Plasma IGFBP-3 and IGFBP-5 levels are decreased during acute manic episodes in bipolar disorder patients.

Introduction: Bipolar disorder (BD) is a recurrent and disabling psychiatric disorder related to low-grade peripheral inflammation and altered levels of the members of the insulin-like growth factor (IGF) family. The aim of this study was to evaluate the plasma levels of IGF-2, insulin-like growth factor-binding protein 1 (IGFBP-1), IGFBP-3, IGFBP-5, IGFBP-7, and inflammatory markers such as tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1ß (MIP-1ß). Methods: We used the Young Mania Rating Scale (YMRS) to determine the severity of the symptomatology, while proteins were measured by enzyme-linked immunosorbent assay (ELISA). We included 20 patients with BD who suffered a manic episode and 20 controls. Some BD patients (n = 10) were evaluated after a period (17 ± 8 days) of pharmacological treatment. Results: No statistical difference was found in IGF-2, IGFBP-1, IGFBP-7, TNF-α, and MIP-1ß levels. However, IGFBP-3 and IGFBP-5 levels were found to be statistically decreased in BD patients. Conversely, the MCP-1 level was significantly increased in BD patients, but their levels were normalized after treatment. Intriguingly, only IGFBP-1 levels were significantly decreased after treatment. No significant correlation was found between the YMRS and any of the proteins studied either before or after treatment or between IGF proteins and inflammatory markers. Discussion: To some extent, IGFBP-3 and IGFBP-5 might be further explored as potential indicators of treatment responsiveness or diagnosis biomarkers in BD.

Protein Plasma Levels of the IGF Signalling System Are Altered in Major Depressive Disorder.

The Insulin-like growth factor 2 (IGF-2) has been recently proven to alleviate depressive-like behaviors in both rats and mice models. However, its potential role as a peripheral biomarker has not been evaluated in depression. To do this, we measured plasma IGF-2 and other members of the IGF family such as Binding Proteins (IGFBP-1, IGFBP-3, IGFBP-5 and IGFBP-7) in a depressed group of patients (n = 51) and in a healthy control group (n = 48). In some of these patients (n = 15), we measured these proteins after a period (19 ± 6 days) of treatment with antidepressants. The Hamilton Depressive Rating Scale (HDRS) and the Self-Assessment Anhedonia Scale (SAAS) were used to measure depression severity and anhedonia, respectively. The general cognition state was assessed by the Mini-Mental State Examination (MMSE) test and memory with the Free and Cued Selective Reminding Test (FCSRT). The levels of both IGF-2 and IGFBP-7 were found to be significantly increased in the depressed group; however, only IGF-2 remained significantly elevated after correction by age and sex. On the other hand, the levels of IGF-2, IGFBP-3 and IGFBP-5 were significantly decreased after treatment, whereas only IGFBP-7 was significantly increased. Therefore, peripheral changes in the IGF family and their response to antidepressants might represent alterations at the brain level in depression.

Genomic Factors and Therapeutic Approaches in HIV-Associated Neurocognitive Disorders: A Comprehensive Review.

HIV-associated neurocognitive disorders (HANDs) still persist despite improved life expectancy, reduced viral loads, and decreased infection severity. The number of patients affected by HANDs ranges from (30 to 50) % of HIV-infected individuals. The pathological mechanisms contributing to HANDs and the most serious manifestation of the disease, HIV-associated dementia (HAD), are not yet well understood. Evidence suggests that these mechanisms are likely multifactorial, producing neurocognitive complications involving disorders such as neurogenesis, autophagy, neuroinflammation, and mitochondrial dysfunction. Over the years, multiple pharmacological approaches with specific mechanisms of action acting upon distinct targets have been approved. Although these therapies are effective in reducing viral loading to undetectable levels, they also present some disadvantages such as common side effects, the need for administration with a very high frequency, and the possibility of drug resistance. Genetic studies on HANDs provide insights into the biological pathways and mechanisms that contribute to cognitive impairment in people living with HIV-1. Furthermore, they also help identify genetic variants that increase susceptibility to HANDs and can be used to tailor treatment approaches for HIV-1 patients. Identification of the genetic markers associated with disease progression can help clinicians predict which individuals require more aggressive management and by understanding the genetic basis of the disorder, it will be possible to develop targeted therapies to mitigate cognitive impairment. The main goal of this review is to provide details on the epidemiological data currently available and to summarise the genetic (specifically, the genetic makeup of the immune system), transcriptomic, and epigenetic studies available on HANDs to date. In addition, we address the potential pharmacological therapeutic strategies currently being investigated. This will provide valuable information that can guide clinical care, drug development, and our overall understanding of these diseases.

