Mice Lacking Glypican 4 Display Juvenile Hyperactivity and Adult Social Interaction Deficits

Glypican 4 (Gpc4) is a heparan sulfate proteoglycan that regulates glutamatergic synapse formation and function in the developing brain. Gpc4 KO mice have been shown to have decreased excitatory synapse number and less synaptic GluA1 AMPA receptors, leading to decreased synaptic transmission. Further, decreased expression of Gpc4 has been linked to autism spectrum disorder (ASD). Gpc4 is expressed by both astrocytes and neurons during postnatal development, with astrocyte expression higher in juvenile stages, and neuronal expression increasing with maturation. We therefore asked if mice lacking Gpc4 display behavioral alterations that are consistent with loss of GluA1 or ASD, and if so if they occur at juvenile ages when astrocyte Gpc4 is high, or at adult ages when both astrocytes and neurons express Gpc4. We found that juvenile (P14) Gpc4 KO mice display hyperactivity in the open field, which is corrected in adult mice (3 month). Adult Gpc4 KO mice show deficient behavior in social novelty, whilst non-social behaviors such as working memory and anxiety are unaffected. Thus, Gpc4 KO mice show age-specific behavioral alterations that are consistent with altered synaptic levels of GluA1 and behaviors associated with ASD.