Astrocytic β-catenin signaling via TCF7L2 regulates synapse development and social behavior.

The Wnt/β-catenin pathway contains multiple high-confidence risk genes that are linked to neurodevelopmental disorders, including autism spectrum disorder. However, its ubiquitous roles across brain cell types and developmental stages have made it challenging to define its impact on neural circuit development and behavior. Here, we show that TCF7L2, which is a key transcriptional effector of the Wnt/β-catenin pathway, plays a cell-autonomous role in postnatal astrocyte maturation and impacts adult social behavior.

Microglial pattern recognition via IL-33 promotes synaptic refinement in developing corticothalamic circuits in mice.

Microglia are critical regulators of brain development that engulf synaptic proteins during postnatal synapse remodeling. However, the mechanisms through which microglia sense the brain environment are not well defined. Here, we characterized the regulatory program downstream of interleukin-33 (IL-33), a cytokine that promotes microglial synapse remodeling.

Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity.

Synapse remodeling is essential to encode experiences into neuronal circuits. Here, we define a molecular interaction between neurons and microglia that drives experience-dependent synapse remodeling in the hippocampus. We find that the cytokine interleukin-33 (IL-33) is expressed by adult hippocampal neurons in an experience-dependent manner and defines a neuronal subset primed for synaptic plasticity.

Variation among intact tissue samples reveals the core transcriptional features of human CNS cell classes.

It is widely assumed that cells must be physically isolated to study their molecular profiles. However, intact tissue samples naturally exhibit variation in cellular composition, which drives covariation of cell-class-specific molecular features. By analyzing transcriptional covariation in 7,221 intact CNS samples from 840 neurotypical individuals, representing billions of cells, we reveal the core transcriptional identities of major CNS cell classes in humans.

Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development.

Neuronal synapse formation and remodeling are essential to central nervous system (CNS) development and are dysfunctional in neurodevelopmental diseases. Innate immune signals regulate tissue remodeling in the periphery, but how this affects CNS synapses is largely unknown. Here, we show that the interleukin-1 family cytokine interleukin-33 (IL-33) is produced by developing astrocytes and is developmentally required for normal synapse numbers and neural circuit function in the spinal cord and thalamus.