MyBrain-Seq: A Pipeline for MiRNA-Seq Data Analysis in Neuropsychiatric Disorders.

High-throughput sequencing of small RNA molecules such as microRNAs (miRNAs) has become a widely used approach for studying gene expression and regulation. However, analyzing miRNA-Seq data can be challenging because it requires multiple steps, from quality control and preprocessing to differential expression and pathway-enrichment analyses, with many tools and databases available for each step. Furthermore, reproducibility of the analysis pipeline is crucial to ensure that the results are accurate and reliable. Here, we present myBrain-Seq, a comprehensive and reproducible pipeline for analyzing miRNA-Seq data that incorporates miRNA-specific solutions at each step of the analysis. The pipeline was designed to be flexible and user-friendly, allowing researchers with different levels of expertise to perform the analysis in a standardized and reproducible manner, using the most common and widely used tools for each step. In this work, we describe the implementation of myBrain-Seq and demonstrate its capacity to consistently and reproducibly identify differentially expressed miRNAs and enriched pathways by applying it to a real case study in which we compared schizophrenia patients who responded to medication with treatment-resistant schizophrenia patients to obtain a 16-miRNA treatment-resistant schizophrenia profile.

Data-Driven Phenotyping of Alzheimer's Disease under Epigenetic Conditions Using Partial Volume Correction of PET Studies and Manifold Learning.

Alzheimer's disease (AD) is the most common form of dementia. An increasing number of studies have confirmed epigenetic changes in AD. Consequently, a robust phenotyping mechanism must take into consideration the environmental effects on the patient in the generation of phenotypes. Positron Emission Tomography (PET) is employed for the quantification of pathological amyloid deposition in brain tissues. The objective is to develop a new methodology for the hyperparametric analysis of changes in cognitive scores and PET features to test for there being multiple AD phenotypes. We used a computational method to identify phenotypes in a retrospective cohort study (532 subjects), using PET and Magnetic Resonance Imaging (MRI) images and neuropsychological assessments, to develop a novel computational phenotyping method that uses Partial Volume Correction (PVC) and subsets of neuropsychological assessments in a non-biased fashion. Our pipeline is based on a Regional Spread Function (RSF) method for PVC and a t-distributed Stochastic Neighbor Embedding (t-SNE) manifold. The results presented demonstrate that (1) the approach to data-driven phenotyping is valid, (2) the different techniques involved in the pipelines produce different results, and (3) they permit us to identify the best phenotyping pipeline. The method identifies three phenotypes and permits us to analyze them under epigenetic conditions.

MiRNA Differences Related to Treatment-Resistant Schizophrenia.

Schizophrenia (SZ) is a serious mental disorder that is typically treated with antipsychotic medication. Treatment-resistant schizophrenia (TRS) is the condition where symptoms remain after pharmacological intervention, resulting in long-lasting functional and social impairments. As the identification and treatment of a TRS patient requires previous failed treatments, early mechanisms of detection are needed in order to quicken the access to effective therapy, as well as improve treatment adherence. In this study, we aim to find a microRNA (miRNA) signature for TRS, as well as to shed some light on the molecular pathways potentially involved in this severe condition. To do this, we compared the blood miRNAs of schizophrenia patients that respond to medication and TRS patients, thus obtaining a 16-miRNA TRS profile. Then, we assessed the ability of this signature to separate responders and TRS patients using hierarchical clustering, observing that most of them are grouped correctly (~70% accuracy). We also conducted a network, pathway analysis, and bibliography search to spot molecular pathways potentially altered in TRS. We found that the response to stress seems to be a key factor in TRS and that proteins p53, SIRT1, MDM2, and TRIM28 could be the potential mediators of such responses. Finally, we suggest a molecular pathway potentially regulated by the miRNAs of the TRS profile.

Insulin-like Growth Factor 2 (IGF-2) and Insulin-like Growth Factor Binding Protein 7 (IGFBP-7) Are Upregulated after Atypical Antipsychotics in Spanish Schizophrenia Patients.

