The Parvalbumin/Somatostatin Ratio Is Increased in Pten Mutant Mice and by Human PTEN ASD Alleles

•Pten regulates the ratio of PV+/SST+ cortical interneurons•Loss of Pten increases PV+ process growth and inhibition•Pten interneuron cKOs have altered social behavior and gamma oscillations•An in vivo screening assay tests human ASD allele function

SummaryMutations in the phosphatase PTEN are strongly implicated in autism spectrum disorder (ASD). Here, we investigate the function of Pten in cortical GABAergic neurons using conditional mutagenesis in mice. Loss of Pten results in a preferential loss of SST+ interneurons, which increases the ratio of parvalbumin/somatostatin (PV/SST) interneurons, ectopic PV+ projections in layer I, and inhibition onto glutamatergic cortical neurons. Pten mutant mice exhibit deficits in social behavior and changes in electroencephalogram (EEG) power. Using medial ganglionic eminence (MGE) transplantation, we test for cell-autonomous functional differences between human PTEN wild-type (WT) and ASD alleles. The PTEN ASD alleles are hypomorphic in regulating cell size and the PV/SST ratio in comparison to WT PTEN. This MGE transplantation/complementation assay is efficient and is generally applicable for functional testing of ASD alleles in vivo.

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