Erythropoietin alleviates intellectual disability and autism-like behavior of mice caused by Zbtb20 haploinsufficiency, a construct-valid model of Primrose syndrome

Among the known genetic causes of syndromic autism spectrum disorders (ASD) are transcription factor deficiencies. In this regard, haploinsufficiency of the ‘zinc finger and broad complex, tramtrack, bric and brac domain-containing protein 20’ (ZBTB20) leads to a prototypical clinical picture, referred to as Primrose syndrome, comprising severe ASD symptoms together with intellectual disability. Here, we present a comprehensive behavioral and phenotypical characterization of Zbtb20 +/- mice, a construct valid model of this thus far untreatable human condition. Zbtb20 +/- mice exhibit diminished sociability, reduced vocalization, distinct repetitive behaviors, impaired cognitive flexibility, hyperactivity and hypoalgesia. Magnetic resonance imaging reveals increased volumes of hippocampus, cerebellum, brain matter, and whole brain, confirmed by postmortem brain weight measurements. Due to our previous observation of enhanced ZBTB20 expression in CA1 pyramidal neurons upon recombinant human erythropoietin (rhEPO) injections, we anticipated a mitigating effect through rhEPO treatment of Zbtb20 deficiency/Primrose syndrome. Indeed, after three weeks of alternate-day rhEPO injections, a remarkable improvement in the behavioral phenotype was observed. Our results highlight rhEPO as a first promising treatment for Primrose syndrome.