Activity-dependent neuroprotective protein (ADNP) is essential for brain formation, and mutations in the ADNP-encoding gene have been linked to an autism-like syndrome in children that is characterized by developmental delay along with intellectual and social disabilities. An 8-amino acid motif derived from ADNP (referred to as NAP) has been shown to be neuroprotective, via enhancing dendritic spine formation, in mice lacking ADNP. In this episode, Illana Gozes and colleagues characterize Adnp+/- mice as a model of ANDP syndrome. Adnp+/- animals had reduced dendritic spine density, developmental delays, impaired vocalizations, and motor dysfunction along with memory and social impairment. Administration of NAP partially reversed behavior and developmental defects and increased dendritic spine density. The results of this study support further exploration of NAP administration for treatment of ADNP syndrome.
Previous findings showed that in mice, complete knockout of activity-dependent neuroprotective protein (ADNP) abolishes brain formation, while haploinsufficiency (Adnp+/–) causes cognitive impairments. We hypothesized that mutations in ADNP lead to a developmental/autistic syndrome in children. Indeed, recent phenotypic characterization of children harboring ADNP mutations (ADNP syndrome children) revealed global developmental delays and intellectual disabilities, including speech and motor dysfunctions. Mechanistically, ADNP includes a SIP motif embedded in the ADNP-derived snippet drug candidate NAP (NAPVSIPQ, also known as CP201), which binds to microtubule end–binding protein 3, essential for dendritic spine formation. Here, we established a unique neuronal membrane–tagged, GFP-expressing Adnp+/– mouse line allowing in vivo synaptic pathology quantification. We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment. Adnp+/–mice further exhibited global developmental delays, vocalization impediments, gait and motor dysfunctions, and social and object memory impairments, all of which were partially reversed by daily NAP administration (systemic/nasal). In conclusion, we have connected ADNP-related synaptic pathology to developmental and behavioral outcomes, establishing NAP in vivo target engagement and identifying potential biomarkers. Together, these studies pave a path toward the clinical development of NAP (CP201) for the treatment of ADNP syndrome.
Gal Hacohen-Kleiman, Shlomo Sragovich, Gidon Karmon, Andy Y. L. Gao, Iris Grigg, Metsada Pasmanik-Chor, Albert Le, Vlasta Korenková, R. Anne McKinney, Illana Gozes