A richness that cures

A study in Nature by Fischer et al. shows that environmental enrichment or increasing histone acetylation rescue the ability to form new memories and re-establish access to remote memories even in the presence of brain degeneration. Chromatin remodeling may be the final gate environmental enrichment opens to enhance plasticity and represents a promising target for therapeutical intervention in neurodegenerative diseases.     

神经元的突触可塑性与学习和记忆

大量研究表明,神经元的突触可塑性包括功能可塑性和结构可塑性,与学习和记忆密切相关.最近,在经过训练的动物海马区,记录到了学习诱导的长时程增强(long term potentiation,LTP),如果用激酶抑制剂阻断晚期LTP,就会使大鼠丧失训练形成的记忆.这些结果指出,LTP可能是形成记忆的分子基础.因此,进一步研究哺乳动物脑内突触可塑性的分子机制,对揭示学习和记忆的神经基础有重要意义.此外,在精神迟滞性疾病和神经退行性疾病患者脑内记录到异常的LTP,并发现神经元的树突棘数量减少,形态上产生畸变或萎缩,同时发现,产生突变的基因大多编码调节突触可塑性的信号通路蛋白,故突触可塑性研究也将促进精神和神经疾病的预防和治疗.综述了突触可塑性研究的最新进展,并展望了其发展前景.     

Valproate Improves Memory Deficits in an Alzheimer’s disease Mouse Model: Investigation of Possible Mechanisms of Action

Alzheimer’s disease (AD) is a very common progressive neurodegenerative disorder affecting the learning and memory abilities in the brain. Key findings from recent studies of epigenetic mechanisms of memory suggest chromatin remodeling disorders via histone hypoacetylation of the lysine residue contribute to the cognitive impairment in AD. Therefore, the deinhibition of histone acetylation induced by histone deacetylases (HDACs) inhibitors contributes to recovery of learning and memory. We show here that the antiepileptic drug sodium valproate (VPA) potently enhanced long-term recognition memory and spatial learning and memory in AD transgenic mice. Possible mechanisms showed VPA could significantly elevate histone acetylation through HDACs activity inhibition and increase plasticity-associated gene expression within the hippocampi of mice. Our study suggests that VPA, serving as a HDACs inhibitor, can be considered as a potential pharmaceutical agent for the improvement of cognitive function in AD.     

Hippocampal Gene Expression Meta-Analysis Identifies Aging and Age-Associated Spatial Learning Impairment (ASLI) Genes and Pathways

A number of gene expression microarray studies have been carried out in the past, which studied aging and age-associated spatial learning impairment (ASLI) in the hippocampus in animal models, with varying results. Data from such studies were never integrated to identify the most significant ASLI genes and to understand their effect. In this study we integrated these data involving rats using meta-analysis. Our results show that proper removal of batch effects from microarray data generated from different laboratories is necessary before integrating them for meta-analysis. Our meta-analysis has identified a number of significant differentially expressed genes across age or across ASLI. These genes affect many key functions in the aged compared to the young rats, which include viability of neurons, cell-to-cell signalling and interaction, migration of cells, neuronal growth, and synaptic plasticity. These functional changes due to the altered gene expression may manifest into various neurodegenerative diseases and disorders, some of which leading into syndromic memory impairments. While other aging related molecular changes can result into altered synaptic plasticity simply causing normal aging related non-syndromic learning or spatial learning impairments such as ASLI.     

K‐Lysine acetyltransferase 2a regulates a hippocampal gene expression network linked to memory formation

Neuronal histone acetylation has been linked to memory consolidation, and targeting histone acetylation has emerged as a promising therapeutic strategy for neuropsychiatric diseases. However, the role of histone‐modifying enzymes in the adult brain is still far from being understood. Here we use RNA sequencing to screen the levels of all known histone acetyltransferases (HATs) in the hippocampal CA1 region and find that K‐acetyltransferase 2a (Kat2a)—a HAT that has not been studied for its role in memory function so far—shows highest expression. Mice that lack Kat2a show impaired hippocampal synaptic plasticity and long‐term memory consolidation. We furthermore show that Kat2a regulates a highly interconnected hippocampal gene expression network linked to neuroactive receptor signaling via a mechanism that involves nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB). In conclusion, our data establish Kat2a as a novel and essential regulator of hippocampal memory consolidation.     

