Abstract
<jats:p>Neurexins are arguably the best-studied presynaptic adhesion molecules. Despite thousands of papers, however, no direct comparisons of overall neurexin functions in different types of synapses is available. A decade ago, we provided such an analysis but we recently retracted this paper because four images contained microduplications that, although without discernible impact on the paper's conclusions, could not be corrected. As a result, the scientific community lost access to data that established the fundamental principle that neurexins perform profound but distinct functions in different types of synapses. In the present study, we have therefore reanalyzed the original raw data and expanded their conclusions with new experiments to document in the same study the basic contributions of neurexins to multiple different synapses. Our experiments use triple conditional knockout mice that target all neurexins except for Neurexin-1r By applying neuron-specific manipulations combined with slice electrophysiology, two-photon Ca2+ imaging and immunohistochemistry, we focus on excitatory climbing-fiber synapses in the cerebellum and on inhibitory synapses formed by parvalbumin- or somatostatin-positive neurons in the cerebellum, hippocampus, and medial prefrontal cortex. Our results show that pan-neurexin deletions produce dramatically different phenotypes in synapses, ranging from modest to massive impairments in synapse assembly (climbing-fiber and parvalbumin-positive synapses) to severe but selective decreases in presynaptic action potential-induced Ca2+-transients (somatostatin-positive synapses). Thus, neurexins perform powerful but distinct context-dependent roles in different synapses that shape the brain's circuits.</jats:p>