β-Neurexins Control Neural Circuits by Regulating Synaptic Endocannabinoid Signaling

Abstract

α- and β-neurexins are presynaptic cell-adhesion molecules implicated in autism and schizophrenia. We find that although β-neurexins are expressed at much lower levels than α-neurexins, conditional knockout of β-neurexins with continued expression of α-neurexins dramatically decreased neurotransmitter release at excitatory synapses in cultured cortical neurons. The β-neurexin knockout phenotype was attenuated by CB1-receptor inhibition which blocks presynaptic endocannabinoid signaling or by 2-arachidonoylglycerol synthesis inhibition which impairs postsynaptic endocannabinoid release. In synapses formed by CA1-region pyramidal neurons onto burst-firing subiculum neurons, presynaptic in vivo knockout of β-neurexins aggravated endocannabinoid-mediated inhibition of synaptic transmission and blocked LTP; presynaptic CB1-receptor antagonists or postsynaptic 2-arachidonoylglycerol synthesis inhibition again reversed this block. Moreover, conditional knockout of β-neurexins in CA1-region neurons impaired contextual fear memories. Thus, our data suggest that presynaptic β-neurexins control synaptic strength in excitatory synapses by regulating postsynaptic 2-arachidonoylglycerol synthesis, revealing an unexpected role for β-neurexins in the endocannabinoid-dependent regulation of neural circuits.

Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

“…In the hippocampus, Nlgn3 deletions produced a selective disinhibition of tonic endocannabinoid signaling in CCK-positive synapses (Földy et al, 2013). This phenotype, which resembles the effect of β-neurexin deletions in hippocampal synapses (Anderson et al, 2015), is consistent with a discrete context-dependent role of Nlgn3. In the striatum, Nlgn3 deletions selectively impaired inhibitory inputs onto N. accumbens medium spiny neurons (Rothwell et al, 2014).…”

“…In the crystal structure, the ‘arms’ of Nrxn1α were stabilized by extensive interdomain contacts that stably connected some domains (e.g., at the hinge between LNS5 with EGFC, or at the contact between EGFC with LNS6 that is predicted to be loosened by the alternatively spliced SS6 insert). The three neurexin genes are transcribed in brain at similar levels, with α-neurexins being much more abundant than β-neurexins (Aoto et al, 2013; Schreiner et al, 2014; Anderson et al, 2015). …”

Carbonic anhydrase-related protein CA10 is an evolutionarily conserved pan-neurexin ligand

“…1B). IP of Nrxn1 caused co-IP of endogenous CA10 [note that as described previously (24), Nrxn1 is primarily expressed as Nrxn1α (>90%) in multiple alternatively spliced variants, with Nrxn1β accounting for a much smaller proportion (<5%)]. In a reciprocal experiment, we performed IPs of CA10 from mouse forebrain and cerebellum, and observed high enrichment of Nrxn1 with CA10 but with an apparently more restricted set of specific Nrxn1α isoforms (Fig.…”

Structural Basis for Regulation of GPR56/ADGRG1 by Its Alternatively Spliced Extracellular Domains

“…AS in the coding region of genes is an important mechanism to greatly expand the functional and regulatory capacity of metazoan genomes and its regulatory role in brain function has been repeatedly demonstrated (Braunschweig et al, 2013, Irimia et al, 2014, Anderson et al, 2015). For instance, recent studies suggest a specific expression pattern for hundreds of alternatively spliced isoforms of neurexins, key proteins that organize synapse architecture and encode cellular identity and diversity (Fuccillo et al, 2015).…”