Epigenetic alterations are critical for fear memory consolidation and synaptic plasticity in the lateral amygdala

Epigenetic mechanisms, including histone acetylation and DNA methylation, have been widely implicated in hippocampal-dependent learning paradigms. Here, we have examined the role of epigenetic alterations in amygdala-dependent auditory Pavlovian fear conditioning and associated synaptic plasticity in the lateral nucleus of the amygdala (LA) in the rat. Using Western blotting, we first show that auditory fear conditioning is associated with an increase in histone H3 acetylation and DNMT3A expression in the LA, and that training-related alterations in histone acetylation and DNMT3A expression in the LA are downstream of ERK/MAPK signaling. Next, we show that intra-LA infusion of the histone deacetylase (HDAC) inhibitor TSA increases H3 acetylation and enhances fear memory consolidation; that is, long-term memory (LTM) is enhanced, while short-term memory (STM) is unaffected. Conversely, intra-LA infusion of the DNA methyltransferase (DNMT) inhibitor 5-AZA impairs fear memory consolidation. Further, intra-LA infusion of 5-AZA was observed to impair training-related increases in H3 acetylation, and pre-treatment with TSA was observed to rescue the memory consolidation deficit induced by 5-AZA. In our final series of experiments, we show that bath application of either 5-AZA or TSA to amygdala slices results in significant impairment or enhancement, respectively, of long-term potentiation (LTP) at both thalamic and cortical inputs to the LA. Further, the deficit in LTP following treatment with 5-AZA was observed to be rescued at both inputs by co-application of TSA. Collectively, these findings provide strong support that histone acetylation and DNA methylation work in concert to regulate memory consolidation of auditory fear conditioning and associated synaptic plasticity in the LA.     

SynPAnal: Software for Rapid Quantification of the Density and Intensity of Protein Puncta from Fluorescence Microscopy Images of Neurons

Continuous modification of the protein composition at synapses is a driving force for the plastic changes of synaptic strength, and provides the fundamental molecular mechanism of synaptic plasticity and information storage in the brain. Studying synaptic protein turnover is not only important for understanding learning and memory, but also has direct implication for understanding pathological conditions like aging, neurodegenerative diseases, and psychiatric disorders. Proteins involved in synaptic transmission and synaptic plasticity are typically concentrated at synapses of neurons and thus appear as puncta (clusters) in immunofluorescence microscopy images. Quantitative measurement of the changes in puncta density, intensity, and sizes of specific proteins provide valuable information on their function in synaptic transmission, circuit development, synaptic plasticity, and synaptopathy. Unfortunately, puncta quantification is very labor intensive and time consuming. In this article, we describe a software tool designed for the rapid semi-automatic detection and quantification of synaptic protein puncta from 2D immunofluorescence images generated by confocal laser scanning microscopy. The software, dubbed as SynPAnal (for Synaptic Puncta Analysis), streamlines data quantification for puncta density and average intensity, thereby increases data analysis throughput compared to a manual method. SynPAnal is stand-alone software written using the JAVA programming language, and thus is portable and platform-free.     

Nature, nurture and neurology: gene-environment interactions in neurodegenerative disease. FEBS Anniversary Prize Lecture delivered on 27 June 2004 at the 29th FEBS Congress in Warsaw

Neurodegenerative disorders, such as Huntington's, Alzheimer's, and Parkinson's diseases, affect millions of people worldwide and currently there are few effective treatments and no cures for these diseases. Transgenic mice expressing human transgenes for huntingtin, amyloid precursor protein, and other genes associated with familial forms of neurodegenerative disease in humans provide remarkable tools for studying neurodegeneration because they mimic many of the pathological and behavioural features of the human conditions. One of the recurring themes revealed by these various transgenic models is that different diseases may share similar molecular and cellular mechanisms of pathogenesis. Cellular mechanisms known to be disrupted at early stages in multiple neurodegenerative disorders include gene expression, protein interactions (manifesting as pathological protein aggregation and disrupted signaling), synaptic function and plasticity. Recent work in mouse models of Huntington's disease has shown that enriching the environment of transgenic animals delays the onset and slows the progression of Huntington's disease-associated motor and cognitive symptoms. Environmental enrichment is known to induce various molecular and cellular changes in specific brain regions of wild-type animals, including altered gene expression profiles, enhanced neurogenesis and synaptic plasticity. The promising effects of environmental stimulation, demonstrated recently in models of neurodegenerative disease, suggest that therapy based on the principles of environmental enrichment might benefit disease sufferers and provide insight into possible mechanisms of neurodegeneration and subsequent identification of novel therapeutic targets. Here, we review the studies of environmental enrichment relevant to some major neurodegenerative diseases and discuss their research and clinical implications.     

