Phosphatidylinositol 4-kinase IIα is a glycogen synthase kinase 3-regulated interaction hub for activity-dependent bulk endocytosis.

Phosphatidylinositol 4-kinase IIα (PI4KIIα) generates essential phospholipids and is a cargo for endosomal adaptor proteins. Activity-dependent bulk endocytosis (ADBE) is the dominant synaptic vesicle endocytosis mode during high neuronal activity and is sustained by glycogen synthase kinase 3β (GSK3β) activity. We reveal the GSK3β substrate PI4KIIα is essential for ADBE via its depletion in primary neuronal cultures.

Fast, precise and cloning-free knock-in of reporter sequences in vivo with high efficiency.

Targeted knock-in of fluorescent reporters enables powerful gene and protein analyses in a physiological context. However, precise integration of long sequences remains challenging in vivo. Here, we demonstrate cloning-free and precise reporter knock-in into zebrafish genes, using PCR-generated templates for homology-directed repair with short homology arms (PCR tagging).

Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration.

Despite advances in uncovering the mechanisms that underlie neuroinflammation and neurodegenerative disease, therapies that prevent neuronal loss remain elusive. Targeting of disease-defining markers in conditions such as Alzheimer disease (amyloid-β and tau) or Parkinson disease (α-synuclein) has been met with limited success, suggesting that these proteins do not act in isolation but form part of a pathological network. This network could involve phenotypic alteration of multiple cell types in the CNS, including astrocytes, which have a major neurosupportive, homeostatic role in the healthy CNS but adopt reactive states under acute or chronic adverse conditions.

Multiscale model of primary motor cortex circuits predicts in vivo cell-type-specific, behavioral state-dependent dynamics.

Understanding cortical function requires studying multiple scales: molecular, cellular, circuit, and behavioral. We develop a multiscale, biophysically detailed model of mouse primary motor cortex (M1) with over 10,000 neurons and 30 million synapses. Neuron types, densities, spatial distributions, morphologies, biophysics, connectivity, and dendritic synapse locations are constrained by experimental data.

Reversal of memory and autism-related phenotypes in mice via inhibition of .

Tuberous sclerosis complex (TSC) is a rare monogenic disorder co-diagnosed with high rates of autism and is caused by loss of function mutations in the TSC1 or TSC2 genes. A key pathway hyperactivated in TSC is the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which regulates cap-dependent mRNA translation. We previously demonstrated that exaggerated cap-dependent translation leads to autism-related phenotypes and increased mRNA translation and protein expression of Neuroligin 1 (Nlgn1) in mice.

Nodes of Ranvier in health and disease.

Action potential propagation along myelinated axons depends on the geometry of the myelin unit and the division of the underlying axon to specialized domains. The latter include the nodes of Ranvier (NOR), the paranodal junction (PNJ) flanking the nodes, and the adjacent juxtaparanodal region that is located below the compact myelin of the internode. Each of these domains contains a unique composition of axoglial adhesion molecules (CAMs) and cytoskeletal scaffolding proteins, which together direct the placement of specific ion channels at the nodal and juxtaparanodal axolemma.

The phospho-regulated amphiphysin/endophilin interaction is required for synaptic vesicle endocytosis.

The multidomain adaptor protein amphiphysin-1 (Amph1) is an important coordinator of clathrin-mediated endocytosis in non-neuronal cells and synaptic vesicle (SV) endocytosis at central nerve terminals. Amph1 contains a lipid-binding N-BAR (Bin/Amphiphysin/Rvs) domain, central proline-rich (PRD) and clathrin/AP2 (CLAP) domains, and a C-terminal SH3 domain. Amph1 interacts with both lipids and proteins, with all of these interactions required for SV endocytosis, with the exception of the Amph1 PRD.

Presynaptic targeting of botulinum neurotoxin type A requires a tripartite PSG-Syt1-SV2 plasma membrane nanocluster for synaptic vesicle entry.

