| Description |
Synaptic target specificity, whereby neurons make distinct types of synapses with distinct target cells, is critical for proper brain function, yet the molecules driving this process are poorly understood. This work demonstrates that, contrary to established dogma, wildtype hippocampal mossy fiber (MF) filopodia do not synapse exclusively onto GABA neurons as previously thought, but instead synapse with similar frequency onto GABA neurons and CA3 neurons in developing mice. Moreover, loss of transmembrane cell adhesion molecule Kirrel3 selectively reduces MF filopodial synapses onto GABA neurons but not those made onto CA3 neurons nor DG-GABA en passant synapses. Consequently, Kirrel3 loss robustly increases CA3 neuron activity during development. In addition, rare Kirrel3 variants found in individuals with neurodevelopmental disorders reduce both cell-cell aggregation and specific synapse formation. In sum, the selective loss of MF filopodial synapses with GABA neurons likely underlies the hippocampal activity imbalance observed in Kirrel3 knockout mice and may impact neural function in patients with Kirrel3-dependent neurodevelopmental disorders. These findings demonstrate that subtle synaptic changes during development can greatly impact circuit function, solidify Kirrel3 as a bona fide synapse specificity molecule, and provide the first insight toward understanding the basis of Kirrel3-dependent neurodevelopmental disorder. |
