Neuroligin-3: A Circuit-Specific Synapse Organizer That Shapes Normal Function and Autism Spectrum Disorder-Associated Dysfunction

Abstract

Chemical synapses provide a vital foundation for neuron-neuron communication and overall brain function. By tethering closely apposed molecular machinery for presynaptic neurotransmitter release and postsynaptic signal transduction, circuit- and context- specific synaptic properties can drive neuronal computations for animal behavior. Trans-synaptic signaling via synaptic cell adhesion molecules (CAMs) serves as a promising mechanism to generate the molecular diversity of chemical synapses. Neuroligins (Nlgns) were discovered as postsynaptic CAMs that can bind to presynaptic CAMs like Neurexins (Nrxns) at the synaptic cleft. Among the four (Nlgn1-4) or five (Nlgn1-3, Nlgn4X, and Nlgn4Y) isoforms in rodents or humans, respectively, Nlgn3 has a heterogeneous expression and function at particular subsets of chemical synapses and strong association with non-syndromic autism spectrum disorder (ASD). Several lines of evidence have suggested that the unique expression and function of Nlgn3 protein underlie circuit-specific dysfunction characteristic of non-syndromic ASD caused by the disruption of Nlgn3 gene. Furthermore, recent studies have uncovered the molecular mechanism underlying input cell-dependent expression of Nlgn3 protein at hippocampal inhibitory synapses, in which trans-synaptic signaling of specific alternatively spliced isoforms of Nlgn3 and Nrxn plays a critical role. In this review article, we overview the molecular, anatomical, and physiological knowledge about Nlgn3, focusing on the circuit-specific function of mammalian Nlgn3 and its underlying molecular mechanism. This will provide not only new insight into specific Nlgn3-mediated trans-synaptic interactions as molecular codes for synapse specification but also a better understanding of the pathophysiological basis for non-syndromic ASD associated with functional impairment in Nlgn3 gene.

Keywords: autism (ASD); cell adhension molecules; development; excitatory synaptic activity; excitatory/inhibitory balance; inhibitory synaptic connection; neuroligin 3 mutation; trans-synaptic adhesion molecule.

FIGURE 1

Genomic and protein structures of Neuroligin 3 (Nlgn3). Upper schema showing the organization of human Nlgn3 and splicing patterns at exons 3 and 4. Bars indicate exons with the coding and untranslational regions colored in dark and bright gray, respectively. Lower schema showing the domain structure of Nlgn3. Bars indicate positions of the mutations associated with ASD and schizophrenia. ChE, cholinesterase-like domain, Gph_BD, gephyrin binding domain; O-glyco, O-linked glycosylation sites; PDZ_BM, PDZ domain-binding motif.

FIGURE 2

Pre- and postsynaptic Neuroligin 3 (Nlgn3) binding partners. Schematic diagram of the major Nlgn3 binding proteins. Shaded circles with dashed lines indicate the protein domains that interact with Nlgn3. HS, Heparin sulfate; LNS, laminin/neurexin/sex-hormone-binding globulin domain; EGFA, epidermal growth factor-like domains; PDZ_BM, PDZ domain-binding motif; ChE, Cholinesterase-like domain; Gph_BD, Gephyrin binding domain, ptp; protein tyrosine phosphatase domain; FN, fibronectin type III domain; Ig, Ig-like domain; A, acidic domain; FL, follistatin-like domain; EC, EF hand Ca²⁺ binding domain; G, G-domain; E, E-domain, PDZ, PDZ domain; SH3, Src-homology-domain-3; GK, guanylate kinase domain; MA, MAM domain; GPI, glycosylphosphatidylinositol anchor.

FIGURE 3

Schematic diagram of the circuit-specific Nlgn3 functions in the mesolimbic pathway. (A) Cell type-specific expression of Nlgn3 in the nucleus accumbens. D1 receptor+ medium spiny neurons (D1-MSN, left) in the nucleus accumbens express higher levels of Nlgn3 than D2-MSNs (right) and regulate motor learning. (B) Nlgn3 function in the VTA. Nlgn3 expressed in DA neurons regulates cap-dependent translational machinery important for oxytocin (OXY) signaling (upper) (Hornberg et al., 2020) and activity-dependent GluR2-lacking AMPA receptor trafficking (lower) (Bariselli et al., 2018). GABA_AR: GABA_A receptor.

FIGURE 4

Schematic diagram of the circuit-specific Nlgn3 functions in the hippocampal CA1 region. (A) Schematic microcircuits in the hippocampus. Schaffer collaterals (SC) form excitatory synapses on both pyramidal cells (Py) and parvalbumin+ interneurons (Pv+ IN). Distinct classes of interneurons including cholecystokinin+/cannabinoid CB1 receptor+/vesicular glutamate transporter type 3+ interneurons (Cck+/CB1R+/VGT3+ IN), Pv+ interneurons and somatostatin+interneurons (Sst+IN) form inhibitory synapses on pyramidal cells. (B) Multiple modes of Nlgn3 regulation in Pv+ interneurons shape hippocampal network activity such as gamma oscillation. Postsynaptic Nlgn3 at SC-Pv+IN synapses regulates NMDA receptor function and retrogradely suppresses release probability through presynaptic group III mGluRs (Polepalli et al., 2017). (C) Inhibitory input-specific Nlgn3 regulation. Postsynaptic Nlgn3 regulates Cck+ but not Pv+ synaptic strength via the activation of tonic endocannabinoid (eCB) signaling (Foldy et al., 2013). (D) Inhibitory input-specific Nlgn3 regulation through trans-synaptic interaction with αNrxn1+AS4. Nlgn3 is selectively expressed at inhibitory synapses expressing VGT3 and CB1, and regulates inhibitory synaptic transmission with presynaptically expressed αNrxn1+AS4 (Uchigashima et al., 2020a). GABA_AR, GABA_A receptor.