Martin EA1, Muralidhar S1, Wang Z1, Cervantes DC1, Basu R1, Taylor MR1, Hunter J1, Cutforth T2, Wilke SA3, Ghosh A4, Williams ME1. Elife. 2015 Nov 17;4. pii: e09395. doi: 10.7554/eLife.09395.
1Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, United States.
2Department of Neurology, Columbia University, New York City, United States.
3Neurobiology Section, Division of Biological Sciences, University of California, San Diego, San Diego, United States.
4Neuroscience Discovery, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland.
Synaptic target specificity, whereby neurons make distinct types of synapses with different target cells, is critical for brain function, yet the mechanisms driving it are poorly understood. In this study, we demonstrate Kirrel3 regulates target-specific synapse formation at hippocampal mossy fiber (MF) synapses, which connect dentate granule (DG) neurons to both CA3 and GABAergic neurons. Here, we show Kirrel3 is required for formation of MF filopodia; the structures that give rise to DG-GABA synapses and that regulate feed-forward inhibition of CA3 neurons. Consequently, loss of Kirrel3 robustly increases CA3 neuron activity in developing mice. Alterations in the Kirrel3 gene are repeatedly associated with intellectual disabilities, but the role of Kirrel3 at synapses remained largely unknown. Our findings demonstrate that subtle synaptic changes during development impact circuit function and provide the first insight toward understanding the cellular basis of Kirrel3-dependent neurodevelopmental disorders.
Kirrel3; cell adhesion; hippocampus; mouse; neuroscience; synaptic specificity