Environmental Enrichment Rescues Social Behavioral Deficits and Synaptic Abnormalities in Pten Haploinsufficient Mice

Pten germline haploinsufficient (Pten(+/−)) mice, which model macrocephaly/autism syndrome, show social and repetitive behavior deficits, early brain overgrowth, and cortical–subcortical hyperconnectivity. Previous work indicated that altered neuronal connectivity may be a substrate for behavioral deficits. We hypothesized that exposing Pten(+/−) mice to environmental enrichment after brain overgrowth has occurred may facilitate adaptation to abnormal “hard-wired” connectivity through enhancing synaptic plasticity. Thus, we reared Pten(+/−) mice and their wild-type littermates from weaning under either standard (4–5 mice per standard-sized cage, containing only bedding and nestlet) or enriched (9–10 mice per large-sized cage, containing objects for exploration and a running wheel, plus bedding and nestlet) conditions. Adult mice were tested on social and non-social assays in which Pten(+/−) mice display deficits. Environmental enrichment rescued sex-specific deficits in social behavior in Pten(+/−) mice and partially rescued increased repetitive behavior in Pten(+/−) males. We found that Pten(+/−) mice show increased excitatory and decreased inhibitory pre-synaptic proteins; this phenotype was also rescued by environmental enrichment. Together, our results indicate that environmental enrichment can rescue social behavioral deficits in Pten(+/−) mice, possibly through normalizing the excitatory synaptic protein abundance.