Comparing the Characteristics of Microglia Preparations Generated Using Different Human iPSC-Based Differentiation Methods to Model Neurodegenerative Diseases

As the resident immune cells of the healthy nervous system, homeostatic microglia can rapidly become activated in response to injury/disease. Dysregulated microglia activation is a hallmark of nervous system disorders including neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. The elucidation of the biological and pathological roles of microglia has recently benefitted from the development of microglia-like cells using human induced pluripotent stem cell (iPSC)-based approaches. The success of iPSC-derived microglia preparations as a disease-relevant model system depends on their representation of the in vivo spatial and temporal heterogeneity of microglia under pathological conditions. Little is currently known about the potential of human iPSC-derived microglia generated using different methods for the study of neurodegenerative diseases. We compared the transcriptomes of human iPSC-derived microglia generated using two frequently used in vitro differentiation methods to determine whether separate strategies can generate microglia with distinct transcriptional signatures in vitro . We show that microglia derived using different differentiation methods display distinct maturation characteristics after equivalent times in culture. We also reveal that iPSC-derived microglia preparations generated using these two methods are composed of different subpopulations with transcriptomic signatures resembling those of in vivo regionally distinct microglia subtypes, specifically white-matter and gray-matter microglia. These findings highlight the need to better characterize the subtype composition of each microglia preparation prior to its use to model neurodegenerative diseases

Evidence of calcium-permeable AMPA receptors in dendritic spines of CA1 pyramidal neurons

Overall view, frontal view; Marble head of Apollo. Roman, about AD 120-140. Found in Rome, formerly in Giustiniani Palace. This work probably copies a lost Hellenistic Greek bronze prototype. The effete features and extravagant hairstyle recall the Apollo Belvedere in the Vatican, Rome. Formerly in the collection of James Pourtalès (Comte James-Alexandre de Pourtalès-Gorgier). Source: British Museum [website]; http://www.britishmuseum.org (accessed 6/14/2009

Visual deficits in a mouse model of Fetal alcohol spectrum disorders

Alcohol consumption during pregnancy can lead to a multitude of neurological problems in offspring, varying from subtle behavioral changes to severe mental retardation. These alterations are collectively referred to as Fetal Alcohol Spectrum Disorders (FASD). Early alcohol exposure can strongly affect the visual system and children with FASD can exhibit an amblyopia-like pattern of visual acuity deficits even in the absence of optical and oculormotor disruption.Here we test whether early alcohol exposure can lead to a disruption in visual acuity, using a model of FASD to mimic alcohol consumption in the last months of human gestation. To accomplish this, mice were exposed to ethanol (5g/kg i.p) or saline on postnatal days (P) 5, 7 and 9. Two to three weeks later we recorded visually evoked potentials (VEPs) to assess spatial frequency detection and contrast sensitivity, conducted electroretinography (ERGs) to further assess visual function and imaged retinotopy using optical imaging of intrinsic signals. We observed that animals exposed to ethanol displayed spatial frequency acuity curves similar to controls. However, ethanol-treated animals showed a significant deficit in contrast sensitivity. Moreover, ERGs revealed a market decrease in both a- and b- waves amplitudes, and optical imaging suggest that both elevation and azimuth maps in ethanol-treated animals have a 10-20o greater map tilt compared to saline-treated controls. Overall, our findings suggest that binge alcohol drinking restricted to the last months of gestation in humans can lead to marked deficits in visual function

Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin

Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic adhesions. An isoform code determines the direct interactions of neurexins and neuroligins across the synapse. However, whether extracellular linker proteins can expand such a code is unknown. Using a combination of in vitro and in vivo approaches, we found that hevin, an astrocyte-secreted synaptogenic protein, assembles glutamatergic synapses by bridging neurexin-1alpha and neuroligin-1B, two isoforms that do not interact with each other. Bridging of neurexin-1alpha and neuroligin-1B via hevin is critical for the formation and plasticity of thalamocortical connections in the developing visual cortex. These results show that astrocytes promote the formation of synapses by modulating neurexin/neuroligin adhesions through hevin secretion. Our findings also provide an important mechanistic insight into how mutations in these genes may lead to circuit dysfunction in diseases such as autism