Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

Abstract

Neurotransmission at different synapses is highly variable, and cell-adhesion molecules like α-neurexins (α-Nrxn) and their extracellular binding partners determine synapse function. Although α-Nrxn affect transmission at excitatory and inhibitory synapses, the contribution of neurexophilin-1 (Nxph1), an α-Nrxn ligand with restricted expression in subpopulations of inhibitory neurons, is unclear. To reveal its role, we investigated mice that either lack or overexpress Nxph1. We found that genetic deletion of Nxph1 impaired GABA B receptor (GABA B R)-dependent short-term depression of inhibitory synapses in the nucleus reticularis thalami, a region where Nxph1 is normally expressed at high levels. To test the conclusion that Nxph1 supports presynaptic GABA B R, we expressed Nxph1 ectopically at excitatory terminals in the neocortex, which normally do not contain this molecule but can be modulated by GABA B R. We generated Nxph1-GFP transgenic mice under control of the Thy1.2 promoter and observed a reduced short-term facilitation at these excitatory synapses, representing an inverse phenotype to the knockout. Consistently, the diminished facilitation could be reversed by pharmacologically blocking GABA B R with CGP-55845. Moreover, a complete rescue was achieved by additional blocking of postsynaptic GABA A R with intracellular picrotoxin or gabazine, suggesting that Nxph1 is able to recruit or stabilize both presynaptic GABA B R and postsynaptic GABA A R. In support, immunoelectron microscopy validated the localization of ectopic Nxph1 at the synaptic cleft of excitatory synapses in transgenic mice and revealed an enrichment of GABA A R and GABA B R subunits compared with wild-type animals. Thus, our data propose that Nxph1 plays an instructive role in synaptic short-term plasticity and the configuration with GABA receptors. synaptic transmission | thalamus | autism | neuroligin | ultrastructure

Regulation and postsynaptic binding of neurexins — drug targets for neurodevelopmental and neuropsychiatric disorders

“…For example, as reviewed above, Nxph1 interacts with LNS2 of α-NRXNs, α-dystroglycan interacts with both LNS2 and LNS6 of α-NRXNs (SS2 -or SS4 -), whereas NLGN2 interacts with LNS6 (SS4 +/ -) of α-NRXNs (Lévi et al, 2002;Born et al, 2014). NLGN2 can form a physiologically relevant trans-synaptic complex with NRXN at inhibitory synapses (Varoqueaux et al, 2004;Fu and Huang, 2010).…”

“…The binding of NRXNs to trans-synaptic partners are mediated by the LNS2 (with SS2 + or SS2 -) and LNS6 domains (with SS4 + or SS4 -) . Nxph binds α-LNS2 domain independently of other alternative splicing (Missler et al, 1998b;Born et al, 2014).…”

“…The function of Nxph is largely unknown, but it is reported that Nxph is restricted to neuronal subpopulations (Petrenko et al, 1996, Beglopoulos et al, 2005, mainly inhibitory neurons (Born et al, 2014). Each Nxph single-knockout mouse shows normal brain morphology.…”

“…However, the increased startle responses and impaired motor coordination of the Nxph3 knockout mice indicate that Nxphs may have a role in specific circuits (Beglopoulos et al, 2005;Craig and Kang, 2007). Recently, Born et al (2014) found that mice lacking Nxph1, showed an impairment of GABA B receptor (GABA B R)-dependent short-term depression of inhibitory synapses in the nucleus reticularis thalami, a region where Nxph1 is normally expressed at high levels. An inverse phenotype to the genetic deletion of Nxph1 can be observed, when Nxph1 is ectopically expressed at excitatory terminals in the neocortex.…”

The atoms of neural computation

“…The state of pre-synaptic neurexin splicing can even influence post-synaptic receptor trafficking (Aoto, Martinelli, Malenka, Tabuchi, & Südhof, 2013), potentially allowing for a configurational code that could integrate intrinsic and extrinsic cues; such neurexins are represented differentially across the brain, and across developmental stages (Iijima et al, 2011). Neurexins also interact with neuroexophilin ligands, which are differentially expressed in sub-populations of synapses (Born et al, 2014), to influence synaptic function.…”