Abstract
Complex brain circuitry with feedforward and feedback systems regulates neuronal activity, enabling neural networks to process and drive the entire spectrum of cognitive, behavioral, sensory, and motor functions. Simultaneous orchestration of distinct cells and interconnected neural circuits is underpinned by hundreds of synaptic adhesion molecules that span synaptic junctions. Dysfunction of a single molecule or molecular interaction at synapses can lead to disrupted circuit activity and brain disorders. Neuroligins, a family of cell adhesion molecules, were first identified as postsynaptic-binding partners of presynaptic neurexins and are essential for synapse specification and maturation. Here, we review recent advances in our understanding of how this family of adhesion molecules controls neuronal circuit assembly by acting in a synapse-specific manner.
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References
Song JY, Ichtchenko K, Südhof TC, Brose N (1999) Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. Proc Natl Acad Sci USA 96:1100–1105. https://doi.org/10.1073/pnas.96.3.1100
Ichtchenko K, Hata Y, Nguyen T et al (1995) Neuroligin 1: a splice site-specific ligand for beta-neurexins. Cell 81:435–443
Bolliger MF, Frei K, Winterhalter KH, Gloor SM (2001) Identification of a novel neuroligin in humans which binds to PSD-95 and has a widespread expression. Biochem J 356:581–588. https://doi.org/10.1042/bj3560581
Bolliger MF, Pei J, Maxeiner S et al (2008) Unusually rapid evolution of Neuroligin-4 in mice. Proc Natl Acad Sci USA 105:6421–6426. https://doi.org/10.1073/pnas.0801383105
Ichtchenko K, Nguyen T, Südhof TC (1996) Structures, alternative splicing, and neurexin binding of multiple neuroligins. J Biol Chem 271:2676–2682. https://doi.org/10.1074/jbc.271.5.2676
Banovic D, Khorramshahi O, Owald D et al (2010) Drosophila neuroligin 1 promotes growth and postsynaptic differentiation at glutamatergic neuromuscular junctions. Neuron 66:724–738. https://doi.org/10.1016/j.neuron.2010.05.020
Sun M, Xing G, Yuan L et al (2011) Neuroligin 2 is required for synapse development and function at the Drosophila neuromuscular junction. J Neurosci 31:687–699. https://doi.org/10.1523/JNEUROSCI.3854-10.2011
Xing G, Gan G, Chen D et al (2014) Drosophila neuroligin3 regulates neuromuscular junction development and synaptic differentiation. J Biol Chem 289:31867–31877. https://doi.org/10.1074/jbc.M114.574897
Li Y, Zhou Z, Zhang X et al (2013) Drosophila neuroligin 4 regulates sleep through modulating GABA transmission. J Neurosci 33:15545–15554. https://doi.org/10.1523/JNEUROSCI.0819-13.2013
Hunter JW, Mullen GP, McManus JR et al (2010) Neuroligin-deficient mutants of C. elegans have sensory processing deficits and are hypersensitive to oxidative stress and mercury toxicity. Dis Model Mech 3:366–376. https://doi.org/10.1242/dmm.003442
Boucard AA, Chubykin AA, Comoletti D et al (2005) A splice code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to α- and β-neurexins. Neuron 48:229–236. https://doi.org/10.1016/j.neuron.2005.08.026
Lee H, Dean C, Isacoff E (2010) Alternative splicing of neuroligin regulates the rate of presynaptic differentiation. J Neurosci 30:11435–11446. https://doi.org/10.1523/JNEUROSCI.2946-10.2010
Chih B, Gollan L, Scheiffele P (2006) Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex. Neuron 51:171–178. https://doi.org/10.1016/j.neuron.2006.06.005
Schreiner D, Nguyen TM, Russo G et al (2014) Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins. Neuron. https://doi.org/10.1016/j.neuron.2014.09.011
