Aberrant TSC-Rheb axis in Oxytocin receptor+ cells mediate stress-induced anxiety.

Stress is a major risk for the onset of several maladaptive processes including pathological anxiety, a diffuse state of heightened apprehension over anticipated threats. Pathological anxiety is prevalent in up to 59% of patients with Tuberous Sclerosis complex (TSC), a neurodevelopmental disorder (NDD) caused by loss-of-function mutations in genes for Tuberin () and/or Hamartin () that together comprise the eponymous protein complex. Here, we generated cell type-specific heterozygous knockout of in cells expressing oxytocin receptor (OTRCs) to model pathological anxiety-like behaviors observed in TSC patient population.

The integrated stress response effector GADD34 is repurposed by neurons to promote stimulus-induced translation.

Neuronal protein synthesis is required for long-lasting plasticity and long-term memory consolidation. Dephosphorylation of eukaryotic initiation factor 2α is one of the key translational control events that is required to increase de novo protein synthesis that underlies long-lasting plasticity and memory consolidation. Here, we interrogate the molecular pathways of translational control that are triggered by neuronal stimulation with brain-derived neurotrophic factor (BDNF), which results in eukaryotic initiation factor 2α (eIF2α) dephosphorylation and increases in de novo protein synthesis.

mRNA translation in astrocytes controls hippocampal long-term synaptic plasticity and memory.

Activation of neuronal protein synthesis upon learning is critical for the formation of long-term memory. Here, we report that learning in the contextual fear conditioning paradigm engenders a decrease in eIF2α (eukaryotic translation initiation factor 2) phosphorylation in astrocytes in the hippocampal CA1 region, which promotes protein synthesis. Genetic reduction of eIF2α phosphorylation in hippocampal astrocytes enhanced contextual and spatial memory and lowered the threshold for the induction of long-lasting plasticity by modulating synaptic transmission.

Presynaptic Protein Synthesis in Brain Function and Disease.

Local protein synthesis in mature brain axons regulates the structure and function of presynaptic boutons by adjusting the presynaptic proteome to local demands. This crucial mechanism underlies experience-dependent modifications of brain circuits, and its dysregulation may contribute to brain disorders, such as autism and intellectual disability. Here, we discuss recent advancements in the axonal transcriptome, axonal RNA localization and translation, and the role of presynaptic local translation in synaptic plasticity and memory.

Autism- and epilepsy-associated mutations lead to translational dysfunction and altered actin bundling.

Protein synthesis is a fundamental cellular process in neurons that is essential for synaptic plasticity and memory consolidation. Here, we describe our investigations of a neuron- and muscle-specific translation factor, ukaryotic longation actor (eEF1A2), which when mutated in patients results in autism, epilepsy, and intellectual disability. We characterize three patient mutations, G70S, E122K, and D252H, and demonstrate that all three mutations decrease de novo protein synthesis and elongation rates in HEK293 cells.

Opto4E-BP, an optogenetic tool for inducible, reversible, and cell type-specific inhibition of translation initiation.

The protein kinase mechanistic target of rapamycin complex 1 (mTORC1) is one of the primary triggers for initiating cap-dependent translation. Amongst its functions, mTORC1 phosphorylates eIF4E-binding proteins (4E-BPs), which prevents them from binding to eIF4E and thereby enables translation initiation. mTORC1 signaling is required for multiple forms of protein synthesis-dependent synaptic plasticity and various forms of long-term memory (LTM), including associative threat memory.

Overexpression of the autism candidate gene pathologically enhances olivo-cerebellar signaling in mice.

, the gene encoding cytoplasmic FMR1 interacting protein 1, has been of interest as an autism candidate gene for years. A potential role in autism spectrum disorder (ASD) is suggested by its location on human chromosome 15q11-13, an instable region that gives rise to a variety of copy number variations associated with syndromic autism. In addition, the CYFIP1 protein acts as a binding partner to Fragile X Messenger Ribonucleoprotein (FMRP) in the regulation of translation initiation.

Cell-type-specific disruption of cortico-striatal circuitry drives repetitive patterns of behavior in fragile X syndrome model mice.

Individuals with fragile X syndrome (FXS) are frequently diagnosed with autism spectrum disorder (ASD), including increased risk for restricted and repetitive behaviors (RRBs). Consistent with observations in humans, FXS model mice display distinct RRBs and hyperactivity that are consistent with dysfunctional cortico-striatal circuits, an area relatively unexplored in FXS. Using a multidisciplinary approach, we dissect the contribution of two populations of striatal medium spiny neurons (SPNs) in the expression of RRBs in FXS model mice.

Autism- and epilepsy-associated mutations lead to translational dysfunction and altered actin bundling.

Unlabelled: Protein synthesis is a fundamental cellular process in neurons that is essential for synaptic plasticity and memory consolidation. Here, we describe our investigations of a neuron- and muscle-specific translation factor, e ukaryotic E longation F actor 1a2 (eEF1A2), which when mutated in patients results in autism, epilepsy, and intellectual disability. We characterize three most common patient mutations, G70S, E122K, and D252H, and demonstrate that all three mutations decrease protein synthesis and elongation rates in HEK293 cells.

