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 5

Classification and molecular markers of distinct lineages in the mouse hippocampus.

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Classification and molecular markers of distinct lineages in the mouse h...
(A) Two-dimensional Uniform Manifold Approximation Plot (UMAP) resolving the 19 distinct lineages of mouse hippocampus (integrated snRNA-seq derived from rhEPO [N = 6] and placebo [N = 6] mice). Cluster identity was assigned manually by retrieving known marker genes. The major cell types are annotated on the plot. Each dot represents a nucleus. (B) Heatmap illustrating the relative expression of the top 6 key genes defining the identity of each cluster in A. The top differentially expressed genes (DEGs) were calculated using Wilcoxon’s rank-sum test for each identified cell type. The color ranges from low (blue) to high (red) expression of marker genes (rows) in the single nuclei (columns). A full list of DEGs in each cell type is given in Supplemental Table 3.