Nguyen TM, Schreiner D, Xiao L et al (2016) An alternative splicing switch shapes neurexin repertoires in principal neurons versus interneurons in the mouse hippocampus. Elife. https://doi.org/10.7554/eLife.22757.001
Südhof TC (2017) Synaptic neurexin complexes: a molecular code for the logic of neural circuits. Cell 171:745–769
Dai J, Aoto J, Südhof TC (2019) Alternative splicing of presynaptic neurexins differentially controls postsynaptic NMDA and AMPA receptor responses. Neuron 102:993–1008.e5. https://doi.org/10.1016/j.neuron.2019.03.032
Lukacsovich D, Winterer J, Que L et al (2019) Single-cell RNA-Seq reveals developmental origins and ontogenetic stability of neurexin alternative splicing profiles. Cell Rep. https://doi.org/10.1016/j.celrep.2019.05.090
Irie M, Hata Y, Takeuchi M et al (1997) Binding of neuroligins to PSD-95. Science. https://doi.org/10.1126/science.277.5331.1511
Arons MH, Thynne CJ, Grabrucker AM et al (2012) Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling. J Neurosci. https://doi.org/10.1523/JNEUROSCI.2215-12.2012
Poulopoulos A, Aramuni G, Meyer G et al (2009) Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin. Neuron 63:628–642. https://doi.org/10.1016/j.neuron.2009.08.023
Scheiffele P, Fan J, Choih J et al (2000) Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 101:657–669. https://doi.org/10.1016/S0092-8674(00)80877-6
Ko J, Zhang C, Arac D et al (2009) Neuroligin-1 performs neurexin-dependent and neurexin-independent functions in synapse validation. EMBO J. https://doi.org/10.1038/emboj.2009.249
Etherton MR, Tabuchi K, Sharma M et al (2011) An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus. EMBO J 30:2908–2919. https://doi.org/10.1038/emboj.2011.182
Zhang C, Milunsky JM, Newton S et al (2009) A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export. J Neurosci. https://doi.org/10.1523/jneurosci.1248-09.2009
Varoqueaux F, Aramuni G, Rawson RL et al (2006) Neuroligins determine synapse maturation and function. Neuron 51:741–754. https://doi.org/10.1016/j.neuron.2006.09.003
Uchigashima M, Ohtsuka T, Kobayashi K, Watanabe M (2016) Dopamine synapse is a neuroligin-2-mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures. Proc Natl Acad Sci U S A 113:201514074. https://doi.org/10.1073/pnas.1514074113
Hoon M, Soykan T, Falkenburger B et al (2011) Neuroligin-4 is localized to glycinergic postsynapses and regulates inhibition in the retina. Proc Natl Acad Sci USA 108:3053–3058. https://doi.org/10.1073/pnas.1006946108
Takács VT, Freund TF, Nyiri G (2013) Neuroligin 2 is expressed in synapses established by cholinergic cells in the mouse brain. PLoS ONE. https://doi.org/10.1371/journal.pone.0072450
Budreck EC, Scheiffele P (2007) Neuroligin-3 is a neuronal adhesion protein at GABAergic and glutamatergic synapses. Eur J Neurosci 26:1738–1748. https://doi.org/10.1111/j.1460-9568.2007.05842.x
Knight D, Xie W, Boulianne GL (2011) Neurexins and neuroligins: recent insights from invertebrates. Mol Neurobiol 44(3):426–440. https://doi.org/10.1007/s12035-011-8213-1
Südhof TC (2008) Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455:903–911. https://doi.org/10.1038/nature07456
Craig AM, Kang Y (2007) Neurexin-neuroligin signaling in synapse development. Curr Opin Neurobiol 17:43–52
Bellone C, Nicoll RA (2007) Rapid bidirectional switching of synaptic NMDA receptors. Neuron 55:779–785. https://doi.org/10.1016/j.neuron.2007.07.035
