Initial characterization of behavior and ketamine response in a mouse knockout of the post-synaptic effector gene Anks1b

NEUROSCIENCE LETTERS

卷:641

Article

Enga, Rachel M.¹  Rice, Ann C.²  Weller, Pamela³  Subler, Mark A.³  Lee, Daiyoon⁴  Hall, Chelsea P.⁴  Windle, Jolene J.³  Beardsley, Patrick M.^1,5  van den Oord, Edwin J.⁵  McClay, Joseph L.⁴ 

[1] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA USA

[2] Virginia Commonwealth Univ, Dept Neurol, Richmond, VA USA

[3] Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA USA

[4] Virginia Commonwealth Univ, Dept Pharmacotherapy & Outcomes Sci, Richmond, VA USA

[5] Virginia Commonwealth Univ, Ctr Biomarker Res & Precis Med, Richmond, VA USA

关键词: Glutamatergic signaling;    NMDA receptors;    Sensorimotor gating;    Locomotor activity;    Post-synaptic density;   

DOI  :  10.1016/j.neulet.2017.01.044

来源: Elsevier

【 摘 要 】

The human ANKS1B gene encodes an activity-dependent effector of post-synaptic signaling. It was recently associated with neuropsychiatric phenotypes in genome-wide studies. While the biological function of ANKS1B has been partly elucidated, its role in behavior is poorly understood. Here, we breed and characterize a full knockout (KO) for murine Anks1b. We found that the homozygous KO genotype was partially lethal, showing significant deviation from expected segregation ratios at weaning. Behaviorally, KOs exhibited no difference in baseline acoustic startle response, but showed deficits in prepulse inhibition (PPI). KOs also exhibited locomotor hyperactivity and increased stereotypy at baseline. Administration of ketamine, a non-competitive NMDA-receptor antagonist, greatly exacerbated locomotor activity in the KOs at lower doses, but genotype groups were almost indistinguishable as dose increased. Stereotypy showed a complex response to ketamine in the KOs, with elevated stereotypy at lower doses and markedly less at high doses, compared to wild type. Our study is the first to probe the behavioral phenotypes associated with ablation ofAnkslb. Deficits in PPI, locomotor hyperactivity, elevated stereotypy and altered response to NMDA receptor antagonism are murine behavioral outcomes with translational relevance for psychiatric disorders. These findings are also consistent with the role ofAnkslb as an effector of glutamatergic signaling. As an intermediary between post-synaptic receptor stimulation and long-term changes to neuronal protein expression, further investigation of Anks1b is warranted. (C) 2017 Elsevier B.V. All rights reserved.

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