Loss of Function in the Neurodevelopmental Disease and Schizophrenia-Associated Gene CYFIP1 in Human Microglia-like Cells Supports a Functional Role in Synaptic Engulfment.

Background: The CYFIP1 gene, located in the neurodevelopmental risk locus 15q11.2, is highly expressed in microglia, but its role in human microglial function as it relates to neurodevelopment is not well understood.

Methods: We generated multiple CRISPR (clustered regularly interspaced short palindromic repeat) knockouts of CYFIP1 in patient-derived models of microglia to characterize function and phenotype.

Microglial WNT5A supports dendritic spines maturation and neuronal firing.

There is increasing evidence showing that microglia play a critical role in mediating synapse formation and spine growth, although the molecular mechanism remains elusive. Here, we demonstrate that the secreted morphogen WNT family member 5A (WNT5A) is the most abundant WNT expressed in microglia and that it promotes neuronal maturation. Co-culture of microglia with Thy1-YFP differentiated neurons significantly increased neuronal spine density and reduced dendritic spine turnover rate, which was diminished by silencing microglial Wnt5a in vitro.

Inhibition of colony stimulating factor 1 receptor corrects maternal inflammation-induced microglial and synaptic dysfunction and behavioral abnormalities.

Maternal immune activation (MIA) disrupts the central innate immune system during a critical neurodevelopmental period. Microglia are primary innate immune cells in the brain although their direct influence on the MIA phenotype is largely unknown. Here we show that MIA alters microglial gene expression with upregulation of cellular protrusion/neuritogenic pathways, concurrently causing repetitive behavior, social deficits, and synaptic dysfunction to layer V intrinsically bursting pyramidal neurons in the prefrontal cortex of mice.

Transcriptional and Epigenetic Regulation of Microglia in Health and Disease.

Microglia are the resident immune cells that maintain brain homeostasis and contribute to neurodegenerative disorders. Recent studies of microglia at transcriptomic and epigenetic levels revealed specific molecular pathways that regulate microglia development, maturation, and reactive states. The transcription factor PU.

Small Molecules Efficiently Reprogram Human Astroglial Cells into Functional Neurons.

We have recently demonstrated that reactive glial cells can be directly reprogrammed into functional neurons by a single neural transcription factor, NeuroD1. Here we report that a combination of small molecules can also reprogram human astrocytes in culture into fully functional neurons. We demonstrate that sequential exposure of human astrocytes to a cocktail of nine small molecules that inhibit glial but activate neuronal signaling pathways can successfully reprogram astrocytes into neurons in 8-10 days.