Bemben MA, Shipman SL, Nicoll RA, Roche KW (2015) The cellular and molecular landscape of neuroligins. Trends Neurosci 38:496–505
Südhof TC (2018) Towards an understanding of synapse formation. Neuron 100:276–293. https://doi.org/10.1016/J.NEURON.2018.09.040
Jorgensen EM, Nonet ML (1995) Neuromuscular junctions in the nematode C. elegans. Semin Dev Biol 6:207–220. https://doi.org/10.1016/S1044-5781(06)80030-7
McIntire SL, Jorgensen E, Horvitz HR (1993) Genes required for GABA function in Caenorhabditis elegans. Nature 364:334–337. https://doi.org/10.1038/364334a0
McIntire SL, Jorgensen E, Kaplan J, Horvitz HR (1993) The GABAergic nervous system of Caenorhabditis elegans. Nature 364:337–341. https://doi.org/10.1038/364337a0
Lewis JA, Wu CH, Levine JH, Berg H (1980) Levamisole-resitant mutants of the nematode Caenorhabditis elegans appear to lack pharmacological acetylcholine receptors. Neuroscience 5:967–989. https://doi.org/10.1016/0306-4522(80)90180-3
Tu H, Pinan-Lucarre B, Ji T et al (2015) C. elegans punctin clusters GABA(A) receptors via neuroligin binding and UNC-40/DCC recruitment. Neuron 86:1407–1419. https://doi.org/10.1016/j.neuron.2015.05.013
Maro GS, Gao S, Olechwier AM et al (2015) MADD-4/punctin and neurexin organize C. elegans GABAergic postsynapses through neuroligin. Neuron 86:1420–1432. https://doi.org/10.1016/j.neuron.2015.05.015
Haklai-Topper L, Soutschek J, Sabanay H et al (2011) The neurexin superfamily of Caenorhabditis elegans. Gene Expr Patterns 11:144–150. https://doi.org/10.1016/j.gep.2010.10.008
Pinan-Lucarré B, Tu H, Pierron M et al (2014) C. elegans punctin specifies cholinergic versus GABAergic identity of postsynaptic domains. Nature 511:466–470. https://doi.org/10.1038/nature13313
Hu Z, Hom S, Kudze T et al (2012) Neurexin and neuroligin mediate retrograde synaptic inhibition in C. elegans. Science. https://doi.org/10.1126/science.1224896
Calahorro F, Holden-Dye L, O’Connor V (2015) Analysis of splice variants for the C. elegans orthologue of human neuroligin reveals a developmentally regulated transcript. Gene Expr Patterns. https://doi.org/10.1016/j.gep.2015.02.002
Soykan T, Schneeberger D, Tria G et al (2014) A conformational switch in collybistin determines the differentiation of inhibitory postsynapses. EMBO J. https://doi.org/10.15252/embj.201488143
Mosca TJ, Hong W, Dani VS et al (2012) Trans-synaptic Teneurin signalling in neuromuscular synapse organization and target choice. Nature 484:237–241. https://doi.org/10.1038/nature10923
Schmid A, Hallermann S, Kittel RJ et al (2008) Activity-dependent site-specific changes of glutamate receptor composition in vivo. Nat Neurosci 11:659–666. https://doi.org/10.1038/nn.2122
Chen Y-C, Lin YQ, Banerjee S et al (2012) Drosophila neuroligin 2 is required presynaptically and postsynaptically for proper synaptic differentiation and synaptic transmission. J Neurosci 32:16018–16030. https://doi.org/10.1523/JNEUROSCI.1685-12.2012
Mozer BA, Sandstrom DJ (2012) Drosophila neuroligin 1 regulates synaptic growth and function in response to activity and phosphoinositide-3-kinase. Mol Cell Neurosci 51:89–100. https://doi.org/10.1016/j.mcn.2012.08.010
Zhang B, Gokce O, Hale WD et al (2018) Autism-associated neuroligin-4 mutation selectively impairs glycinergic synaptic transmission in mouse brainstem synapses. J Exp Med 215:1543–1553. https://doi.org/10.1084/jem.20172162
Ichtchenko K, Nguyen T, Südhof TC (1996) Structures, alternative splicing, and neurexin binding of multiple neuroligins. J Biol Chem. https://doi.org/10.1074/jbc.271.5.2676
