title: Initial characterization of behavior and ketamine response in a mouse knockout of the post-synaptic effector gene Anks1b.
abstract: 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 of Anks1b. 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 of Anks1b 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.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Enga
authors.affiliation: Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Rice
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Weller
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Subler
authors.affiliation: Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Daiyoon
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Chelsea P
authors.initials: CP
authors.lastname: Hall
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Jolene J
authors.initials: JJ
authors.lastname: Windle
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA; Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Beardsley
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: van den Oord
authors.affiliation: Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA, USA. Electronic address: jlmcclay@vcu.edu.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: McClay
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007649:Ketamine / Q000494:pharmacology*; D018345:Mice, Knockout; D009043:Motor Activity; D065808:Prepulse Inhibition; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013216:Reflex, Startle; D013239:Stereotyped Behavior
chemical_list: C000625344:Anks1b protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine
keywords: Glutamatergic signaling; Locomotor activity; NMDA receptors; Post-synaptic density; Sensorimotor gating