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 3

Working memory, exploration, pre-pulse inhibition, obsessive-compulsive readouts, and related control testing in Zbtb20+/– mice.

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Working memory, exploration, pre-pulse inhibition, obsessive-compulsive ...
(A and B) Working memory was assessed in the Y-maze test and shows significantly more alternating (a) than non-alternating (na) entries in all 4 groups (A, t test, mean ± SEM). Comparing Δ of entries (B) reveals further improved preference of alternating entries in rhEPO-treated Zbtb20+/– mice compared with placebo-treated controls (2-way ANOVA with Bonferroni’s post hoc test, mean ± SEM). (C) Placebo-treated Zbtb20+/– mice show increased time spent in peripheral zone and reduced time spent in intermediate zone in the open field test (2-way ANOVA with Bonferroni’s post hoc test, mean ± SEM). (D) Explorative behavior was also assessed in hole board test, revealing reduced rigorous revisits of placebo-treated Zbtb20+/– mice and a rescue effect upon rhEPO treatment (2-way ANOVA with Bonferroni’s post hoc test, mean ± SEM). (E) Prepulse inhibition test shows a genotype effect, namely increased inhibition of startle response in both placebo- and rhEPO-treated Zbtb20+/– mice (3-way ANOVA with Bonferroni’s post hoc test, mean ± SEM). (F and G) Marble burying test resulted in reduced numbers of buried marbles in the main (F) and, as control for this unexpected result, in an additional (G) cohort (2-way ANOVA with Bonferroni’s post hoc test, mean ± SEM). (H) Neophobia test shows increased interaction time with objects in placebo-treated Zbtb20+/– mice and no treatment effect (2-way ANOVA with Bonferroni’s post hoc test, mean ± SEM). (I) Sucrose preference test demonstrates absence of anhedonia-like (depressive) behavior in placebo- and rhEPO-treated Zbtb20+/– mice (3-way ANOVA with Bonferroni’s post hoc test, mean ± SEM).