Singh SK, Stogsdill JA, Pulimood NS et al (2016) Astrocytes assemble thalamocortical synapses by bridging NRX1α and NL1 via hevin. Cell. https://doi.org/10.1016/j.cell.2015.11.034
Aoto J, Martinelli DC, Malenka RC et al (2013) Presynaptic neurexin-3 alternative splicing trans-synaptically controls postsynaptic AMPA receptor trafficking. Cell. https://doi.org/10.1016/j.cell.2013.05.060
Dai J, Aoto J, Südhof TC (2019) Alternative splicing of presynaptic neurexins differentially controls postsynaptic NMDA and AMPA receptor responses. Neuron. https://doi.org/10.1016/j.neuron.2019.03.032
Varoqueaux F, Jamain S, Brose N (2004) Neuroligin 2 is exclusively localized to inhibitory synapses. Eur J Cell Biol 83:449–456. https://doi.org/10.1078/0171-9335-00410
Zhang B, Chen LY, Liu X et al (2015) Neuroligins sculpt cerebellar Purkinje-cell circuits by differential control of distinct classes of synapses. Neuron 87:781–796. https://doi.org/10.1016/j.neuron.2015.07.020
Kakegawa W, Mitakidis N, Miura E et al (2015) Anterograde C1ql1 signaling is required in order to determine and maintain a single-winner climbing fiber in the mouse cerebellum. Neuron 85:316–330. https://doi.org/10.1016/j.neuron.2014.12.020
Sigoillot SM, Iyer K, Binda F et al (2015) The secreted protein C1QL1 and its receptor BAI3 control the synaptic connectivity of excitatory inputs converging on cerebellar purkinje cells. Cell Rep. https://doi.org/10.1016/j.celrep.2015.01.034
Landsend AS, Amiry-Moghaddam M, Matsubara A et al (1997) Differential localization of δ glutamate receptors in the rat cerebellum: coexpression with AMPA receptors in parallel fiber-spine synapses and absence from climbing fiber-spine synapses. J Neurosci. https://doi.org/10.1523/jneurosci.17-02-00834.1997
Zhao HM, Wenthold RJ, Petralia RS (1998) Glutamate receptor targeting to synaptic populations on Purkinje cells is developmentally regulated. J Neurosci 18:5517–5528
Zhang B, Seigneur E, Wei P et al (2017) Developmental plasticity shapes synaptic phenotypes of autism-associated neuroligin-3 mutations in the calyx of Held. Mol Psychiatry 22:1483–1491. https://doi.org/10.1038/mp.2016.157
Seigneur E, Südhof TC (2018) Genetic ablation of all cerebellins reveals synapse organizer functions in multiple regions throughout the brain. J Neurosci. https://doi.org/10.1523/JNEUROSCI.0360-18.2018
Hirai H, Pang Z, Bao D et al (2005) Cbln1 is essential for synaptic integrity and plasticity in the cerebellum. Nat Neurosci 8:1534–1541. https://doi.org/10.1038/nn1576
Uemura T, Lee SJ, Yasumura M et al (2010) Trans-synaptic interaction of GluRδ2 and neurexin through Cbln1 mediates synapse formation in the cerebellum. Cell 141:1068–1079. https://doi.org/10.1016/j.cell.2010.04.035
Matsuda K, Miura E, Miyazaki T et al (2010) Cbln1 is a ligand for an orphan glutamate receptor delta2, a bidirectional synapse organizer. Science 328:363–368. https://doi.org/10.1126/science.1185152
Zhang B, Südhof TC (2016) Neuroligins are selectively essential for NMDAR signaling in cerebellar stellate interneurons. J Neurosci 36:9070–9083. https://doi.org/10.1523/JNEUROSCI.1356-16.2016
Nozawa K, Hayashi A, Motohashi J et al (2018) Cellular and subcellular localization of endogenous neuroligin-1 in the cerebellum. Cerebellum. https://doi.org/10.1007/s12311-018-0966-x
Konno K, Matsuda K, Nakamoto C et al (2014) Enriched expression of GluD1 in higher brain regions and its involvement in parallel fiber-interneuron synapse formation in the cerebellum. J Neurosci 34:7412–7424. https://doi.org/10.1523/JNEUROSCI.0628-14.2014
