# Erythropoietin alleviates syndrome-associated intellectual disability and autism-like behavior in Zbtb20-haploinsufficient Primrose syndrome mouse model

## TL;DR

Erythropoietin treatment improved autism-like behaviors and intellectual disability in a mouse model of Primrose syndrome, suggesting a potential therapy for this genetic condition.

## Contribution

Demonstrates erythropoietin as a promising treatment for Primrose syndrome, an untreatable genetic condition linked to autism and intellectual disability.

## Key findings

- Zbtb20+/– mice showed autism-like behaviors, intellectual disability, and brain abnormalities.
- Erythropoietin treatment significantly improved behavioral and cognitive symptoms in the mice.
- Magnetic resonance imaging confirmed increased brain volumes in the mouse model.

## Abstract

Among the known genetic causes of syndromic autism spectrum disorders (ASDs) 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 exhibited diminished sociability, reduced vocalization, distinct repetitive behaviors, impaired cognitive flexibility, hyperactivity, and hypoalgesia. Magnetic resonance imaging revealed 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 3 weeks of alternate-day rhEPO injections, a remarkable improvement in the behavioral phenotype was observed. Our results highlight rhEPO as promising treatment for Primrose syndrome.

Mice with Primrose syndrome traits, comparable to the human condition, improve after erythropoietin treatment, suggesting a potential therapy for these autism-related symptoms and intellectual disability.