CA3 cFOS Quantification

Trans-synaptic adhesion molecules are proposed to confer specificity to neural circuits, yet how they function in vivo and how disease-associated variants perturb their activity remain unclear. Here, we define how the homophilic adhesion molecule Kirrel3 shapes synapse formation and circuit function in the mouse hippocampus. Using conditional genetics, we show that Kirrel3 is absolutely required in both presynaptic dentate gyrus neurons and postsynaptic GABAergic interneurons to drive formation of mossy fiber filopodial synapses and constrain CA3 activity, providing in vivo evidence for a trans-synaptic mechanism. Despite this strict requirement, partial loss of Kirrel3 produces only modest synaptic deficits without altering circuit activity, revealing that this pathway is robust to reduced gene dosage. In contrast, expression of a disease-associated, adhesion-deficient Kirrel3 variant dominantly disrupts synapse formation, cell adhesion, and elevates CA3 activity, whereas a binding adhesion-competent variant likely behaves as a loss-of-function allele. These results advance the understanding of how cell adhesion molecules function in vivo and indicate why one Kirrel3 missense variant allele could contribute to disease.

Data and Resources

Field Value
Contact Email megan.williams@neuro.utah.edu
Creator ORCIDs https://orcid.org/0000-0002-5461-4126
DOI 10.7278/S5d-sw4s-gey8
Date Collected 2022/2026
Funding National Institutes of Health
Hive Date Modified 2026-07-02T00:12:59.206236+00:00
Hive Date Uploaded 2026-07-02T00:02:47.695317+00:00
License Creative Commons Attribution Non Commercial 4.0 International (https://creativecommons.org/licenses/by-nc/4.0/)
Parent ID cwj43-08z66
Publication Date 2026-07-01
Publisher The Hive: University of Utah Research Data Repository
Resource Type Dataset
Resource URL https://hive.utah.edu/records/cwj43-08z66
Subjects Hippocampi imaging; Kirrel3; CA3; Hippocampus synapse formation; Hippocampus function; Mouse hippocampus
Version 1
ndp_creator_md5 c28ceb2036e404504d019148adef79c9
ndp_group_id J. Willard Marriott Library
ndp_user_id 3383da5ae47ae984
Groups
  • NSF
  • United States
Tags
  • NSF
  • United States
  • ca3
  • hippocampi-imaging
  • hippocampus-function
  • hippocampus-synapse-formation
  • kirrel3
  • mouse-hippocampus
isopen True
license_id other-open
license_title Other (Open)
metadata_created 2026-10-30T17:33:30.563578
metadata_modified 2026-10-30T17:33:30.563583
notes Trans-synaptic adhesion molecules are proposed to confer specificity to neural circuits, yet how they function in vivo and how disease-associated variants perturb their activity remain unclear. Here, we define how the homophilic adhesion molecule Kirrel3 shapes synapse formation and circuit function in the mouse hippocampus. Using conditional genetics, we show that Kirrel3 is absolutely required in both presynaptic dentate gyrus neurons and postsynaptic GABAergic interneurons to drive formation of mossy fiber filopodial synapses and constrain CA3 activity, providing in vivo evidence for a trans-synaptic mechanism. Despite this strict requirement, partial loss of Kirrel3 produces only modest synaptic deficits without altering circuit activity, revealing that this pathway is robust to reduced gene dosage. In contrast, expression of a disease-associated, adhesion-deficient Kirrel3 variant dominantly disrupts synapse formation, cell adhesion, and elevates CA3 activity, whereas a binding adhesion-competent variant likely behaves as a loss-of-function allele. These results advance the understanding of how cell adhesion molecules function in vivo and indicate why one Kirrel3 missense variant allele could contribute to disease.
num_resources 13
num_tags 8
title CA3 cFOS Quantification