Conditional Deletion of All Neurexins Defines Diversity of Essential Synaptic Organizer Functions for Neurexins

Neurexins are recognized as key organizers of synapses that are essential for normal brain function. However, it is unclear whether neurexins are fundamental building blocks of all synapses with similar overall functions or context-dependent specifiers of synapse properties. To address this question, we produced triple cKO (conditional knockout) mice that allow ablating all neurexin expression in mice. Using neuron-specific manipulations combined with immunocytochemistry, paired recordings, and two-photon Ca2+ imaging, we analyzed excitatory synapses formed by climbing fibers on Purkinje cells in cerebellum and inhibitory synapses formed by parvalbumin- or somatostatin-positive interneurons on pyramidal layer 5 neurons in the medial prefrontal cortex. After pan-neurexin deletions, we observed in these synapses severe but dramatically different synaptic phenotypes that ranged from major impairments in their distribution and function (climbing-fiber synapses) to large decreases in synapse numbers (parvalbumin-positive synapses) and severe alterations in action potential-induced presynaptic Ca2+ transients (somatostatin-positive synapses). Thus, neurexins function primarily as context-dependent specifiers of synapses. •Pan-neurexin KO causes diverse synaptic phenotypes in a synapse-specific manner•Neurexin deficiency phenotypes range from synapse numbers to synaptic Ca2+ dynamics•Phenotypes in neurexin-deficient synapses confirm organizer function of neurexins•Diversity of pan-neurexin KO phenotypes argues against canonical neurexin functions Using conditional deletions of all mouse neurexin genes, Chen et al. show that neurexins are key synaptic organizers that perform synapse-specific functions, ranging from synapse loss to impairments of synaptic transmission and a suppression of action potential-induced calcium influx.