The unique nerve terminal targeting of botulinum neurotoxin type A (BoNT/A) is due to its capacity to bind two receptors on the neuronal plasma membrane: polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2). Whether and how PSGs and SV2 may coordinate other proteins for BoNT/A recruitment and internalization remains unknown. Here, we demonstrate that the targeted endocytosis of BoNT/A into synaptic vesicles (SVs) requires a tripartite surface nanocluster.

Drug screening in zebrafish larvae reveals inflammation-related modulators of secondary damage after spinal cord injury in mice.

Prolonged inflammation after spinal cord injury is detrimental to recovery. To find pharmacological modulators of the inflammation response, we designed a rapid drug screening paradigm in larval zebrafish followed by testing of hit compounds in a mouse spinal cord injury model. We used reduced linked green fluorescent protein (GFP) reporter gene expression as a read-out for reduced inflammation in a screen of 1081 compounds in larval zebrafish.

Synaptic oligomeric tau in Alzheimer's disease - A potential culprit in the spread of tau pathology through the brain.

In Alzheimer's disease, fibrillar tau pathology accumulates and spreads through the brain and synapses are lost. Evidence from mouse models indicates that tau spreads trans-synaptically from pre- to postsynapses and that oligomeric tau is synaptotoxic, but data on synaptic tau in human brain are scarce. Here we used sub-diffraction-limit microscopy to study synaptic tau accumulation in postmortem temporal and occipital cortices of human Alzheimer's and control donors.

Predictive blood biomarkers and brain changes associated with age-related cognitive decline.

Growing evidence supports the use of plasma levels of tau phosphorylated at threonine 181, amyloid-β, neurofilament light and glial fibrillary acidic protein as promising biomarkers for Alzheimer's disease. While these blood biomarkers are promising for distinguishing people with Alzheimer's disease from healthy controls, their predictive validity for age-related cognitive decline without dementia remains unclear. Further, while tau phosphorylated at threonine 181 is a promising biomarker, the distribution of this phospho-epitope of tau in the brain is unknown.

Mass spectrometric analysis of bioactive conditioned media of bacteria isolated from reptilian gut.

Aim: To determine whether selected gut bacteria of crocodile exhibit antibacterial properties.

Materials & Methods: Two bacteria isolated from gut were used, namely: and . Conditioned media were tested against pathogenic bacteria and metabolites were analyzed using liquid chromatography-mass spectrometry.

Making a good egg: human oocyte health, aging, and in vitro development.

Mammalian eggs (oocytes) are formed during fetal life and establish associations with somatic cells to form primordial follicles that create a store of germ cells (the primordial pool). The size of this pool is influenced by key events during the formation of germ cells and by factors that influence the subsequent activation of follicle growth. These regulatory pathways must ensure that the reserve of oocytes within primordial follicles in humans lasts for up to 50 years, yet only approximately 0.

The effect of thioredoxin-1 in a rat model of traumatic brain injury depending on diurnal variation.

Introduction: Traumatic brain injury (TBI) is a public health concern with limited treatment options because it causes a cascade of side effects that are the leading cause of hospital death. Thioredoxin is an enzyme with neuroprotective properties such as antioxidant, antiapoptotic, immune response modulator, and neurogenic, among others; it has been considered a therapeutic target for treating many disorders.

Methods: The controlled cortical impact (CCI) model was used to assess the effect of recombinant human thioredoxin 1 (rhTrx1) (1 μg/2 μL, intracortical) on rats subjected to TBI at two different times of the light-dark cycle (01:00 and 13:00 h).

Role of cerebellum in sleep-dependent memory processes.

The activities and role of the cerebellum in sleep have, until recently, been largely ignored by both the sleep and cerebellum fields. Human sleep studies often neglect the cerebellum because it is at a position in the skull that is inaccessible to EEG electrodes. Animal neurophysiology sleep studies have focussed mainly on the neocortex, thalamus and the hippocampus.

mRNA Sequencing Reveals Upregulation of Glutathione S-Transferase Genes during Encystation.

