The effects of postnatal erythropoietin and nano‐erythropoietin on behavioral alterations by mediating K‐Cl co‐transporter 2 in the valproic acid‐induced rat model of autism

Abstract In this study, based on the excitatory/inhibitory imbalance theory of autism, the time window of GABA switch, the role of K‐Cl co‐transporter 2 (KCC2) in adjustment GABA switch, and brain permeability to erythropoietin (EPO), the effects of postnatal ‐EPO and‐ nano‐ erythropoietin (NEPO) have been evaluated in the valproic acid (VPA) rat model of autism. The VPA was administered for animal modeling of autism at gestational day (GD) 12.5 (600 mg/kg). Male offsprings were injected with EPO and NEPO in a clinically proper postnatal dosing regimen on postnatal days (PND) 1–5, and autistic‐like behaviors were tested at the end of the first month. Then animals were sacrificed, and neuron morphology and KCC2 expression were examined by Nissl staining and Western blot. According to our findings, high‐dose NEPO improved autism‐associated phenotypes. Neuroprotective effects of EPO and NEPO have been shown in the hippocampus. Postnatal NEPO treatment reversed KCC2 expression abnormalities induced by prenatal VPA. Our results might support the role of KCC2 in ASD and the excitatory/inhibitory imbalance hypothesis. We suggested Nano‐ erythropoietin and other KCC2 interventions as a new approach to the early treatment and prevention of autism.