Family Medicine consultation? Interventional study.

OBJECTIVES: To understand the influence of the white coat on patient satisfaction, opinions about medical clothing, perception about confidence, empathy and medical knowledge and the satisfaction and comfort level of physicians in consultation. SETTING: An interventional study was conducted with a representative sample of the population attending primary care in central Portugal. PARTICIPANTS: The sample was composed by 286 patients divided into two groups exposed or not to a doctor wearing a white coat. The first and last patients in consultation every day for 10 consecutive days were included. INTERVENTIONS: Every other day the volunteer physicians consulted with or without the use of a white coat. At the end of the consultation, a questionnaire was distributed to the patient with simple questions with a Likert scale response, the Portuguese version of the 'Trust in physician' scale and the Jefferson Scale of Patient Perceptions of Physician Empathy - Portuguese Version (JSPPPE-VP scale). A questionnaire was also distributed to the physician. OUTCOMES: Planned and measured primary outcomes were patient satisfaction, trust and perception about empathy and secondary outcomes were opinion about medical clothing, satisfaction and comfort level of physicians in consultation. RESULTS: The sample was homogeneous in terms of sociodemographic variables. There were no statistically significant differences between the groups in terms of satisfaction, trust, empathy and knowledge perceived by the patients. There were differences in the opinion of the patients about the white coat, and when the physician was wearing the white coat this group of patients tended to think that this was the only acceptable attire for the physician (p<0.001). But when the family physician was in consultation without the white coat, this group of patients tended to agree that communication was easier (p=0.001). CONCLUSIONS: There was no significant impact of the white coat in patient satisfaction, empathy and confidence in the family physician. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov ID number: NCT03965416.

Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy.

Spinocerebellar ataxia type 2 (SCA2) is an incurable and genetic neurodegenerative disorder. The disease is characterized by progressive degeneration of several brain regions, resulting in severe motor and non-motor clinical manifestations. The mutation causing SCA2 disease is an abnormal expansion of CAG trinucleotide repeats in the ATXN2 gene, leading to a toxic expanded polyglutamine segment in the translated ataxin-2 protein. While the genetic cause is well established, the exact mechanisms behind neuronal death induced by mutant ataxin-2 are not yet completely understood. Thus, the goal of this study is to investigate the role of autophagy in SCA2 pathogenesis and investigate its suitability as a target for therapeutic intervention. For that, we developed and characterized a new striatal lentiviral mouse model that resembled several neuropathological hallmarks observed in SCA2 disease, including formation of aggregates, neuronal marker loss, cell death and neuroinflammation. In this new model, we analyzed autophagic markers, which were also analyzed in a SCA2 cellular model and in human post-mortem brain samples. Our results showed altered levels of SQSTM1 and LC3B in cells and tissues expressing mutant ataxin-2. Moreover, an abnormal accumulation of these markers was detected in SCA2 patients' striatum and cerebellum. Importantly, the molecular activation of autophagy, using the compound cordycepin, mitigated the phenotypic alterations observed in disease models. Overall, our study suggests an important role for autophagy in the context of SCA2 pathology, proposing that targeting this pathway could be a potential target to treat SCA2 patients.

Gitelman Syndrome Provisionally Diagnosed During the First Presentation of Diabetic Ketoacidosis.

Gitelman syndrome (GS) is an autosomal recessive disease characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria. It is caused by mutations in gene SLC12A3 (located in chromosome 16q) encoding NaCl cotransporter. GS is usually asymptomatic for several years and is diagnosed in late childhood or adulthood. The association between GS and diabetic ketoacidosis (DKA) is rare. We present a case of a 25-year-old man with newly diagnosed diabetes mellitus and DKA with profound hypokalemia and hypomagnesemia who was provisionally found to have GS.

Engram reactivation during memory retrieval predicts long-term memory performance in aged mice.

Age-related cognitive decline preferentially targets long-lasting episodic memories that require intact hippocampal function. Memory traces (or engrams) are believed to be encoded within the neurons activated during learning (neuronal ensembles), and recalled by reactivation of the same population. However, whether engram reactivation dictates memory performance late in life is not known. Here, we labeled neuronal ensembles formed during object location recognition learning in the dentate gyrus, and analyzed the reactivation of this population during long-term memory recall in young adult, cognitively impaired- and unimpaired-aged mice. We found that reactivation of memory-encoding neuronal ensembles at long-term memory recall was disrupted in impaired but not unimpaired-aged mice. Furthermore, we showed that the memory performance in the aged population correlated with the degree of engram reactivation at long-term memory recall. Overall, our data implicates recall-induced engram reactivation as a prediction factor of memory performance in aging. Moreover, our findings suggest impairments in neuronal ensemble stabilization and/or reactivation as an underlying mechanism in age-dependent cognitive decline.

