Abstract
Germline mutations in PTEN account for ~10% of cases of autism spectrum disorder (ASD) with coincident macrocephaly. To explore the importance of nuclear PTEN in the development of ASD and macrocephaly, we previously generated a mouse model with predominantly cytoplasmic localization of Pten (Ptenm3m4/m3m4).Cytoplasmic predominant Pten localization results in a phenotype of extreme macrocephaly and autistic-like traits. Transcriptomic analysis of the Ptenm3m4/m3m4 cortex found upregulated gene pathways related to myeloid cell activation, myeloid cell migration, and phagocytosis. These transcriptomic findings were used to direct in vitro assays on Pten wild-type and Ptenm3m4/m3m4 microglia. We found increased Iba1 and C1q expression with enhanced phagocytic capacity in Ptenm3m4/m3m4 microglia, indicating microglial activation. Moreover, through a series of neuron-microglia co-culture experiments, we found Ptenm3m4/m3m4 microglia are more efficient at synaptic pruning compared with wild-type controls. In addition, we found evidence for neuron-microglia cross-talk, where Ptenm3m4/m3m4 neurons elicit enhanced pruning from innately activated microglia. Subsequent in vivo studies validated our in vitro findings. We observed a concurrent decline in the expression of Pten and synaptic markers in the Ptenm3m4/m3m4 cortex. At ~3 weeks of age, with a 50% drop in Pten expression compared with wild-type levels, we observed enhanced activation of microglia in the Ptenm3m4/m3m4 brain. Collectively, our data provide evidence that dysregulated Pten in microglia has an etiological role in microglial activation, phagocytosis, and synaptic pruning, creating avenues for future studies on the importance of PTEN in maintaining microglia homeostasis.
Highlights
IntroductionThe gene encoding Phosphatase and TENsin homolog deleted on chromosome TEN (PTEN) is a well-recognized, syndromic risk allele for autism spectrum disorder (ASD), a neurodevelopmental disorder defined by deficits in two core symptom domains: social communication/interaction and restricted/repetitive behavior [1,2,3,4]
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.The gene encoding Phosphatase and TENsin homolog deleted on chromosome TEN (PTEN) is a well-recognized, syndromic risk allele for autism spectrum disorder (ASD), a neurodevelopmental disorder defined by deficits in two core symptom domains: social communication/interaction and restricted/repetitive behavior [1,2,3,4]
The Ptenm3m4 neural transcriptome is enriched in neuroinflammation networks, including microglial activation and phagocytic activity
Summary
The gene encoding Phosphatase and TENsin homolog deleted on chromosome TEN (PTEN) is a well-recognized, syndromic risk allele for autism spectrum disorder (ASD), a neurodevelopmental disorder defined by deficits in two core symptom domains: social communication/interaction and restricted/repetitive behavior [1,2,3,4]. Carrying a germline PTEN mutation is the molecular criterion for a diagnosis of PTEN Hamartoma Tumor Syndrome (PHTS), irrespective of clinical phenotype. PHTS (OMIM 601728) is an autosomal dominant, cancer predisposition syndrome, where patients present variably but generally have macrocephaly, benign hamartoma of all three germ layers, elevated risks for specific malignancies, and macrocephalic ASD, the latter occurring in about 20% of PHTS individuals [5,6,7]. ~17% of individuals with ASD and macrocephaly harbor a germline PTEN mutation [2].
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