Activity

Microglia are important for central nervous system (CNS) homeostasis and first to respond to tissue damage and perturbations. Microglia are heterogeneous cells; in case of pathology, microglia adopt a range of phenotypes with altered functions. However, how these different microglia subtypes are implicated in CNS disease is largely unresolved. NEO2734 Multiple sclerosis (MS) is a chronic demyelinating disease of the CNS, characterized by inflammation and axonal degeneration, ultimately leading to neurological decline. One way microglia are implicated in MS is through stimulation of remyelination. They facilitate efficient remyelination by phagocytosis of myelin debris. In addition, microglia recruit oligodendrocyte precursor cells (OPCs) to demyelinated areas and stimulate remyelination. The development of high-resolution technologies to profile individual cells has greatly contributed to our understanding of microglia heterogeneity and function under normal and pathological conditions. Gene expression profiling technologies have evolved from whole tissue RNA sequencing toward single-cell or nucleus sequencing. Single microglia proteomic profiles are also increasingly generated, offering another layer of high-resolution data. Here, we will review recent studies that have employed these technologies in the context of MS and their respective advantages and disadvantages. Moreover, recent developments that allow for (single) cell profiling while retaining spatial information and tissue context will be discussed.In mammals, the sensory experience can regulate the development of various brain structures, including the cortex, hippocampus, retina, and olfactory bulb (OB). Odor experience-evoked neural activity drives the development of dendrites on excitatory projection neurons in the OB, such as mitral and tufted cells, as well as inhibitory interneurons. OB interneurons are generated continuously in the subventricular zone and differentiate into granule cells (GCs) and periglomerular cells (PGCs). However, it remains unknown what role each type of OB interneuron plays in controlling olfactory behaviors. Recent studies showed that among the various types of OB interneurons, a subtype of GCs expressing oncofetal trophoblast glycoprotein 5T4 is required for simple odor detection and discrimination behaviors. Mouse 5T4 (also known as Tpbg) is a type I membrane glycoprotein whose extracellular domain contains seven leucine-rich repeats (LRRs) sandwiched between characteristic LRR-N and LRR-C regions. Recently, it was found that the developmental expression of 5T4 increases dramatically in the retina just before eye-opening. Single-cell transcriptomics further suggests that 5T4 is involved in the development and maintenance of functional synapses in a subset of retinal interneurons, including rod bipolar cells (RBCs) and amacrine cells (ACs). Collectively, 5T4, expressed in interneurons of the OB and retina, plays a key role in sensory processing in the olfactory and visual systems.The cytoplasmic fragile X mental retardation 1 (FMR1)-interacting protein 2 (CYFIP2) gene is associated with epilepsy, intellectual disability (ID), and developmental delay, suggesting its critical role in proper neuronal development and function. CYFIP2 is involved in regulating cellular actin dynamics and also interacts with RNA-binding proteins. However, the adult brain function of CYFIP2 remains unclear because investigations thus far are limited to Cyfip2 heterozygous (Cyfip2+/- ) mice owing to the perinatal lethality of Cyfip2-null mice. Therefore, we generated Cyfip2 conditional knock-out (cKO) mice with reduced CYFIP2 expression in postnatal forebrain excitatory neurons (CaMKIIα-Cre). We found that in the medial prefrontal cortex (mPFC) of adult Cyfip2 cKO mice, CYFIP2 expression was decreased in both layer 2/3 (L2/3) and layer 5 (L5) neurons, unlike the L5-specific CYFIP2 reduction observed in adult Cyfip2+/- mice. Nevertheless, filamentous actin (F-actin) levels were increased only in L5 of Cyfip2 cKO mPFC possibly because of a compensatory increase in CYFIP1, the other member of CYFIP family, in L2/3 neurons. Abnormal dendritic spines on basal, but not on apical, dendrites were consistently observed in L5 neurons of Cyfip2 cKO mPFC. Meanwhile, neuronal excitability and activity were enhanced in both L2/3 and L5 neurons of Cyfip2 cKO mPFC, suggesting that CYFIP2 functions of regulating F-actin and excitability/activity may be mediated through independent mechanisms. Unexpectedly, adult Cyfip2 cKO mice did not display locomotor hyperactivity or reduced anxiety observed in Cyfip2+/- mice. Instead, both exhibited enhanced social dominance accessed by the tube test. Together, these results provide additional insights into the functions of CYFIP2 in the adult brain.The development of methods for the activity-dependent tagging of neurons enabled a new way to tackle the problem of engram identification at the cellular level, giving rise to groundbreaking findings in the field of memory studies. However, the resolution of activity-dependent tagging remains limited to the whole-cell level. Notably, events taking place at the synapse level play a critical role in the establishment of new memories, and strong experimental evidence shows that learning and synaptic plasticity are tightly linked. Here, we provide a comprehensive review of the currently available techniques that enable to identify and track the neuronal activity with synaptic spatial resolution. We also present recent technologies that allow to selectively interfere with specific subsets of synapses. Lastly, we discuss how these technologies can be applied to the study of learning and memory.Hyperphosphorylated Tau protein is the main component of the neurofibrillary tangles, characterizing degenerating neurons in Alzheimer’s disease and other Tauopathies. Expression of human Tau protein in Drosophila CNS results in increased toxicity, premature mortality and learning and memory deficits. Herein we use novel transgenic lines to investigate the contribution of specific phosphorylation sites previously implicated in Tau toxicity. These three different sites, Ser238, Thr245, and Ser262 were tested either by blocking their phosphorylation, by Ser/Thr to Ala substitution, or pseudophosphorylation, by changing Ser/Thr to Glu. We validate the hypothesis that phosphorylation at Ser262 is necessary for Tau-dependent learning deficits and a “facilitatory gatekeeper” to Ser238 occupation, which is linked to Tau toxicity. Importantly we reveal that phosphorylation at Thr245 acts as a “suppressive gatekeeper”, preventing phosphorylation of many sites including Ser262 and consequently of Ser238. Therefore, we elucidate novel interactions among phosphosites central to Tau mediated neuronal dysfunction and toxicity, likely driven by phosphorylation-dependent conformational plasticity.