MeCP2 gates spatial learning-induced alternative splicing events in the mouse hippocampus.

Long-term memory formation is supported by functional and structural changes of neuronal networks, which rely on de novo gene transcription and protein synthesis. The modulation of the neuronal transcriptome in response to learning depends on transcriptional and post-transcriptional mechanisms. DNA methylation writers and readers regulate the activity-dependent genomic program required for memory consolidation. The most abundant DNA methylation reader, the Methyl CpG binding domain protein 2 (MeCP2), has been shown to regulate alternative splicing, but whether it establishes splicing events important for memory consolidation has not been investigated. In this study, we identified the alternative splicing profile of the mouse hippocampus in basal conditions and after a spatial learning experience, and investigated the requirement of MeCP2 for these processes. We observed that spatial learning triggers a wide-range of alternative splicing events in transcripts associated with structural and functional remodeling and that virus-mediated knockdown of MeCP2 impairs learning-dependent post-transcriptional responses of mature hippocampal neurons. Furthermore, we found that MeCP2 preferentially affected the splicing modalities intron retention and exon skipping and guided the alternative splicing of distinct set of genes in baseline conditions and after learning. Lastly, comparative analysis of the MeCP2-regulated transcriptome with the alternatively spliced mRNA pool, revealed that MeCP2 disruption alters the relative abundance of alternatively spliced isoforms without affecting the overall mRNA levels. Taken together, our findings reveal that adult hippocampal MeCP2 is required to finetune alternative splicing events in basal conditions, as well as in response to spatial learning. This study provides new insight into how MeCP2 regulates brain function, particularly cognitive abilities, and sheds light onto the pathophysiological mechanisms of Rett syndrome, that is characterized by intellectual disability and caused by mutations in the Mecp2 gene.

Modeling human age-associated increase in Gadd45γ expression leads to spatial recognition memory impairments in young adult mice.

Aging is associated with the progressive decay of cognitive function. Hippocampus-dependent processes, such as the formation of spatial memory, are particularly vulnerable to aging. Currently, the molecular mechanisms responsible for age-dependent cognitive decline are largely unknown. Here, we investigated the expression and function of the growth arrest DNA damage gamma (Gadd45γ) during aging and cognition. We report that Gadd45γ expression is increased in the hippocampus of aged humans and that Gadd45γ overexpression in the young adult mouse hippocampus compromises cognition. Moreover, Gadd45γ overexpression in hippocampal neurons disrupted cAMP response element-binding protein signaling and the expression of well-established activity-regulated genes. This work shows that Gadd45γ expression is tightly controlled in the hippocampus and its disruption may be a mechanism contributing to age-related cognitive impairments observed in humans.

Neuronal ensemble-specific DNA methylation strengthens engram stability.

Memories are encoded by memory traces or engrams, represented within subsets of neurons that are synchronously activated during learning. However, the molecular mechanisms that drive engram stabilization during consolidation and consequently ensure its reactivation by memory recall are not fully understood. In this study we manipulate, during memory consolidation, the levels of the de novo DNA methyltransferase 3a2 (Dnmt3a2) selectively within dentate gyrus neurons activated by fear conditioning. We found that Dnmt3a2 upregulation enhances memory performance in mice and improves the fidelity of reconstitution of the original neuronal ensemble upon memory retrieval. Moreover, similar manipulation in a sparse, non-engram subset of neurons does not bias engram allocation or modulate memory strength. We further show that neuronal Dnmt3a2 overexpression changes the DNA methylation profile of synaptic plasticity-related genes. Our data implicates DNA methylation selectively within neuronal ensembles as a mechanism of stabilizing engrams during consolidation that supports successful memory retrieval.

Mimicking Age-Associated Gadd45γ Dysregulation Results in Memory Impairments in Young Adult Mice.