Insulin-like growth factor 2 (IGF-2) and IGF binding protein 7 (IGFBP-7) have been related to schizophrenia (SZ) due to their implication in neurodevelopment. The purpose of this study was to assess whether the alterations in IGF-2 and IGFBP-7 in SZ patients are intrinsically related to the psychiatric disorder itself or are a secondary phenomenon due to antipsychotic treatment. In order to test this hypothesis, we measured plasma IGF-2 and IGFBP-7 in drug-naïve first episode (FE) and multiple episodes or chronic (ME) SZ Caucasian patients who have been following treatment for years. A total of 55 SZ patients (FE = 15, ME = 40) and 45 healthy controls were recruited. The Positive and Negative Syndrome Scale (PANSS) and the Self-Assessment Anhedonia Scale (SAAS) were employed to check schizophrenic symptomatology and anhedonia, respectively. Plasma IGF-2 and IGFBP-7 levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA). The FE SZ patients had much lower IGF-2, but not IGFBP-7, than controls. Moreover, both IGF-2 and IGFBP-7 significantly increased after atypical antipsychotic treatment (aripiprazole, olanzapine, or risperidone) in these patients. On the other hand, chronic patients showed higher levels of both proteins when compared to controls. Our study suggests that circulatory IGF-2 and IGFBP-7 increase after antipsychotic treatment, regardless of long-term conditions and being lower in drug-naïve FE patients.

Microglia: The Real Foe in HIV-1-Associated Neurocognitive Disorders?

The current use of combined antiretroviral therapy (cART) is leading to a significant decrease in deaths and comorbidities associated with human immunodeficiency virus type 1 (HIV-1) infection. Nonetheless, none of these therapies can extinguish the virus from the long-lived cellular reservoir, including microglia, thereby representing an important obstacle to curing HIV. Microglia are the foremost cells infected by HIV-1 in the central nervous system (CNS) and are believed to be involved in the development of HIV-1-associated neurocognitive disorder (HAND). At present, the pathological mechanisms contributing to HAND remain unclear, but evidence suggests that removing these infected cells from the brain, as well as obtaining a better understanding of the specific molecular mechanisms of HIV-1 latency in these cells, should help in the design of new strategies to prevent HAND and achieve a cure for these diseases. The goal of this review was to study the current state of knowledge of the neuropathology and research models of HAND containing virus susceptible target cells (microglial cells) and potential pharmacological treatment approaches under investigation.

The neurobiological hypothesis of neurotrophins in the pathophysiology of schizophrenia: A meta-analysis.

BACKGROUND: Schizophrenia is associated with patterns of aberrant neurobiological circuitry. The disease complexity is mirrored by multiple biological interactions known to contribute to the disease pathology. One potential contributor is the family of neurotrophins which are proteins involved in multiple functional processes in the nervous system, with crucial roles in neurodevelopment, synaptogenesis and neuroplasticity. With these roles in mind, abnormal neurotrophin profiles have been hypothesized to contribute to the pathology of schizophrenia. METHODS: We performed a systematic review and a meta-analysis to scrutinize the neurobiological hypothesis of neurotrophins in schizophrenia, examining the correlation between peripheral levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3) and neurotrophin 4/5 (NT-4/5) associated with schizophrenia. RESULTS: Fifty-two studies were reviewed and twenty-two studies were included in this meta-analysis. Using a random effects model, we confirmed that decreased levels of neurotrophins (BDNF, NGF and NT-4/5) were associated with schizophrenia (Hedges's g = -0.846; SE = 0.058; 95% confidence interval: -0.960 to -0.733; Z-value = -14.632; p-value = 0.000). Subgroup analysis indicated that neurotrophin levels are significantly decreased in both medicated and drug-näive patients. Meta-regression of continuous variables such as mean age, duration of illness and PANSS total score did not show significant effects (p > 0.05) in relation to neurotrophins levels. DISCUSSION: We confirm that decreased peripheral neurotrophin levels are significantly associated with schizophrenia, thereby confirming the neurobiological hypothesis of neurotrophins in schizophrenia. Low levels of neurotrophins in peripheral blood of patients with schizophrenia may explain, in part, the pathophysiology of schizophrenia.

The role of the gut microbiota in schizophrenia: Current and future perspectives.

