Development of an compound screening system that replicate the spine phenotype of idiopathic ASD model mice.

Autism Spectrum Disorder (ASD) is a developmental condition characterized by core symptoms including social difficulties, repetitive behaviors, and sensory abnormalities. Aberrant morphology of dendritic spines within the cortex has been documented in genetic disorders associated with ASD and ASD-like traits. We hypothesized that compounds that ameliorate abnormalities in spine dynamics might have the potential to ameliorate core symptoms of ASD.

Microglia induce auditory dysfunction after status epilepticus in mice.

Auditory dysfunction and increased neuronal activity in the auditory pathways have been reported in patients with temporal lobe epilepsy, but the cellular mechanisms involved are unknown. Here, we report that microglia play a role in the disinhibition of auditory pathways after status epilepticus in mice. We found that neuronal activity in the auditory pathways, including the primary auditory cortex and the medial geniculate body (MGB), was increased and auditory discrimination was impaired after status epilepticus.

[Synaptic phagocytosis by multiple glial cell types].

Neurons in the brain build circuits by synapsing with each other, and glial cells are involved in the formation and elimination of synapses. Glial cells include microglia, astrocytes, and oligodendrocytes, each with distinctive functions supported by different gene expression patterns and morphologies, but all have been shown to regulate the number of synapses in the neuronal circuits through a common function, synaptic phagocytosis. It has also been reported that specific glial cell types phagocytose specific synapses in different brain regions and at different times, and some of the molecular mechanisms involved in each phagocytotic process have been elucidated.

Microarray dataset of gene transcription in mouse microglia and peripheral monocytes in contextual fear conditioning.

The transcription profile of microglia related to fear conditioning remains unclear. Here, we used Illumina MouseWG-6v2 microarrays to investigate the gene transcription changes in microglia and peripheral monocytes after contextual fear conditioning of C57BL/6 J mice. Mice were trained with or without a single minimized footshock stimulation (0-s or 2-s, 0.

Microglia states and nomenclature: A field at its crossroads.

Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions.

Microglia and GABA: Diverse functions of microglia beyond GABA-receiving cells.

Neurotransmitters modulate intracellular signaling not only in neurons but also in glial cells such as astrocytes, which form tripartite synapses, and oligodendrocytes, which produce the myelin sheath on axons. Another major glial cell type, microglia, which are often referred to as brain-resident immune cells, also express receptors for neurotransmitters. Recent studies have mainly focused on excitatory neurotransmitters such as glutamate, and few have examined microglial responses to the inhibitory neurotransmitter GABA.

Replacement of Mouse Microglia With Human Induced Pluripotent Stem Cell (hiPSC)-Derived Microglia in Mouse Organotypic Slice Cultures.

Microglia, the major immune cells in the brain, are reported to differ in gene expression patterns among species. Therefore, it would be preferable in some cases to use human microglia rather than mouse microglia in microglia-targeted disease research. In the past half a decade, researchers have developed transplantation methods in which human induced pluripotent stem cell-derived microglia (hiPSC-MG) are transplanted into a living mouse brain.

[Microglial Response to Brain Temperature and Neuronal Circuit Reorganization].

Brain tissue is vulnerable to temperature changes, which are known to affect the structure and function of neural circuits. Owing to their dynamic ramified processes, microglia, which serve as immune cells in the brain, are associated with surveillance of the brain environment and mediate synaptic pruning to reorganize neural circuits. In this section, we discuss the possible role of microglia as temperature sensors in the brain via thermosensitive transient receptor potential channels and their role in reorganization of neural circuits.

Identification of an exporter that regulates vitamin C supply from blood to the brain.

Vitamin C (VC) distribution in our body requires VC transporters. However, mammalian VC exporters are yet to be identified. Herein, to unravel this long-standing mystery, we focused on the pathways whereby VC moves from blood to the brain, which should require a VC entrance and exit system composed of an importer and a latent exporter.

Thermosensitive receptors in neural stem cells link stress-induced hyperthermia to impaired neurogenesis via microglial engulfment.

Social stress impairs hippocampal neurogenesis and causes psychiatric disorders such as depression. Recent studies have highlighted the significance of increased body temperature in stress responses; however, whether and how social stress–induced hyperthermia affects hippocampal neurogenesis remains unknown. Here, using transgenic mice in which the thermosensitive transient receptor potential vanilloid 4 (TRPV4) is conditionally knocked out in Nestin-expressing neural stem cells (NSCs), we found that social defeat stress (SDS)–induced hyperthermia activates TRPV4 in NSCs in the dentate gyrus and thereby impairs hippocampal neurogenesis.

Comparative Review of Microglia and Monocytes in CNS Phagocytosis.

Macrophages maintain tissue homeostasis by phagocytosing and removing unwanted materials such as dead cells and cell debris. Microglia, the resident macrophages of the central nervous system (CNS), are no exception. In addition, a series of recent studies have shown that microglia phagocytose the neuronal synapses that form the basis of neural circuit function.

