Regional heterogeneity of astrocyte morphogenesis dictated by the formin protein, Daam2, modifies circuit function

Astrocytes display extraordinary morphological complexity that is essential to support brain circuit development and function. Formin proteins are key regulators of the cytoskeleton; however, their role in astrocyte morphogenesis across diverse brain regions and neural circuits is unknown. Here, we show that loss of the formin protein Daam2 in astrocytes increases morphological complexity in the cortex and olfactory bulb, but elicits opposing effects on astrocytic calcium dynamics. These differential physiological effects result in increased excitatory synaptic activity in the cortex and increased inhibitory synaptic activity in the olfactory bulb, leading to altered olfactory behaviors. Proteomic profiling and immunoprecipitation experiments identify Slc4a4 as a binding partner of Daam2 in the cortex, and combined deletion of Daam2 and Slc4a4 restores the morphological alterations seen in Daam2 mutants. Our results reveal new mechanisms regulating astrocyte morphology and show that congruent changes in astrocyte morphology can differentially influence circuit function.

Automated summary

Loss of the formin protein Daam2 in astrocytes leads to increased morphological complexity in the cortex and olfactory bulb, but has opposing effects on astrocytic calcium dynamics. These differential physiological effects result in increased excitatory synaptic activity in the cortex and increased inhibitory synaptic activity in the olfactory bulb, altering olfactory behaviors. Proteomic profiling and immunoprecipitation experiments reveal Slc4a4 as a binding partner of Daam2 in the cortex, and deletion of both Daam2 and Slc4a4 restores the morphological alterations seen in Daam2 mutants.