OBJECTIVES: Schizophrenia is a poorly understood chronic disease. Its pathophysiology is complex, dynamic, and linked to epigenetic mechanisms and microbiota involvement. Nowadays, correlating schizophrenia with the environment makes sense owing to its multidimensional implications: temporal and spatial variability. Microbiota involvement and epigenetic mechanisms are factors that are currently being considered to better understand another dimension of schizophrenia. METHODS: This review summarises and discusses currently available information, focussing on the microbiota, epigenetic mechanisms, technological approaches aimed at performing exhaustive analyses of the microbiota, and psychotherapies, to establish future perspectives. RESULTS: The connection between the microbiota, epigenetic mechanisms and technological developments allows for formulating new approaches objectively oriented towards the development of alternative psychotherapies that may help treat schizophrenia. CONCLUSIONS: In this review, the gut microbiota and epigenetic mechanisms were considered as key regulators, revealing a potential new aetiology of schizophrenia. Likewise, continuous technological advances (e.g. culturomics), aimed at the microbiota-gut-brain axis generate new evidence on this concept.

Formin 2 links neuropsychiatric phenotypes at young age to an increased risk for dementia.

Age-associated memory decline is due to variable combinations of genetic and environmental risk factors. How these risk factors interact to drive disease onset is currently unknown. Here we begin to elucidate the mechanisms by which post-traumatic stress disorder (PTSD) at a young age contributes to an increased risk to develop dementia at old age. We show that the actin nucleator Formin 2 (Fmn2) is deregulated in PTSD and in Alzheimer's disease (AD) patients. Young mice lacking the Fmn2 gene exhibit PTSD-like phenotypes and corresponding impairments of synaptic plasticity, while the consolidation of new memories is unaffected. However, Fmn2 mutant mice develop accelerated age-associated memory decline that is further increased in the presence of additional risk factors and is mechanistically linked to a loss of transcriptional homeostasis. In conclusion, our data present a new approach to explore the connection between AD risk factors across life span and provide mechanistic insight to the processes by which neuropsychiatric diseases at a young age affect the risk for developing dementia.

Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders.

Ageing is the main risk factor for human neurological disorders. Among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. Epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. On the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. The reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. Rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ameliorate neural decline during normal ageing and especially in neurological disorders. We will firstly discuss recent progress that supports a key role of epigenetic regulation during healthy ageing with an emphasis on the role of epigenetic regulation in adult neurogenesis. Then, we will focus on epigenetic alterations associated with ageing-related human disorders of the central nervous system. We will discuss examples in the context of psychiatric disorders, including schizophrenia and posttraumatic stress disorders, and also dementia or Alzheimer's disease as the most frequent neurodegenerative disease. Finally, methodological limitations and future perspectives are discussed.

KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions.

Kmt2a and Kmt2b are H3K4 methyltransferases of the Set1/Trithorax class. We have recently shown the importance of Kmt2b for learning and memory. Here, we report that Kmt2a is also important in memory formation. We compare the decrease in H3K4 methylation and de-regulation of gene expression in hippocampal neurons of mice with knockdown of either Kmt2a or Kmt2b. Kmt2a and Kmt2b control largely distinct genomic regions and different molecular pathways linked to neuronal plasticity. Finally, we show that the decrease in H3K4 methylation resulting from Kmt2a knockdown partially recapitulates the pattern previously reported in CK-p25 mice, a model for neurodegeneration and memory impairment. Our findings point to the distinct functions of even closely related histone-modifying enzymes and provide essential insight for the development of more efficient and specific epigenetic therapies against brain diseases.

Serotonin transporter clustering in blood lymphocytes predicts the outcome on anhedonia scores in naïve depressive patients treated with antidepressant medication.

BACKGROUND: We have shown that serotonin transporter (SERT) clustering in blood lymphocytes is altered in major depression and correlates with pharmacological therapeutic responses measured with the Hamilton scale. In the present report, we extend these results to the self-assessment anhedonia scale, as anhedonia is a cardinal symptom of major depression that is difficult to treat with first-line antidepressants. METHODS: We collected blood samples from 38 untreated depression patients at the time of enrolment and 8 weeks after pharmacological treatment. We used the self-assessment anhedonia scale to evaluate anhedonia symptoms before and after treatment. We also used quantitative immunocytochemistry to measure SERT clusters in blood lymphocytes. RESULTS: Evaluation of the distribution of SERT clusters size in the plasma membrane of lymphocytes identified two subpopulations of naive depression patients: Depression I (D-I) and Depression II (D-II). While naïve D-I and D-II patients initially showed similar anhedonia scores, D-II patients showed a good response in anhedonia symptoms after 8 weeks of psychopharmacological treatment, whereas D-I patients failed to show any improvement. Psychopharmacological treatment also induced an increase in the number of SERT clusters in lymphocytes in the D-II group, and this increase correlated with the improvement in anhedonia symptoms. CONCLUSIONS: SERT clustering in peripheral lymphocytes can be used to identify patient response to antidepressant therapy as ascertained by anhedonia scores.

