---
title: "ANK3 p.W1989R Variant Alters Somatostatin Interneuron Connectivity and Function in Human and Mouse"
id: "biorxiv-8-human-and-mouse-models-of-the-bipolar-disorder-associated-ank3-p-w1989r-variant"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-8-human-and-mouse-models-of-the-bipolar-disorder-associated-ank3-p-w1989r-variant"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.10.23.760718v1?rss=1"
published_at: "2026-10-23T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# ANK3 p.W1989R Variant Alters Somatostatin Interneuron Connectivity and Function in Human and Mouse
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-8-human-and-mouse-models-of-the-bipolar-disorder-associated-ank3-p-w1989r-variant
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.10.23.760718v1?rss=1)
- **Published At:** 2026-10-23T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study examined an **ANK3** p.W1989R variant previously identified in a family with bipolar disorder; investigators used human iPSC-derived neurons and a heterozygous mouse model. - Authors reported that the p.W1989R change abolishes the ankyrin-G/**GABARAP** interaction, a mechanism tied to stabilizing inhibitory synapses. - In patient-derived hiPSC neurons, CRISPR correction of the variant increased inhibitory synapse density on both glutamatergic and GABAergic cells, indicating a reversible connectivity deficit. - Integrated spatial transcriptomics paired with calcium imaging revealed cell-type-dependent gene expression shifts and altered calcium dynamics in the cohort. - Somatostatin-positive (SST) interneurons carrying the variant showed reduced **SST** expression and atypical calcium signaling, per the authors. - In heterozygous Ank3 p.W1989R mice, selective stimulation of prefrontal cortical SST interneurons produced reduced optically evoked IPSC peak amplitude, charge transfer, and decay times recorded from pyramidal neurons. - The paired-pulse ratio did not differ significantly in the mouse recordings, suggesting a postsynaptic or synapse-stability effect rather than a simple presynaptic release probability change. - The combined human and mouse data point to altered SST interneuron-mediated inhibition as a functional consequence of the ANK3 variant. - The source did not report detailed sample sizes, specific electrophysiological parameters beyond the described metrics, or clinical phenotyping of the human subject beyond variant status.
## Clinical Analysis & Structured Key Points
Human and Mouse Models of the Bipolar Disorder-Associated ANK3 p.W1989R Variant Display Altered Somatostatin Interneuron Connectivity and Function | bioRxiv Skip to main content New Results Human and Mouse Models of the Bipolar Disorder-Associated ANK3 p.W1989R Variant Display Altered Somatostatin Interneuron Connectivity and Function View ORCID Profile Kendall P Dean , View ORCID Profile Sarah C. Verduci , View ORCID Profile Clayton C. Kramm , View ORCID Profile Cooper W. Stinson , View ORCID Profile Lia Min , View ORCID Profile Jennifer S. Smith , Cynthia J. DeLong , View ORCID Profile Mingjia Yao , Kun H. Lee , View ORCID Profile Jacob M. Reeves , View ORCID Profile William T Birdsong , View ORCID Profile Joshua D. Welch , View ORCID Profile Paul M Jenkins doi: https://doi.org/10.64898/2026.10.23.760718 Kendall P Dean 1 University of Michigan Medical School; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Kendall P Dean Sarah C. Verduci 1 University of Michigan Medical School; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sarah C. Verduci Clayton C. Kramm 1 University of Michigan Medical School; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Clayton C. Kramm Cooper W. Stinson 1 University of Michigan Medical School; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Cooper W. Stinson Lia Min 1 University of Michigan Medical School; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Lia Min Jennifer S. Smith 2 University of Michigan Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jennifer S. Smith Cynthia J. DeLong 1 University of Michigan Medical School; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mingjia Yao 1 University of Michigan Medical School; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Mingjia Yao Kun H. Lee 1 University of Michigan Medical School; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jacob M. Reeves 1 University of Michigan Medical School; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jacob M. Reeves William T Birdsong 2 University of Michigan Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for William T Birdsong Joshua D. Welch 1 University of Michigan Medical School; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Joshua D. Welch Paul M Jenkins 1 University of Michigan Medical School; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Paul M Jenkins For correspondence: pjenkins{at}umich.edu Abstract Info/History Metrics Supplementary material Preview PDF Abstract Bipolar disorder (BD) is a debilitating neuropsychiatric disorder characterized by recurrent mood perturbations, cognitive and functional impairment, and increased risk of suicide. Genome-wide association studies (GWAS) have repeatedly identified the gene ANK3, which encodes the neuronal scaffolding protein ankyrin-G, as a risk locus for BD. Ankyrin-G interacts directly with the GABAA receptor-associated protein (GABARAP) to stabilize inhibitory synapses, providing a potential mechanistic link between ANK3 variation and GABAergic dysfunction observed in BD. Previously, we identified an ANK3 p.W1989R variant in a family with BD and demonstrated that this variant abolishes the ankyrin-G/GABARAP interaction, resulting in inhibitory signaling deficits in mice. Here, we investigated the effects of this variant in human induced pluripotent stem cell (hiPSC)-derived neurons generated from an affected individual heterozygous for the ANK3 p.W1989R variant. CRISPR correction of the variant increased inhibitory synapse density on both glutamatergic and GABAergic patient-derived neurons. Integrated spatial transcriptomics and calcium imaging identified cell-type-dependent changes in gene expression and calcium dynamics. ANK3 p.W1989R somatostatin (SST) positive interneurons displayed altered calcium dynamics and reduced SST expression. To determine whether the variant impacts SST interneuron-mediated inhibition of cortical circuits, we selectively stimulated prefrontal cortical SST interneurons in heterozygous Ank3 p.W1989R mice and recorded optically evoked inhibitory postsynaptic currents (oIPSCs) from cortical pyramidal neurons. SST interneuron-mediated oIPSC peak amplitude, charge transfer, and decay times were reduced in variant mice, without a significant change in the paired-pulse ratio. These findings, using complementary human and mouse models, identify novel roles for ankyrin-G in SST interneuron-mediated inhibitory signaling and demonstrate that altered inhibitory connectivity and SST interneuron function are associated with ANK3 p.W1989R. This work provides mechanistic insight into how disrupted ankyrin-G-dependent synaptic function may contribute to inhibitory signaling deficits relevant to BD. Competing Interest Statement Dr. Jenkins reports having received consulting funds from Flux Therapeutics and research funds from Neuropharmaka, Inc. All other authors report no biomedical financial interests or potential conflicts of interest. Funder Information Declared National Institute of Neurological Disorders and Stroke , R21NS113022 National Institute of Mental Health , R01MH126960 National Institute of General Medical Sciences , T32GM007315 , T32GM007315 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Back to top Previous Posted October 23, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Human and Mouse Models of the Bipolar Disorder-Associated ANK3 p.W1989R Variant Display Altered Somatostatin Interneuron Connectivity and Function Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Human and Mouse Models of the Bipolar Disorder-Associated ANK3 p.W1989R Variant Display Altered Somatostatin Interneuron Connectivity and Function Kendall P Dean , Sarah C. Verduci , Clayton C. Kramm , Cooper W. Stinson , Lia Min , Jennifer S. Smith , Cynthia J. DeLong , Mingjia Yao , Kun H. Lee , Jacob M. Reeves , William T Birdsong , Joshua D. Welch , Paul M Jenkins bioRxiv 2026.10.23.760718; doi: https://doi.org/10.64898/2026.10.23.760718 Share This Article: Copy Citation Tools Human and Mouse Models of the Bipolar Disorder-Associated ANK3 p.W1989R Variant Display Altered Somatostatin Interneuron Connectivity and Function Kendall P Dean , Sarah C. Verduci , Clayton C. Kramm , Cooper W. Stinson , Lia Min , Jennifer S. Smith , Cynthia J. DeLong , Mingjia Yao , Kun H. Lee , Jacob M. Reeves , William T Birdsong , Joshua D. Welch , Paul M Jenkins bioRxiv 2026.10.23.760718; doi: https://doi.org/10.64898/2026.10.23.760718 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (8164) Biochemistry (19027) Bioengineering (15171) Bioinformatics (45344) Biophysics (22958) Cancer Biology (20114) Cell Biology (27308) Clinical Trials (138) Developmental Biology (14146) Ecology (21399) Epidemiology (2067) Evolutionary Biology (25810) Genetics (16343) Genomics (23839) Immunology (19025) Microbiology (43194) Molecular Biology (18344) Neuroscience (95069) Paleontology (713) Pathology (3033) Pharmacology and Toxicology (5200) Physiology (8280) Plant Biology (16271) Scientific Communication and Education (2116) Synthetic Biology (4646) Systems Biology (10385) Zoology (2427)
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