Erythropoietin alleviates syndrome-associated intellectual disability and autism-like behavior in Zbtb20-haploinsufficient Primrose syndrome mouse model
Martin Hindermann, Justus B.H. Wilke, Yasmina Curto, Stefan N. Oline, Vinicius Daguano Gastaldi, Umer Javed Butt, Rakshit Dadarwal, Umut Çakır, Anja Ronnenberg, Kurt Hammerschmidt, Susann Boretius, Anastassia Stoykova, Anton B. Tonchev, Klaus-Armin Nave, Manvendra Singh, Hannelore Ehrenreich
Martin Hindermann, Justus B.H. Wilke, Yasmina Curto, Stefan N. Oline, Vinicius Daguano Gastaldi, Umer Javed Butt, Rakshit Dadarwal, Umut Çakır, Anja Ronnenberg, Kurt Hammerschmidt, Susann Boretius, Anastassia Stoykova, Anton B. Tonchev, Klaus-Armin Nave, Manvendra Singh, Hannelore Ehrenreich
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Research Article Clinical Research Neuroscience

Erythropoietin alleviates syndrome-associated intellectual disability and autism-like behavior in Zbtb20-haploinsufficient Primrose syndrome 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.

Authors

Martin Hindermann, Justus B.H. Wilke, Yasmina Curto, Stefan N. Oline, Vinicius Daguano Gastaldi, Umer Javed Butt, Rakshit Dadarwal, Umut Çakır, Anja Ronnenberg, Kurt Hammerschmidt, Susann Boretius, Anastassia Stoykova, Anton B. Tonchev, Klaus-Armin Nave, Manvendra Singh, Hannelore Ehrenreich

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Figure 6

rhEPO induces Zbtb20 expression in the newly formed migratory pyramidal lineage.

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rhEPO induces Zbtb20 expression in the newly formed migratory pyramidal ...
(A) Feature plot (lower panel) based on UMAP (upper panel) demonstrating the wider pattern of Zbtb20 levels, denoted as the density of relative expression. Midnight blue area represents lower expression whereas the nuclei under the golden area exhibit higher expression of Zbtb20. Note: Zbtb20 expression in multiple locations suggests the intricacy of Zbtb20 regulation in the hippocampus needs to be unveiled in future studies. (B) Violin plot showing the expression distribution of Zbtb20 across the lineages coded by colors as denoted in A. Stars signify the adjusted P values obtained by Benjamini-Hochberg (BH) correction followed by Wilcoxon’s rank-sum test (1-way), comparing Zbtb20 expression in intermediate cell versus the remaining lineages (***P < 0.001, BH test). (C) Grouped violin plot visualizes the comparison of expression dynamics of Zbtb20 between placebo (light gray) and rhEPO (red) across lineages; level of significance is calculated similarly as shown in previous plot, except here, the comparison is made between placebo and rhEPO samples (*P < 0.05, **P < 0.01, ***P < 0.001, BH test). (D) Left panel: Stacked bar plot of pyramidal (NFM) cell type illustrating the percentage of cells expressing Zbtb20 (gold) and the remaining cells (gray) separately in placebo- and rhEPO-treated samples. Asterisks denote the P value of difference in cells expressing Zbtb20 between rhEPO- and placebo-treated samples (***P < 0.001, 2-sided Fisher’s exact test). Right panel: Violin plot quantifying the density and distribution of Zbtb20 expression in pyramidal (NFM) cell type from rhEPO- and placebo-treated samples in pairwise manner (***P < 0.001, Wilcoxon’s rank-sum test, 1-way).