5α-reductase type I expression is downregulated in the prefrontal cortex/Brodmann's area 9 (BA9) of depressed patients.

RATIONALE: The implications of the neurosteroid 3α-hydroxy-5α-pregnan-20-one [allopregnanolone (Allo)] in neuropsychiatric disorders have been highlighted in several recent clinical investigations. For instance, Allo levels are decreased in the cerebrospinal fluid (CSF) of patients with posttraumatic stress disorder (PTSD) and major unipolar depression. Neurosteroidogenic antidepressants [i.e., selective brain steroidogenic stimulants (SBSSs)], including fluoxetine and analogs, correct this decrease in a manner that correlates with improved depressive symptoms. Allo positively and allosterically modulates GABA action at postsynaptic and extrasynaptic GABAA receptors. It is synthesized in both the human and rodent brain cortices by principal glutamatergic pyramidal neurons from progesterone by the sequential action of 5α-reductase type I (5α-RI), which is the rate-limiting step enzyme in Allo biosynthesis, and 3α-hydroxysteroid dehydrogenase (3α-HSD), which converts 5α-dehydroprogesterone into Allo. HYPOTHESIS: We thus hypothesized that decreased CSF levels of Allo in depressed patients could reflect a brain dysfunction of 5α-RI. METHODS: In a pilot study of samples from six patients per group [six depressed patients and six nonpsychiatric subjects (NPS)], we studied the expression of 5α-RI messenger RNA (mRNA) in prefrontal cortex Brodmann's area 9 (BA9) and cerebellum from depressed patients obtained from the Maryland Brain Collection at the Maryland Psychiatric Research Center (Baltimore, MD) that were age-matched with NPS. RESULTS: The levels of 5α-RI mRNA were decreased from 25 ± 5.8 in NPS to 9.1 ± 3.1 fmol/pmol neuronal specific enolase (NSE) (t1,10 = 2.7, P = 0.02) in depressed patients. These differences are absent in the cerebellum of the same patients. The levels of neurosteroids were determined in the prefrontal cortex BA9 of depressed patients obtained from the Stanley Foundation Brain Bank Neuropathology Consortium, Bethesda (MD). The BA9 levels of Allo in male depressed patients failed to reach statistical difference from the levels of NPS (1.63 ± 1.01 pg/mg, n = 8, in NPS and 0.82 ± 0.33 pg/mg, n = 5, in nontreated depressed patients). However, depressed patients who had received antidepressant treatment (three patients SSRI and one TCA) exhibited increased BA9 Allo levels (6.16 ± 2.5 pg/mg, n = 4, t1,9 = 2.4, P = 0.047) when compared with nontreated depressed patients. CONCLUSIONS: Although in a small number of patients, this finding is in-line with previous reports in the field that have observed an increase of Allo levels in CSF and plasma of depressed patients following antidepressant treatment. Hence, the molecular mechanisms underlying major depression may include a GABAergic neurotransmission deficit caused by a brain Allo biosynthesis downregulation, which can be normalized by SBSSs.

Loss of GABAergic cortical neurons underlies the neuropathology of Lafora disease.

BACKGROUND: Lafora disease is an autosomal recessive form of progressive myoclonic epilepsy caused by defects in the EPM2A and EPM2B genes. Primary symptoms of the pathology include seizures, ataxia, myoclonus, and progressive development of severe dementia. Lafora disease can be caused by defects in the EPM2A gene, which encodes the laforin protein phosphatase, or in the NHLRC1 gene (also called EPM2B) codifying the malin E3 ubiquitin ligase. Studies on cellular models showed that laforin and malin interact and operate as a functional complex apparently regulating cellular functions such as glycogen metabolism, cellular stress response, and the proteolytic processes. However, the pathogenesis and the molecular mechanism of the disease, which imply either laforin or malin are poorly understood. Thus, the aim of our study is to elucidate the molecular mechanism of the pathology by characterizing cerebral cortex neurodegeneration in the well accepted murine model of Lafora disease EPM2A-/- mouse. RESULTS: In this article, we want to asses the primary cause of the neurodegeneration in Lafora disease by studying GABAergic neurons in the cerebral cortex. We showed that the majority of Lafora bodies are specifically located in GABAergic neurons of the cerebral cortex of 3 months-old EPM2A-/- mice. Moreover, GABAergic neurons in the cerebral cortex of younger mice (1 month-old) are decreased in number and present altered neurotrophins and p75NTR signalling. CONCLUSIONS: Here, we concluded that there is impairment in GABAergic neurons neurodevelopment in the cerebral cortex, which occurs prior to the formation of Lafora bodies in the cytoplasm. The dysregulation of cerebral cortex development may contribute to Lafora disease pathogenesis.

