Tuñon-Ortiz Arnulfo, Tränkner Dimitri, Peterson Chandler M, Shennib Omar, Ye Fangfei, Shi Jiani, Brockway Sarah N, Raines Olivia, Mahnke Abbey, Grega Matthew, Kim Keun-Young, Ellisman Mark H, Heys James G, Zelikowsky Moriel, Williams Megan E
Department of Neurobiology, University of Utah School of Medicine, Salt Lake City, Utah 84112.
Department of Neuroscience, University of California at San Diego School of Medicine, San Diego, California 92093.
J Neurosci. 2025 Sep 17;45(38):e1760242025. doi: 10.1523/JNEUROSCI.1760-24.2025.
The homophilic adhesion molecule Kirrel3 drives synapse formation between dentate granule (DG) neurons and GABA neurons, and Kirrel3 gene variants are associated with neurodevelopmental disorders in humans. However, the circuit function and behavioral relevance of Kirrel3-expressing neurons are unknown. Using intersectional genetics, we identified a population of Kirrel3-expressing GABA neurons that regulate memory discrimination in male and female mice. Using chemogenetics with in vivo electrophysiology and behavioral assays, we discovered that activating Kirrel3-expressing GABA neurons, but not parvalbumin neurons, potently inhibits CA3 neuron activity and impairs contextual memory discrimination during recall, revealing a critical role for these neurons in the retrieval of precise memories. Light and electron microscopy of Kirrel3-expressing GABA neurons suggests that they receive direct excitation from DG neurons and project onto CA3 dendrites. Together, this multiscale approach demonstrates how cell type-specific expression of adhesion molecules mark subsets of neurons that control key features guiding memory and behavior.
同嗜性黏附分子Kirrel3驱动齿状颗粒（DG）神经元与GABA能神经元之间的突触形成，并且Kirrel3基因变体与人类神经发育障碍相关。然而，表达Kirrel3的神经元的回路功能和行为相关性尚不清楚。利用交叉遗传学，我们鉴定出一群表达Kirrel3的GABA能神经元，它们调节雄性和雌性小鼠的记忆辨别。通过结合体内电生理学和行为分析的化学遗传学方法，我们发现激活表达Kirrel3的GABA能神经元，而非小白蛋白神经元，会强烈抑制CA3神经元活动，并损害回忆过程中的情境记忆辨别，揭示了这些神经元在精确记忆检索中的关键作用。对表达Kirrel3的GABA能神经元进行的光学和电子显微镜观察表明，它们直接接受DG神经元的兴奋，并投射到CA3树突上。总之，这种多尺度方法展示了黏附分子的细胞类型特异性表达如何标记控制记忆和行为关键特征的神经元亚群。