Some members of the genus are facultative pathogens typically with a biphasic lifestyle: trophozoites and cysts. is capable of infecting the cornea, resulting in keratitis. The cyst is one of the key components for the persistence of infection.

Current Best Practices for Analysis of Dendritic Spine Morphology and Number in Neurodevelopmental Disorder Research.

Quantitative methods for assessing neural anatomy have rapidly evolved in neuroscience and provide important insights into brain health and function. However, as new techniques develop, it is not always clear when and how each may be used to answer specific scientific questions posed. Dendritic spines, which are often indicative of synapse formation and neural plasticity, have been implicated across many brain regions in neurodevelopmental disorders as a marker for neural changes reflecting neural dysfunction or alterations.

Mid-Adulthood Cognitive Training Improves Performance in a Spatial Task but Does Not Ameliorate Hippocampal Pathology in a Mouse Model of Alzheimer's Disease.

Background: Prior experience in early life has been shown to improve performance in aging and mice with Alzheimer's disease (AD) pathology. However, whether cognitive training at a later life stage would benefit subsequent cognition and reduce pathology in AD mice needs to be better understood.

Objective: This study aimed to verify if behavioral training in mid-adulthood would improve subsequent cognition and reduce AD pathology and astrogliosis.

Astrocyte-neuron subproteomes and obsessive-compulsive disorder mechanisms.

Astrocytes and neurons extensively interact in the brain. Identifying astrocyte and neuron proteomes is essential for elucidating the protein networks that dictate their respective contributions to physiology and disease. Here we used cell-specific and subcompartment-specific proximity-dependent biotinylation to study the proteomes of striatal astrocytes and neurons in vivo.

The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome.

Background: Fragile X syndrome (FXS), the most common inherited intellectual disability, is caused by the loss of expression of the Fragile X Messenger Ribonucleoprotein (FMRP). FMRP is an RNA-binding protein that negatively regulates the expression of many postsynaptic as well as presynaptic proteins involved in action potential properties, calcium homeostasis and neurotransmitter release. FXS patients and mice lacking FMRP suffer from multiple behavioral alterations, including deficits in motor learning for which there is currently no specific treatment.

Astrocytes mediate cell non-autonomous correction of aberrant firing in human FXS neurons.

Pre-clinical studies of fragile X syndrome (FXS) have focused on neurons, with the role of glia remaining largely underexplored. We examined the astrocytic regulation of aberrant firing of FXS neurons derived from human pluripotent stem cells. Human FXS cortical neurons, co-cultured with human FXS astrocytes, fired frequent short-duration spontaneous bursts of action potentials compared with less frequent, longer-duration bursts of control neurons co-cultured with control astrocytes.

Evolution and immunopathology of chikungunya virus informs therapeutic development.

Chikungunya virus (CHIKV), a mosquito-borne alphavirus, is an emerging global threat identified in more than 60 countries across continents. The risk of CHIKV transmission is rising due to increased global interactions, year-round presence of mosquito vectors, and the ability of CHIKV to produce high host viral loads and undergo mutation. Although CHIKV disease is rarely fatal, it can progress to a chronic stage, during which patients experience severe debilitating arthritis that can last from several weeks to months or years.

Origin and Emergence of Microglia in the CNS-An Interesting (Hi)story of an Eccentric Cell.

Microglia belong to tissue-resident macrophages of the central nervous system (CNS), representing the primary innate immune cells. This cell type constitutes ~7% of non-neuronal cells in the mammalian brain and has a variety of biological roles integral to homeostasis and pathophysiology from the late embryonic to adult brain. Its unique identity that distinguishes its "glial" features from tissue-resident macrophages resides in the fact that once entering the CNS, it is perennially exposed to a unique environment following the formation of the blood-brain barrier.