Altered striatal actin dynamics drives behavioral inflexibility in a mouse model of fragile X syndrome.

The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurodevelopmental disorders (NDDs). Among those is fragile X syndrome (FXS), an NDD caused by the absence of the functional RNA-binding protein FMRP. Here, we demonstrate how the brain region-specific composition of postsynaptic density (PSD) contributes to FXS.

Analysis of microglial BDNF function and expression in the motor cortex.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates several aspects of brain function. Although numerous studies have demonstrated the expression and function of BDNF in neurons, its expression in microglia remains controversial. Using a combination of genetic tools and fluorescence imaging, we analyzed BDNF expression patterns and investigated the effect of microglial deletion on neuronal activity, early-stage spine formation, and microglia-neuron attraction in the motor cortex.

The modulation of emotional and social behaviors by oxytocin signaling in limbic network.

Neuropeptides can exert volume modulation in neuronal networks, which account for a well-calibrated and fine-tuned regulation that depends on the sensory and behavioral contexts. For example, oxytocin (OT) and oxytocin receptor (OTR) trigger a signaling pattern encompassing intracellular cascades, synaptic plasticity, gene expression, and network regulation, that together function to increase the signal-to-noise ratio for sensory-dependent stress/threat and social responses. Activation of OTRs in emotional circuits within the limbic forebrain is necessary to acquire stress/threat responses.

Optical Control of Translation with a Puromycin Photoswitch.

Translation is an elementary cellular process that involves a large number of factors interacting in a concerted fashion with the ribosome. Numerous natural products have emerged that interfere with the ribosomal function, such as puromycin, which mimics an aminoacyl tRNA and causes premature chain termination. Here, we introduce a photoswitchable version of puromycin that, in effect, puts translation under optical control.

Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome.

Background: Fragile X syndrome (FXS), the most common genetic cause of autism spectrum disorder and intellectual disability, is caused by the lack of fragile X mental retardation protein (FMRP) expression. FMRP is an mRNA binding protein with functions in mRNA transport, localization, and translational control. In Fmr1 knockout mice, dysregulated translation has been linked to pathophysiology, including abnormal synaptic function and dendritic morphology, and autistic-like behavioral phenotypes.

Astrocytes derived from ASD individuals alter behavior and destabilize neuronal activity through aberrant Ca signaling.

The cellular mechanisms of autism spectrum disorder (ASD) are poorly understood. Cumulative evidence suggests that abnormal synapse function underlies many features of this disease. Astrocytes regulate several key neuronal processes, including the formation of synapses and the modulation of synaptic plasticity.

Spatiotemporally resolved protein synthesis as a molecular framework for memory consolidation.

De novo protein synthesis is required for long-term memory consolidation. Dynamic regulation of protein synthesis occurs via a complex interplay of translation factors and modulators. Many components of the protein synthesis machinery have been targeted either pharmacologically or genetically to establish its requirement for memory.

eIF2-dependent translation initiation: Memory consolidation and disruption in Alzheimer's disease.

Memory storage is a conserved survivability feature, present in virtually any complex species. During the last few decades, much effort has been devoted to understanding how memories are formed and which molecular switches define whether a memory should be stored for a short or a long period of time. Among these, de novo protein synthesis is known to be required for the conversion of short- to long-term memory.

Age-dependent shift in the de novo proteome accompanies pathogenesis in an Alzheimer's disease mouse model.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with memory loss, but the AD-associated neuropathological changes begin years before memory impairments. Investigation of the early molecular abnormalities in AD might offer innovative opportunities to target memory impairment prior to onset. Decreased protein synthesis plays a fundamental role in AD, yet the consequences of this dysregulation for cellular function remain unknown.

Reciprocal control of translation and transcription in autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and the presence of restricted patterns of interest and repetitive behaviors. ASD is genetically heterogeneous and is believed to be caused by both inheritable and de novo gene variations. Studies have revealed an extremely complex genetic landscape of ASD, favoring the idea that mutations in different clusters of genes interfere with interconnected downstream signaling pathways and circuitry, resulting in aberrant behavior.

Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice.

Loss of the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS). FMRP is widely thought to repress protein synthesis, but its translational targets and modes of control remain in dispute. We previously showed that genetic removal of p70 S6 kinase 1 (S6K1) corrects altered protein synthesis as well as synaptic and behavioral phenotypes in FXS mice.

Cell-type-specific disruption of PERK-eIF2α signaling in dopaminergic neurons alters motor and cognitive function.

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) has been shown to activate the eIF2α kinase PERK to directly regulate translation initiation. Tight control of PERK-eIF2α signaling has been shown to be necessary for normal long-lasting synaptic plasticity and cognitive function, including memory. In contrast, chronic activation of PERK-eIF2α signaling has been shown to contribute to pathophysiology, including memory impairments, associated with multiple neurological diseases, making this pathway an attractive therapeutic target.