Deletion of α‐neurexins does not cause a major impairment of axonal pathfinding or synapse formation

Abstract

Alpha-neurexins are synaptic cell-surface molecules that are required for Ca(2+)-triggered exocytosis. Mice lacking all three alpha-neurexins show drastically reduced neurotransmitter release at excitatory and inhibitory synapses and die early postnatally. Although previous histological analysis of newborn alpha-neurexin triple mutants revealed only a moderate reduction in the density of type II synapses in the brainstem, cell culture studies proposed that neurexins are prominently involved in synapse formation. To assess the contribution of alpha-neurexins to the formation and structural properties of synapses in vivo, we performed a detailed morphological analysis of the brains from surviving adult double knockout mice lacking two of the three alpha-neurexins. Despite their impaired neurotransmission, we did not observe any gross anatomical defects or changes in the distribution of synaptic proteins in adult mutants. Only mild structural alterations were found: a approximately 20% reduction of neuropil area in many brain regions, resulting predominantly from shortened distal dendritic branches and fewer spines, as demonstrated by Golgi impregnation of pyramidal neurons. Quantitative electron microscopy revealed ultrastructurally normal type I and II terminals and a approximately 30% decrease in the density of type II synapses in the neocortex. To exclude errors in pathfinding, we investigated axonal projections in the olfactory bulb of newborn knockouts and did not observe any changes. Therefore, alpha-neurexins are not essential for the formation of the vast majority of synapses in vivo but rather regulate the function of these synapses.

Induction of GABAergic Postsynaptic Differentiation by α-Neurexins

“…In addition to the calcium channel coupling phenotype, ␣-neurexin 1/2/3 triple knock-out mice had a 2-fold reduction in the density of type II symmetric GABAergic synapses in neonatal brainstem with no change in density of type I asymmetric glutamatergic synapses (27). A 30% reduction in type II symmetric synapses but not type I asymmetric synapses was also found in adult neocortex of neurexin 1/2␣ and 2/3␣ double knock-out mice (53). It was not clear whether this loss of inhibitory synapses reflected a direct function of ␣-neurexin in GABA synapse development or an indirect effect of reduced synaptic activity due to the presynaptic calcium channel coupling defect.…”

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

“…In support of this overall concept, ␣-neurexin triple KO mice exhibit major impairments in synaptic transmission that manifest largely, but not exclusively, as presynaptic changes (9)(10)(11)(12)(13). Importantly, ␣-neurexin KO mice do not display a major decrease in the number of excitatory synapses, and only a moderate decrease in inhibitory synapses (9,13). Thus, neurexins appear to be essential components of synaptic function whose roles extend to several different components of synapses.…”

Neurexin-1α Contributes to Insulin-containing Secretory Granule Docking

“…Studies with double and triple ␣-NRXN KO mice have indicated that ␣-NRXNs in neurons are essential for the organization and stabilization of the presynaptic machinery (21)(22)(23). In vitro work suggests that NRXNs interact with the synaptic vesicle-associated protein rabphilin-3A via CASK (24) and contribute to synaptic vesicle docking (16,25).…”