The environment versus genetics in controlling the contribution of MAP kinases to synaptic plasticity

BACKGROUND: A challenge in biomedical research is to design experimental paradigms that reflect a natural setting. Even when freshly isolated tissues are used, they are almost always derived from animals housed in cages that poorly reflect the animal's native environment. This issue is highlighted by studies on brain function, where mice housed in a more natural "enriched environment" display enhanced learning and memory and delayed onset of symptoms of neurodegenerative diseases compared to mice housed conventionally. How the environment mediates its effects on brain function is poorly understood. RESULTS: We show that after exposure of adolescent mice to an "enriched environment," the induction of long-term potentiation (LTP), a form of synaptic plasticity that is thought to contribute to learning and memory, involves a novel signal transduction pathway that is nonfunctional in comparable mice housed conventionally. This environmentally gated signaling pathway, which rescues defective LTP induction in adolescent Ras-GRF knockout mice, consists of NMDA glutamate receptor activation of p38, a MAP kinase that does not contribute to LTP in mice housed conventionally. Interestingly, the same exposure to environmental enrichment does not have this effect in adult mice. CONCLUSIONS: This study reveals a new level of cell signaling control whereby environmental factors gate the efficacy of a specific signaling cascade to control how LTP is induced in adolescent animals. The suppression of this gating mechanism in mature animals represents a new form of age-dependent decline in brain plasticity.     

Tip off the HAT– Epigenetic control of learning and memory by Drosophila Tip60

Disruption of epigenetic gene control mechanisms involving histone acetylation in the brain causes cognitive impairment, a debilitating hallmark of most neurodegenerative disorders. Histone acetylation regulates cognitive gene expression via chromatin packaging control in neurons. Unfortunately, the histone acetyltransferases (HATs) that generate such neural epigenetic signatures and their mechanisms of action remain unclear. Our recent findings provide insight into this question by demonstrating that Tip60 HAT action is critical for morphology and function of the mushroom body (MB), the learning and memory center in the Drosophila brain. We show that Tip60 is robustly produced in MB Kenyon cells and extending axonal lobes and that targeted MB Tip60 HAT loss results in axonal outgrowth disruption. Functional consequences of loss and gain of Tip60 HAT levels in the MB are evidenced by defects in memory. Tip60 ChIP-Seq analysis reveals enrichment for genes that function in cognitive processes and accordingly, key genes representing these pathways are misregulated in the Tip60 HAT mutant fly brain. Remarkably, increasing levels of Tip60 in the MB rescues learning and memory deficits resulting from Alzheimer's disease associated amyloid precursor protein (APP) induced neurodegeneration. Our studies highlight the potential of HAT activators as a therapeutic option for cognitive disorders.     

Tip off the HAT– Epigenetic control of learning and memory by Drosophila Tip60

Disruption of epigenetic gene control mechanisms involving histone acetylation in the brain causes cognitive impairment, a debilitating hallmark of most neurodegenerative disorders. Histone acetylation regulates cognitive gene expression via chromatin packaging control in neurons. Unfortunately, the histone acetyltransferases (HATs) that generate such neural epigenetic signatures and their mechanisms of action remain unclear. Our recent findings provide insight into this question by demonstrating that Tip60 HAT action is critical for morphology and function of the mushroom body (MB), the learning and memory center in the Drosophila brain. We show that Tip60 is robustly produced in MB Kenyon cells and extending axonal lobes and that targeted MB Tip60 HAT loss results in axonal outgrowth disruption. Functional consequences of loss and gain of Tip60 HAT levels in the MB are evidenced by defects in memory. Tip60 ChIP-Seq analysis reveals enrichment for genes that function in cognitive processes and accordingly, key genes representing these pathways are misregulated in the Tip60 HAT mutant fly brain. Remarkably, increasing levels of Tip60 in the MB rescues learning and memory deficits resulting from Alzheimer''s disease associated amyloid precursor protein (APP) induced neurodegeneration. Our studies highlight the potential of HAT activators as a therapeutic option for cognitive disorders.     

Failure of Long-Term Memory Formation in Juvenile Snails Is Determined by Acetylation Status of Histone H3 and Can Be Improved by NaB Treatment

Background

Animals’ capacities for different forms of learning do not mature simultaneously during ontogenesis but the molecular mechanisms behind the delayed development of specific types of memory are not fully understood. Mollusks are considered to be among the best models to study memory formation at the molecular level. Chromatin remodeling in developmental processes, as well as in long-term memory formation, was recently shown to play a major role. Histone acetylation is a key process in the chromatin remodeling and is regulated through the signaling cascades, for example MAPK/ERK. Previously, we found that MAPK/ERK is a key pathway in the formation of the food aversion reflex in Helix. Pretreatment with upstream ERK kinase inhibitor PD98059 prevented food avoidance learning in adult Helix. In contrast to adult snails, juveniles possess immature plasticity mechanisms of the avoidance reflex until the age of 2–3 months while the MAPK/ERK cascade is not activated after aversive learning. In the present study, we focused on the potential MAPK/ERK target - histone H3.

