Epigenetic regulation of autophagy in neuroinflammation and synaptic plasticity.

Autophagy is a conserved cellular mechanism that enables the degradation and recycling of cellular organelles and proteins the lysosomal pathway. In neurodevelopment and maintenance of neuronal homeostasis, autophagy is required to regulate presynaptic functions, synapse remodeling, and synaptic plasticity. Deficiency of autophagy has been shown to underlie the synaptic and behavioral deficits of many neurological diseases such as autism, psychiatric diseases, and neurodegenerative disorders.

CPEB3-dependent increase in GluA2 subunits impairs excitatory transmission onto inhibitory interneurons in a mouse model of fragile X.

Fragile X syndrome (FXS) is a leading cause of inherited intellectual disability and autism. Whereas dysregulated RNA translation in Fmr1 knockout (KO) mice, a model of FXS, is well studied, little is known about aberrant transcription. Using single-molecule mRNA detection, we show that mRNA encoding the AMPAR subunit GluA2 (but not GluA1) is elevated in dendrites and at transcription sites of hippocampal neurons of Fmr1 KO mice, indicating elevated GluA2 transcription.

Donor-derived vasculature is required to support neocortical cell grafts after stroke.

Neural precursor cells (NPCs) transplanted into the adult neocortex generate neurons that synaptically integrate with host neurons, supporting the possibility of achieving functional tissue repair. However, poor survival and functional neuronal recovery of transplanted NPCs greatly limits engraftment. Here, we test the hypothesis that combining blood vessel-forming vascular cells with neuronal precursors improves engraftment.

The Role of NF-κB Triggered Inflammation in Cerebral Ischemia.

Cerebral ischemia is a devastating disease that affects many people worldwide every year. The neurodegenerative damage as a consequence of oxygen and energy deprivation, to date, has no known effective treatment. The ischemic insult is followed by an inflammatory response that involves a complex interaction between inflammatory cells and molecules which play a role in the progression towards cell death.

Autophagy and synaptic plasticity: epigenetic regulation.

In neurons, autophagy is crucial to proper axon guidance, vesicular release, dendritic spine architecture, spine pruning and synaptic plasticity and, when dysregulated, is associated with brain disorders, including autism spectrum disorders, and neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Once thought to play a housekeeping function of removing misfolded proteins or compromised organelles, neuronal autophagy is now regarded as a finely tuned, real time surveillance and clearance system crucial to synaptic integrity and function. Here we review the role of autophagy in synaptic plasticity and its regulation by epigenetic mechanisms.

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders.

Altered synaptic structure and function is a major hallmark of fragile X syndrome (FXS), autism spectrum disorders (ASDs), and other intellectual disabilities (IDs), which are therefore classified as synaptopathies. FXS and ASDs, while clinically and genetically distinct, share significant comorbidity, suggesting that there may be a common molecular and/or cellular basis, presumably at the synapse. In this article, we review brain architecture and synaptic pathways that are dysregulated in FXS and ASDs, including spine architecture, signaling in synaptic plasticity, local protein synthesis, (m)RNA modifications, and degradation.

Gadd45b Acts as Neuroprotective Effector in Global Ischemia-Induced Neuronal Death.

Purpose: Transient global ischemia arising in human due to cardiac arrest causes selective, delayed neuronal death in hippocampal CA1 and cognitive impairment. Growth arrest and DNA-damage-inducible protein 45 beta (Gadd45b) is a wellknown molecule in both DNA damage-related pathogenesis and therapies. Emerging evidence suggests that Gadd45b is an anti-apoptotic factor in nonneuronal cells and is an intrinsic neuroprotective molecule in neurons.

Author Correction: The emerging field of epigenetics in neurodegeneration and neuroprotection.

In Box 1 of this article, the positioning of the amino acid residues on the tail of histone H3 in part b of the figure was incorrect. These should have been oriented so that the K4 residue was the most distal labelled residue from the nucleosome core region. The corrected figure is shown below.

Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice.

Fragile X syndrome (FXS) is the most frequent form of heritable intellectual disability and autism. Fragile X (-KO) mice exhibit aberrant dendritic spine structure, synaptic plasticity, and cognition. Autophagy is a catabolic process of programmed degradation and recycling of proteins and cellular components via the lysosomal pathway.

Early uneven ear input induces long-lasting differences in left-right motor function.

How asymmetries in motor behavior become established normally or atypically in mammals remains unclear. An established model for motor asymmetry that is conserved across mammals can be obtained by experimentally inducing asymmetric striatal dopamine activity. However, the factors that can cause motor asymmetries in the absence of experimental manipulations to the brain remain unknown.

REST, a master transcriptional regulator in neurodegenerative disease.

The restrictive element-1 silencing transcription factor)/NRSF (neuron-restrictive silencing factor (NRSF) is a transcriptional repressor which acts via epigenetic remodeling to silence target genes. Emerging evidence indicates that REST is a master transcriptional regulator of neuron-specific genes not only in neurogenesis and neuronal differentiation, but also in differentiated neurons during the critical period in postnatal brain development, where it plays a role in fine-tuning of genes involved in synaptic plasticity, and in normal aging, where it promotes neuroprotection by repressing genes involved in oxidative stress and β-amyloid toxicity. This review focuses on recent findings that dysregulation of REST and REST-dependent epigenetic remodeling provide a central mechanism critical to the progressive neurodegeneration associated with neurologic disorders and diseases including global ischemia, stroke, epilepsy, Alzheimer's and Huntington's disease.

