The first Pten knockout mouse models showed that homozygous deletion of exons 4 and 5 (Di Cristofano et al., 1998) or exons 3, 4, and 5 (Suzuki et al., 1998) results in embryonic lethality, whereas heterozygous deletions result in widespread tumorigenesis, resembling PHTS. More recently, conditional Pten knockouts have been developed that more closely resemble PTEN-related ASDs. Although these models do not have good construct validity because humans with PTEN-related ASDs have germline missense mutations in PTEN, the various models provide insight into different brain regions and cell types involved in ASDs. Mice with Pten deleted selectively in a subset of mature neurons in cortex and hippocampus (Nse-Cre) show deficits in social interactions (Kwon et al., 2006a) and increased repetitive behaviors (Napoli et al., 2012). Similar behaviors have been observed in mice with Pten deleted in granule cells of the cerebellum and neurons in the dentate gyrus of the hippocampus (Gfap-Cre; Lugo et al., 2014). Another mouse model of PTEN-related ASD (Ptenm3m4) was created by knocking in missense mutations which decrease the amount of nuclear Pten (Tilot et al., 2014).