Age-related memory loss is observed across multiple mammalian species and preferentially affects hippocampus-dependent memory. Memory impairments are characterized by accelerated decay of spatial memories. Nevertheless, the molecular mechanisms underlying these deficits are still largely unknown. Here, we investigated the expression and function of the growth arrest DNA damage (Gadd45) family during aging and cognition, respectively. We report that aging impairs the expression of Gadd45γ in the hippocampus of cognitively impaired male mice. Mimicking this decrease in young adult male mice led to age-like memory deficits in hippocampus-dependent memory tasks. Gadd45γ reduction impaired the activity of key components of the mitogen-activated protein kinase (MAPK) pathway (p38 and JNK) in mouse hippocampal cultures. Furthermore, we found that activation of downstream targets, such as ATF-2, c-Jun, and CREB (cAMP response element-binding protein), was disrupted. Finally, we showed that Gadd45γ is required for induction of key early- and late-response genes that have been associated with aging. Together, these findings indicate that Gadd45γ expression regulates cognitive abilities and synapse-to-nucleus communication and suggest Gadd45γ dysfunction as a potential mechanism contributing to age-related cognitive impairments.SIGNIFICANCE STATEMENT A high percentage of subjects experience age-related memory loss that burdens daily performance. Although many advances have been made, the precise changes in the brain governing these deficits are unclear. Identifying molecular processes that are required for cognition and are altered during old age is crucial to develop preventive or therapeutic strategies. Here, we show that baseline and learning-induced expression of the growth arrest DNA damage (Gadd45) γ is selectively impaired in the hippocampus of aged mice with cognitive deficits. Next, we show that modeling this impairment in young adult mice with normal cognitive performance disrupts long- and short-term memories in an age-like manner. Finally, we demonstrate that Gadd45γ regulates synapse-to-nucleus communication processes that are needed for plasticity-associated gene expression.

A dispersão da psicologia: do debate epistemológico ao estudo de uma divisão de psicologia aplicada / La dispersión de la psicología: del debate epistemológico al estudio de una división de psicología aplicada / The dispersion of Psychology: from the epistemological debate to the study of a division of applied psychology

Resumo: Este artigo trabalhará a discussão quanto a pluralidade ou unidade da psicologia. Destacaremos como este tema se projetou no cenário dos países francófonos ao longo do século passado. Como contraponto, investigaremos os modos de articulação produzidos pelos saberes e práticas psicológicos, através dos atuais Estudos em Ciência, Tecnologia e Sociedade, a partir da Teoria Ator-Rede e da Epistemologia Política. Examinaremos os modos de engajamento que certas técnicas terapêuticas produzem no intercurso com diversos atores humanos, mas igualmente com dispositivos sociotécnicos. Estas técnicas terapêuticas estão sendo acompanhadas na Divisão de Psicologia Aplicada da UFRJ desde 2010 por meio de: descrições dos artefatos presentes em certas práticas terapêuticas e dos dispositivos nela presentes; entrevistas com pessoas em entrada e intercurso de terapia, estagiários, orientadores e responsáveis pela triagem; e observações etnográficas em sessões de supervisão de abordagens diversas. Por meio dos resultados destas pesquisas, discutiremos as formas de conexão das práticas psi.

Resumen: Este artículo trabajará en la discusión sobre la pluralidad o unidad de la psicología. Vamos a destacar cómo este tema fue proyectado en el escenario de los países francófonos a lo largo del último siglo. Como contrapunto, investigaremos los modos de articulación producidos por los saberes y prácticas psicológicas, a través de los actuales Estudios en Ciencia, Tecnología y Sociedad, basados ​​en la Teoría Actor-Red y en la Epistemología Política. Examinaremos los modos de compromiso que ciertas técnicas terapéuticas producen en el intercurso con varios actores humanos, pero también con dispositivos sociotécnicos. Estas técnicas terapéuticas vienen siendo acompañadas en la División de Psicología Aplicada de la UFRJ desde 2010 por medio de: descripciones de los artefactos presentes en determinadas prácticas terapéuticas y de los dispositivos presentes; entrevistas con personas en renta y pasantía de terapia, pasantes, consejeros y responsables de la selección; y observaciones etnográficas en sesiones de supervisión de diversos enfoques. A través de los resultados de estas investigaciones, discutiremos las formas de conectar prácticas psi.