Alcami P, Marty A (2013) Estimating functional connectivity in an electrically coupled interneuron network. Proc Natl Acad Sci USA 110:E4798–E4807. https://doi.org/10.1073/pnas.1310983110
Chen LY, Jiang M, Zhang B et al (2017) Conditional deletion of all neurexins defines diversity of essential synaptic organizer functions for neurexins. Neuron 94:611–625.e4. https://doi.org/10.1016/j.neuron.2017.04.011
Andersen P, Morris R, Amaral D et al (2007) The hippocampus book. Oxford University Press, New York
Amaral DG, Witter MP (1989) The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31:571–591. https://doi.org/10.1016/0306-4522(89)90424-7
Donato F, Jacobsen RI, Moser M-B, Moser EI (2017) Stellate cells drive maturation of the entorhinal-hippocampal circuit. Science. https://doi.org/10.1126/science.aai8178
Pokorný J, Yamamoto T (1981) Postnatal ontogenesis of hippocampal CA1 area in rats. I. Development of dendritic arborisation in pyramidal neurons. Brain Res Bull. https://doi.org/10.1016/0361-9230(81)90075-7
Paolicelli RC, Bolasco G, Pagani F et al (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333:1456–1458. https://doi.org/10.1126/science.1202529
Cohen AS, Lin DD, Coulter DA (2000) Protracted postnatal development of inhibitory synaptic transmission in rat hippocampal area CA1 neurons. J Neurophysiol. https://doi.org/10.1152/jn.2000.84.5.2465
Jiang M, Polepalli J, Chen LY et al (2016) Conditional ablation of neuroligin-1 in CA1 pyramidal neurons blocks LTP by a cell-autonomous NMDA receptor-independent mechanism. Mol Psychiatry. https://doi.org/10.1038/mp.2016.80
Wu X, Morishita WK, Riley AM et al (2019) Neuroligin-1 signaling controls LTP and NMDA receptors by distinct molecular pathways. Neuron. https://doi.org/10.1016/j.neuron.2019.02.013
Dang R, Qi J, Liu A et al (2018) Regulation of hippocampal long term depression by neuroligin 1. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2018.09.035
Soler-Llavina GJ, Fuccillo MV, Ko J et al (2011) Inaugural article: the neurexin ligands, neuroligins and leucine-rich repeat transmembrane proteins, perform convergent and divergent synaptic functions in vivo. Proc Natl Acad Sci 108:16502–16509. https://doi.org/10.1073/pnas.1114028108
Bhouri M, Morishita W, Temkin P et al (2018) Deletion of LRRTM1 and LRRTM2 in adult mice impairs basal AMPA receptor transmission and LTP in hippocampal CA1 pyramidal neurons. Proc Natl Acad Sci. https://doi.org/10.1073/pnas.1803280115
Soler-Llavina GJ, Fuccillo MV, Ko J et al (2011) The neurexin ligands, neuroligins and leucine-rich repeat transmembrane proteins, perform convergent and divergent synaptic functions in vivo. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1114028108
Tao W, Díaz-Alonso J, Sheng N, Nicoll RA (2018) Postsynaptic d1 glutamate receptor assembles and maintains hippocampal synapses via Cbln2 and neurexin. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1802737115
Polepalli JS, Wu H, Goswami D et al (2017) Modulation of excitation on parvalbumin interneurons by neuroligin-3 regulates the hippocampal network. Nat Neurosci 20:219–229. https://doi.org/10.1038/nn.4471
Cao W, Lin S, Xia Q et al (2018) Gamma oscillation dysfunction in mPFC leads to social deficits in neuroligin 3 R451C knockin mice. Neuron 97:1253–1260.e7. https://doi.org/10.1016/j.neuron.2018.02.001
Pettem KL, Yokomaku D, Takahashi H et al (2013) Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development. J Cell Biol 200:321–336. https://doi.org/10.1083/jcb.201206028