Extracellular Vesicles Taken up by Astrocytes.

Extracellular vesicles (EVs) are composed of lipid bilayer membranes and contain various molecules, such as mRNA and microRNA (miRNA), that regulate the functions of the recipient cell. Recent studies have reported the importance of EV-mediated intercellular communication in the brain. The brain contains several types of cells, including neurons and glial cells.

Optical manipulation of local cerebral blood flow in the deep brain of freely moving mice.

An artificial tool for manipulating local cerebral blood flow (CBF) is necessary for understanding how CBF controls brain function. Here, we generate vascular optogenetic tools whereby smooth muscle cells and endothelial cells express optical actuators in the brain. The illumination of channelrhodopsin-2 (ChR2)-expressing mice induces a local reduction in CBF.

Phagocytic Glial Cells in Brain Homeostasis.

Phagocytosis by glial cells has been shown to play an important role in maintaining brain homeostasis. Microglia are currently considered to be the major phagocytes in the brain parenchyma, and these cells phagocytose a variety of materials, including dead cell debris, abnormally aggregated proteins, and, interestingly, the functional synapses of living neurons. The intracellular signaling mechanisms that regulate microglial phagocytosis have been studied extensively, and several important factors, including molecules known as "find me" signals and "eat me" signals and receptors on microglia that are involved in phagocytosis, have been identified.

Assessing Microglial Dynamics by Live Imaging.

Microglia are highly dynamic in the brain in terms of their ability to migrate, proliferate, and phagocytose over the course of an individual's life. Real-time imaging is a useful tool to examine how microglial behavior is regulated and how it affects the surrounding environment. However, microglia are sensitive to environmental stimuli, so they possibly change their state during live imaging , mainly due to surgical damage, and due to various effects associated with culture conditions.

Highly active neurons emerging in vitro.

Mean firing rates vary across neurons in a neuronal network. Although most neurons infrequently emit spikes, a small fraction of neurons exhibit extremely high frequencies of spikes; this fraction of neurons plays a pivotal role in information processing, however, little is known about how these outliers emerge and whether they are maintained over time. In primary cultures of mouse hippocampal neurons, we traced highly active neurons every 24 h for 7 wk by optically observing the fluorescent protein dVenus; the expression of dVenus was controlled by the promoter of , an immediate early gene that is induced by neuronal activity.

Microglia regulate synaptic development and plasticity.

Synapses are fundamental structures of neural circuits that transmit information between neurons. Thus, the process of neural circuit formation via proper synaptic connections shapes the basis of brain functions and animal behavior. Synapses continuously undergo repeated formation and elimination throughout the lifetime of an organism, reflecting the dynamics of neural circuit function.

Astrocytic cAMP modulates memory via synaptic plasticity.

Astrocytes play a key role in brain homeostasis and functions such as memory. Specifically, astrocytes express multiple receptors that transduce signals via the second messenger cAMP. However, the involvement of astrocytic cAMP in animal behavior and the underlying glial-neuronal interactions remains largely unknown.

Pro- and anti-epileptic roles of microglia.

Microglia are brain-resident immune cells that contribute to the maintenance of brain homeostasis. In the epileptic brain, microglia show various activation phenotypes depending on the stage of epileptogenesis. Therefore, it remains unclear whether microglial activation acts in a pro-epileptic or anti-epileptic manner.

Neuronal brain-derived neurotrophic factor manipulates microglial dynamics.

Brain-derived neurotrophic factor (BDNF), a main member of the neurotrophin family that is active in the brain, supports neuronal survival and growth. Microglial BDNF affects both the structural and functional properties of neurons. In contrast, whether and how neuronal BDNF affects microglial dynamics remain largely undetermined.

Microglia modulate the structure and function of the hippocampus after early-life seizures.

The hippocampus is a brain region well-known to exhibit structural and functional changes in temporal lobe epilepsy. Studies analyzing the brains of patients with epilepsy and those from animal models of epilepsy have revealed that microglia are excessively activated, especially in the hippocampus. These findings suggest that microglia may contribute to the onset and aggravation of epilepsy; however, direct evidence for microglial involvement or the underlying mechanisms by which this occurs remain to be fully discovered.

The effects of microglia- and astrocyte-derived factors on neurogenesis in health and disease.

Hippocampal neurogenesis continues throughout life and has been suggested to play an essential role in maintaining spatial cognitive function under physiological conditions. An increasing amount of evidence has indicated that adult neurogenesis is tightly controlled by environmental conditions in the neurogenic niche, which consists of multiple types of cells including microglia and astrocytes. Microglia maintain the environment of neurogenic niche through their phagocytic capacity and interaction with neurons via fractalkine-CX3CR1 signaling.