Methodology/Principal Findings

Here we found that a significant increase in histone H3 acetylation occurs in adult animals after learning, whereas no corresponding increase was observed in juveniles. The acetylation of histone H3 is regulated by ERK kinase, since the upstream ERK kinase inhibitor PD98059 prevented the increase of histone H3 acetylation upon learning. We found that the injection of histone deacetylase inhibitor sodium butyrate (NaB) prior to training led to induction in histone H3 acetylation and significantly ameliorated long-term memory formation in juvenile snails.

Conclusions/Significance

Thus, MAPK/ERK-dependent histone H3 acetylation plays an essential role in the formation of food aversion in Helix. Dysfunction of the MAPK/ERK dependent histone H3 acetylation might determine the deficiency of avoidance behavior and long-term plasticity in juvenile animals. Stimulation of histone H3 acetylation in juvenile animals by NaB promoted avoidance plasticity.     

SRC3 acetylates calmodulin in the mouse brain to regulate synaptic plasticity and fear learning

Protein acetylation is a reversible posttranslational modification, which is regulated by lysine acetyltransferase (KAT) and lysine deacetyltransferase (KDAC). Although protein acetylation has been shown to regulate synaptic plasticity, this was mainly for histone protein acetylation. The function and regulation of nonhistone protein acetylation in synaptic plasticity and learning remain largely unknown. Calmodulin (CaM), a ubiquitous Ca²⁺ sensor, plays critical roles in synaptic plasticity such as long-term potentiation (LTP). During LTP induction, activation of NMDA receptor triggers Ca²⁺ influx, and the Ca²⁺ binds with CaM and activates calcium/calmodulin-dependent protein kinase IIα (CaMKIIα). In our previous study, we demonstrated that acetylation of CaM was important for synaptic plasticity and fear learning in mice. However, the KAT responsible for CaM acetylation is currently unknown. Here, following an HEK293 cell-based screen of candidate KATs, steroid receptor coactivator 3 (SRC3) is identified as the most active KAT for CaM. We further demonstrate that SRC3 interacts with and acetylates CaM in a Ca²⁺ and NMDA receptor-dependent manner. We also show that pharmacological inhibition or genetic downregulation of SRC3 impairs CaM acetylation, synaptic plasticity, and contextual fear learning in mice. Moreover, the effects of SRC3 inhibition on synaptic plasticity and fear learning could be rescued by 3KQ-CaM, a mutant form of CaM, which mimics acetylation. Together, these observations demonstrate that SRC3 acetylates CaM and regulates synaptic plasticity and learning in mice.     

Increased neuronal excitability, synaptic plasticity, and learning in aged Kvbeta1.1 knockout mice

BACKGROUND: Advancing age is typically accompanied by deficits in learning and memory. These deficits occur independently of overt pathology and are often considered to be a part of "normal aging." At the neuronal level, normal aging is known to be associated with numerous cellular and molecular changes, which include a pronounced decrease in neuronal excitability and an altered induction in the threshold for synaptic plasticity. Because both of these mechanisms (neuronal excitability and synaptic plasticity) have been implicated as putative cellular substrates for learning and memory, it is reasonable to propose that age-related changes in these mechanisms may contribute to the general cognitive decline that occurs during aging. RESULTS: To further investigate the relationship between aging, learning and memory, neuronal excitability, and synaptic plasticity, we have carried out experiments with aged mice that lack the auxiliary potassium channel subunit Kvbeta1.1. In aged mice, the deletion of the auxiliary potassium channel subunit Kvbeta1.1 resulted in increased neuronal excitability, as measured by a decrease in the post-burst afterhyperpolarization. In addition, long-term potentiation (LTP) was more readily induced in aged Kvbeta1.1 knockout mice. Finally, the aged Kvbeta1.1 mutants outperformed age-matched controls in the hidden-platform version of the Morris water maze. Interestingly, the enhancements in excitability and learning were both sensitive to genetic background: The enhanced learning was only observed in a genetic background in which the mutants exhibited increased neuronal excitability. CONCLUSIONS: Neuronal excitability is an important determinant of both synaptic plasticity and learning in aged subjects.