Loss of HDAC5 impairs memory function: implications for Alzheimer's disease.

Epigenetic mechanisms such as histone-acetylation have been implicated with learning and memory and are believed to contribute to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Histone-deacetylase (HDAC) inhibitors were shown to exhibit neuroprotective and neurodegenerative properties in AD animal models, and targeting HDACs appears to be a promising therapeutic strategy for brain diseases. The role of the distinct HDAC proteins in the adult brain is, however, not well understood and so far only pan-HDAC inhibitors have been tested in preclinical settings. Understanding the role of individual HDACs in cognition and AD pathogenesis is therefore vital to develop more selective HDAC inhibitors for the treatment of AD. In this study we investigated the role of HDAC5 in memory function and AD pathogenesis. We show that loss of HDAC5 impairs memory function but has little impact on pathogenesis in a mouse model for amyloid pathology. Our data reveals a novel role of HDAC5 in memory consolidation and shows that future approaches to develop more selective HDAC inhibitors for the treatment of AD should avoid targeting HDAC5.

A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories.

Extinction learning refers to the phenomenon that a previously learned response to an environmental stimulus, for example, the expression of an aversive behaviour upon exposure to a specific context, is reduced when the stimulus is repeatedly presented in the absence of a previously paired aversive event. Extinction of fear memories has been implicated with the treatment of anxiety disease but the molecular processes that underlie fear extinction are only beginning to emerge. Here, we show that fear extinction initiates upregulation of hippocampal insulin-growth factor 2 (Igf2) and downregulation of insulin-growth factor binding protein 7 (Igfbp7). In line with this observation, we demonstrate that IGF2 facilitates fear extinction, while IGFBP7 impairs fear extinction in an IGF2-dependent manner. Furthermore, we identify one cellular substrate of altered IGF2 signalling during fear extinction. To this end, we show that fear extinction-induced IGF2/IGFBP7 signalling promotes the survival of 17-19-day-old newborn hippocampal neurons. In conclusion, our data suggest that therapeutic strategies that enhance IGF2 signalling and adult neurogenesis might be suitable to treat disease linked to excessive fear memory.

Sodium butyrate improves memory function in an Alzheimer's disease mouse model when administered at an advanced stage of disease progression.

Dysregulation of histone acetylation has been implicated in the onset of age-associated memory impairment and the pathogenesis of neurodegenerative diseases. Elevation of histone acetylation via administration of histone deacetylase (HDAC) inhibitors is currently being pursued as a novel therapeutic avenue to treat memory impairment linked to Alzheimer's disease (AD). Here we show that severe amyloid pathology correlates with a pronounced dysregulation of histone acetylation in the forebrain of APPPS1-21 mice. Importantly, prolonged treatment with the pan-HDAC inhibitor sodium butyrate improved associative memory in APPPS1-21 mice even when administered at a very advanced stage of pathology. The recovery of memory function correlated with elevated hippocampal histone acetylation and increased expression of genes implicated in associative learning. These data advance our understanding of the potential applicability of HDAC inhibitors for the treatment of AD and suggest that HDAC inhibitors may have beneficial effects even when administered long after the onset of disease-associated symptoms.

Altered histone acetylation is associated with age-dependent memory impairment in mice.

As the human life span increases, the number of people suffering from cognitive decline is rising dramatically. The mechanisms underlying age-associated memory impairment are, however, not understood. Here we show that memory disturbances in the aging brain of the mouse are associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific deregulation of histone H4 lysine 12 (H4K12) acetylation and fail to initiate a hippocampal gene expression program associated with memory consolidation. Restoration of physiological H4K12 acetylation reinstates the expression of learning-induced genes and leads to the recovery of cognitive abilities. Our data suggest that deregulated H4K12 acetylation may represent an early biomarker of an impaired genome-environment interaction in the aging mouse brain.