Towards Preclinical Validation of Arbaclofen (R-baclofen) Treatment for 16p11.2 Deletion Syndrome

Brigitta B Gundersen; William T O'Brien; Melanie D Schaffler; Maria N Schultz; Tatsuya Tsukahara; Sandra Martin Lorenzo; Valerie Nalesso; Alice H Luo Clayton; Ted Abel; Jacqueline N Crawley; Sandeep Robert Datta; Yann Herault

doi:10.1101/2023.05.01.538987

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Towards Preclinical Validation of Arbaclofen (R-baclofen) Treatment for 16p11.2 Deletion Syndrome

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Towards Preclinical Validation of Arbaclofen (R-baclofen) Treatment for 16p11.2 Deletion Syndrome

Brigitta B Gundersen, William T O'Brien, Melanie D Schaffler, Maria N Schultz, Tatsuya Tsukahara, Sandra Martin Lorenzo, Valerie Nalesso, Alice H Luo Clayton, Ted Abel, Jacqueline N Crawley, …

bioRxiv : the preprint server for biology

Cold Spring Harbor Laboratory

09/14/2023

DOI: 10.1101/2023.05.01.538987

PMCID: PMC10515778

PMID: 37745360

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Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

A microdeletion on human chromosome 16p11.2 is one of the most common copy number variants associated with autism spectrum disorder and other neurodevelopmental disabilities. Arbaclofen, a GABA(B) receptor agonist, is a component of racemic baclofen, which is FDA-approved for treating spasticity, and has been shown to alleviate behavioral phenotypes, including recognition memory deficits, in animal models of 16p11.2 deletion. Given the lack of reproducibility sometimes observed in mouse behavioral studies, we brought together a consortium of four laboratories to study the effects of arbaclofen on behavior in three different mouse lines with deletions in the mouse region syntenic to human 16p11.2 to test the robustness of these findings. Arbaclofen rescued cognitive deficits seen in two 16p11.2 deletion mouse lines in traditional recognition memory paradigms. Using an unsupervised machine-learning approach to analyze behavior, one lab found that arbaclofen also rescued differences in exploratory behavior in the open field in 16p11.2 deletion mice. Arbaclofen was not sedating and had modest off-target behavioral effects at the doses tested. Our studies show that arbaclofen consistently rescues behavioral phenotypes in 16p11.2 deletion mice, providing support for clinical trials of arbaclofen in humans with this deletion.

Details

Title: Subtitle: Towards Preclinical Validation of Arbaclofen (R-baclofen) Treatment for 16p11.2 Deletion Syndrome
Creators: Brigitta B Gundersen - Simons Foundation
William T O'Brien - University of Pennsylvania
Melanie D Schaffler - University of California, Davis
Maria N Schultz - University of California, Davis
Tatsuya Tsukahara - Harvard Medical School
Sandra Martin Lorenzo - Inserm
Valerie Nalesso - Inserm
Alice H Luo Clayton - NIH BRAIN Initiative, Bethesda, MD
Ted Abel - University of Iowa
Jacqueline N Crawley - University of California, Davis
Sandeep Robert Datta - Harvard Medical School
Yann Herault - Inserm
Resource Type: Preprint
Publication Details: bioRxiv : the preprint server for biology
DOI: 10.1101/2023.05.01.538987
PMID: 37745360
PMCID: PMC10515778
Publisher: Cold Spring Harbor Laboratory; United States
Grant note: P50 HD103526 / NICHD NIH HHS P50 HD105351 / NICHD NIH HHS P50 HD105354 / NICHD NIH HHS
Language: English
Date posted: 09/14/2023
Academic Unit: Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
Record Identifier: 9984572499102771

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