Abstract: This paper will discuss the plurality or unity of psychology. We will highlight how this theme was projected in the francophone countries scenery over the past century. As counterpoint we will investigate the ways of articulation produced by psychological knowledges and practices through the recent Science, Technology and Society Studies, from Actor-Network Theory and from Political-Epistemology. We will examine the modalities of engagement that certain therapeutic techniques produce in the relation with diverse human actors and socio technical devices. These therapeutic techniques are being accompanied in UFRJ's Division of Applied Psychology since 2010 through: the description of the artifacts present in certain therapeutic practices and of the devices present in those; interviews with people entering and under therapy, trainees, mentors and the ones responsible for the screening; and ethnographic observations in supervision sessions of diverse approaches. Through the obtained results, we will discuss the ways of connection of psi practices.

Tratamiento funcional de la lesión de ligamento cruzado anterior de la rodilla: una revisión / Functional Treatment of Anterior Knee Cruciate Ligament Injury: A Review

Introducción: la ruptura del ligamento cruzado anterior de la rodilla es una de las lesiones que se presenta frecuentemente en las personas que realizan deporte o actividad física. Objetivo: comparar los tratamientos funcionales utilizados para la recuperación de la ruptura de ligamento cruzado anterior. Metodología: se realizó una revisión bibliográfica de artículos científicos publicados desde enero del 2000 hasta enero de 2018. Las bases de datos consultadas fueron Medline, Scopus y Scielo. Utilizando las siguientes palabras claves: lesión de rodilla, ligamento cruzado anterior, rehabilitación funcional. Se seleccionaron aquellos estudios en los que se hubiese analizado lesiones de ligamento cruzado anterior en cualquier disciplina deportiva. Resultados: se encontró seis estudios, todos de aplicación en los diferentes niveles de experimentación (pre-, cuasi- y experimental). Discusión y conclusiones: el ejercicio funcional, prescrito de una manera individualizada, con un seguimiento mediante test apropiados que se realicen antes durante y después de la rehabilitación de lesiones del ligamento cruzado anterior reduce los tiempos de recuperación de la lesión.

MeCP2: A Critical Regulator of Chromatin in Neurodevelopment and Adult Brain Function.

Methyl CpG binding protein 2 (MeCP2) was first identified as a nuclear protein with a transcriptional repressor role that recognizes DNA methylation marks. MeCP2 has a well-established function in neurodevelopment, as evidenced by the severe neurological impairments characteristic of the Rett syndrome (RTT) pathology and the MeCP2 duplication syndrome (MDS), caused by loss or gain of MeCP2 function, respectively. Research aimed at the underlying pathophysiological mechanisms of RTT and MDS has significantly advanced our understanding of MeCP2 functions in the nervous system. It has revealed, however, that MeCP2 has more varied and complex roles than previously thought. Here we review recent insights into the functions of MeCP2 in neurodevelopment and the less explored requirement for MeCP2 in adult brain function. We focus on the emerging view that MeCP2 is a global chromatin organizer. Finally, we discuss how the individual functions of MeCP2 in neurodevelopment and adulthood are linked to its role as a chromatin regulator.

Adult hippocampal MeCP2 preserves the genomic responsiveness to learning required for long-term memory formation.

MeCP2 is required both during postnatal neurodevelopment and throughout the adult life for brain function. Although it is well accepted that MeCP2 in the maturing nervous system is critical for establishing normal development, the functions of MeCP2 during adulthood are poorly understood. Particularly, the requirement of hippocampal MeCP2 for cognitive abilities in the adult is not studied. To characterize the role of MeCP2 in adult neuronal function and cognition, we used a temporal and region-specific disruption of MeCP2 expression in the hippocampus of adult male mice. We found that MeCP2 is required for long-term memory formation and that it controls the learning-induced transcriptional response of hippocampal neurons required for memory consolidation. Furthermore, we uncovered MeCP2 functions in the adult hippocampus that may underlie cognitive integrity. We showed that MeCP2 maintains the developmentally established chromatin configuration and epigenetic landscape of CA1 neurons throughout the adulthood, and that it regulates the expression of neuronal and immune-related genes in the adult hippocampus. Overall, our findings identify MeCP2 as a maintenance factor in the adult hippocampus that preserves signal responsiveness of the genome and allows for integrity of cognitive functions. This study provides new insight into how MeCP2 maintains adult brain functions, but also into the mechanisms underlying the cognitive impairments observed in RTT patients and highlights the understudied role of DNA methylation interpretation in adult cognitive processes.