Aberrant Rac1-cofilin signaling mediates defects in dendritic spines, synaptic function, and sensory perception in fragile X syndrome.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and a leading cause of autism. FXS is caused by a trinucleotide expansion in the gene on the X chromosome. The neuroanatomical hallmark of FXS is an overabundance of immature dendritic spines, a factor thought to underlie synaptic dysfunction and impaired cognition.

The emerging field of epigenetics in neurodegeneration and neuroprotection.

Epigenetic mechanisms - including DNA methylation, histone post-translational modifications and changes in nucleosome positioning - regulate gene expression, cellular differentiation and development in almost all tissues, including the brain. In adulthood, changes in the epigenome are crucial for higher cognitive functions such as learning and memory. Striking new evidence implicates the dysregulation of epigenetic mechanisms in neurodegenerative disorders and diseases.

Global ischemia induces lysosomal-mediated degradation of mTOR and activation of autophagy in hippocampal neurons destined to die.

The mammalian target of rapamycin (mTOR) is a key regulator of cell growth, autophagy, translation, and survival. Dysregulation of mTOR signaling is associated with cancer, diabetes, and autism. However, a role for mTOR signaling in neuronal death is not well delineated.

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice.

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and a leading genetic form of autism. The Fmr1 KO mouse, a model of FXS, exhibits elevated translation in the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling regulate protein synthesis by activating downstream targets critical to translation initiation and elongation and are known to contribute to hippocampal defects in fragile X.

Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models.

Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene.

hERG 1a LQT2 C-terminus truncation mutants display hERG 1b-dependent dominant negative mechanisms.

Background: The human ether-à-go-go-related gene (hERG 1a) potassium channel is critical for cardiac repolarization. hERG 1b, another variant subunit, co-assembles with hERG 1a, modulates channel biophysical properties and plays an important role in repolarization. Mutations of hERG 1a lead to type 2 long QT syndrome (LQT2), and increased risk for fatal arrhythmias.

Dysregulation of Mammalian Target of Rapamycin Signaling in Mouse Models of Autism.

The mammalian target of rapamycin (mTOR) is a central regulator of a diverse array of cellular processes, including cell growth, proliferation, autophagy, translation, and actin polymerization. Components of the mTOR cascade are present at synapses and influence synaptic plasticity and spine morphogenesis. A prevailing view is that the study of mTOR and its role in autism spectrum disorders (ASDs) will elucidate the molecular mechanisms by which mTOR regulates neuronal function under physiological and pathological conditions.

Schizophrenia: Evidence implicating hippocampal GluN2B protein and REST epigenetics in psychosis pathophysiology.

The hippocampus is strongly implicated in the psychotic symptoms of schizophrenia. Functionally, basal hippocampal activity (perfusion) is elevated in schizophrenic psychosis, as measured with positron emission tomography (PET) and with magnetic resonance (MR) perfusion techniques, while hippocampal activation to memory tasks is reduced. Subfield-specific hippocampal molecular pathology exists in human psychosis tissue which could underlie this neuronal hyperactivity, including increased GluN2B-containing NMDA receptors in hippocampal CA3, along with increased postsynaptic density protein-95 (PSD-95) along with augmented dendritic spines on the pyramidal neuron apical dendrites.

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels.

Estradiol pretreatment ameliorates impaired synaptic plasticity at synapses of insulted CA1 neurons after transient global ischemia.

Global ischemia in humans or induced experimentally in animals causes selective and delayed neuronal death in pyramidal neurons of the hippocampal CA1. The ovarian hormone estradiol administered before or immediately after insult affords histological protection in experimental models of focal and global ischemia and ameliorates the cognitive deficits associated with ischemic cell death. However, the impact of estradiol on the functional integrity of Schaffer collateral to CA1 (Sch-CA1) pyramidal cell synapses following global ischemia is not clear.

The gene silencing transcription factor REST represses miR-132 expression in hippocampal neurons destined to die.

The gene silencing transcription factor REST [repressor element 1 silencing transcription factor]/NRSF (neuron-restrictive silencer factor) actively represses a large array of coding and noncoding neuron-specific genes important to synaptic plasticity including miR-132. miR-132 is a neuron-specific microRNA and plays a pivotal role in synaptogenesis, synaptic plasticity and structural remodeling. However, a role for miR-132 in neuronal death is not, as yet, well-delineated.

Casein kinase 1 suppresses activation of REST in insulted hippocampal neurons and halts ischemia-induced neuronal death.

Repressor Element-1 (RE1) Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF) is a gene-silencing factor that is widely expressed during embryogenesis and plays a strategic role in neuronal differentiation. Recent studies indicate that REST can be activated in differentiated neurons during a critical window of time in postnatal development and in adult neurons in response to neuronal insults such as seizures and ischemia. However, the mechanism by which REST is regulated in neurons is as yet unknown.

Phosphorylation of Ser1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca2+ signaling in spines.

The NMDA-type glutamate receptor (NMDAR) is essential for synaptogenesis, synaptic plasticity, and higher cognitive function. Emerging evidence indicates that NMDAR Ca(2+) permeability is under the control of cAMP/protein kinase A (PKA) signaling. Whereas the functional impact of PKA on NMDAR-dependent Ca(2+) signaling is well established, the molecular target remains unknown.