Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling.

Astrocytes and microglia are emerging key regulators of activity-dependent synapse remodeling that engulf and remove synapses in response to changes in neural activity. Yet, the degree to which these cells communicate to coordinate this process remains an open question. Here, we use whisker removal in postnatal mice to induce activity-dependent synapse removal in the barrel cortex.

Vascular Dysfunction in Alzheimer's Disease: Alterations in the Plasma Contact and Fibrinolytic Systems.

Alzheimer's disease (AD) is the most common neurodegenerative disease, affecting millions of people worldwide. The classical hallmarks of AD include extracellular beta-amyloid (Aβ) plaques and neurofibrillary tau tangles, although they are often accompanied by various vascular defects. These changes include damage to the vasculature, a decrease in cerebral blood flow, and accumulation of Aβ along vessels, among others.

The contact activation system and vascular factors as alternative targets for Alzheimer's disease therapy.

Alzheimer's disease (AD) is the most common neurodegenerative disease, affecting millions of people worldwide. Extracellular beta-amyloid (Aβ) plaques and neurofibrillary tau tangles are classical hallmarks of AD pathology and thus are the prime targets for AD therapeutics. However, approaches to slow or stop AD progression and dementia by reducing Aβ production, neutralizing toxic Aβ aggregates, or inhibiting tau aggregation have been largely unsuccessful in clinical trials.

Negative feedback control of neuronal activity by microglia.

Microglia, the brain's resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival. Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures.

CSF-1 controls cerebellar microglia and is required for motor function and social interaction.

Microglia, the brain resident macrophages, critically shape forebrain neuronal circuits. However, their precise function in the cerebellum is unknown. Here we show that human and mouse cerebellar microglia express a unique molecular program distinct from forebrain microglia.

Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling.

Microglia rapidly respond to changes in neural activity and inflammation to regulate synaptic connectivity. The extracellular signals, particularly neuron-derived molecules, that drive these microglial functions at synapses remain a key open question. Here we show that whisker lesioning, known to dampen cortical activity, induces microglia-mediated synapse elimination.

Epigenetic regulation of brain region-specific microglia clearance activity.

The rapid elimination of dying neurons and nonfunctional synapses in the brain is carried out by microglia, the resident myeloid cells of the brain. Here we show that microglia clearance activity in the adult brain is regionally regulated and depends on the rate of neuronal attrition. Cerebellar, but not striatal or cortical, microglia exhibited high levels of basal clearance activity, which correlated with an elevated degree of cerebellar neuronal attrition.

Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration.

Normal brain function depends on the interaction between highly specialized neurons that operate within anatomically and functionally distinct brain regions. Neuronal specification is driven by transcriptional programs that are established during early neuronal development and remain in place in the adult brain. The fidelity of neuronal specification depends on the robustness of the transcriptional program that supports the neuron type-specific gene expression patterns.

Autism-like syndrome is induced by pharmacological suppression of BET proteins in young mice.

Studies investigating the causes of autism spectrum disorder (ASD) point to genetic, as well as epigenetic, mechanisms of the disease. Identification of epigenetic processes that contribute to ASD development and progression is of major importance and may lead to the development of novel therapeutic strategies. Here, we identify the bromodomain and extraterminal domain-containing proteins (BETs) as epigenetic regulators of genes involved in ASD-like behaviors in mice.

Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation.

Induction of histone acetylation in the nucleus accumbens (NAc), a key brain reward region, promotes cocaine-induced alterations in gene expression. Histone deacetylases (HDACs) tightly regulate the acetylation of histone tails, but little is known about the functional specificity of different HDAC isoforms in the development and maintenance of cocaine-induced plasticity, and previous studies of HDAC inhibitors report conflicting effects on cocaine-elicited behavioral adaptations. Here we demonstrate that specific and prolonged blockade of HDAC1 in NAc of mice increased global levels of histone acetylation, but also induced repressive histone methylation and antagonized cocaine-induced changes in behavior, an effect mediated in part through a chromatin-mediated suppression of GABAA receptor subunit expression and inhibitory tone on NAc neurons.