Connor SA, Ammendrup-Johnsen I, Kishimoto Y et al (2017) Loss of synapse repressor MDGA1 enhances perisomatic inhibition, confers resistance to network excitation, and impairs cognitive function. Cell Rep. https://doi.org/10.1016/j.celrep.2017.11.109
Connor SA, Ammendrup-Johnsen I, Chan AW et al (2016) Altered cortical dynamics and cognitive function upon haploinsufficiency of the autism-linked excitatory synaptic suppressor MDGA2. Neuron. https://doi.org/10.1016/j.neuron.2016.08.016
Lee K, Kima Y, Lee SJ et al (2013) MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1219987110
Yamasaki T, Hoyos-Ramirez E, Martenson JS et al (2017) GARLH Family proteins stabilize GABAA receptors at synapses. Neuron. https://doi.org/10.1016/j.neuron.2017.02.023
Wu M, Tian HL, Liu X et al (2018) Impairment of inhibitory synapse formation and motor behavior in mice lacking the NL2 binding partner LHFPL4/GARLH4. Cell Rep. https://doi.org/10.1016/j.celrep.2018.04.015
Sando R, Jiang X, Südhof TC (2019) Latrophilin GPCRs direct synapse specificity by coincident binding of FLRTs and teneurins. Science. https://doi.org/10.1126/science.aav7969
Anderson GR, Maxeiner S, Sando R et al (2017) Postsynaptic adhesion GPCR latrophilin-2 mediates target recognition in entorhinal-hippocampal synapse assembly. J Cell Biol. https://doi.org/10.1083/jcb.201703042
Kelley AE, Domesick VB, Nauta WJH (1982) The amygdalostriatal projection in the rat-an anatomical study by anterograde and retrograde tracing methods. Neuroscience. https://doi.org/10.1016/0306-4522(82)90067-7
Gerfen CR (1984) The neostriatal mosaic: compartmentalization of corticostriatal input and striatonigral output systems. Nature 311:461–464. https://doi.org/10.1038/311461a0
Voorn P, Vanderschuren LJMJ, Groenewegen HJ et al (2004) Putting a spin on the dorsal-ventral divide of the striatum. Trends Neurosci 27:468–474
Pan WX, Mao T, Dudman JT (2010) Inputs to the dorsal striatum of the mouse reflect the parallel circuit architecture of the forebrain. Front Neuroanat 4:147. https://doi.org/10.3389/fnana.2010.00147
Gerfen CR, Engber TM, Mahan LC et al (1990) D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250:1429–1432. https://doi.org/10.1126/science.2147780
Kreitzer AC, Malenka RC (2008) Striatal plasticity and basal ganglia circuit function. Neuron 60:543–554
Gerfen CR, Surmeier DJ (2011) Modulation of striatal projection systems by dopamine. Annu Rev Neurosci 34:441–466. https://doi.org/10.1146/annurev-neuro-061010-113641
Espinosa F, Xuan Z, Liu S, Powell CM (2015) Neuroligin 1 modulates striatal glutamatergic neurotransmission in a pathway and NMDAR subunit-specific manner. Front Synaptic Neurosci. https://doi.org/10.3389/fnsyn.2015.00011
Witten IB, Lin S-C, Brodsky M et al (2010) Cholinergic interneurons control local circuit activity and cocaine conditioning. Science 330:1677–1681. https://doi.org/10.1126/science.1193771
Brown MTC, Tan KR, O’Connor EC et al (2012) Ventral tegmental area GABA projections pause accumbal cholinergic interneurons to enhance associative learning. Nature 492:452–456. https://doi.org/10.1038/nature11657
Karayannis T, Au E, Patel JC et al (2014) Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission. Nature 511:236–240. https://doi.org/10.1038/nature13248
Rothwell PE, Fuccillo MV, Maxeiner S et al (2014) Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors. Cell 158:198–212. https://doi.org/10.1016/j.cell.2014.04.045
Cao W, Lin S, Xia QQ et al (2018) Gamma oscillation dysfunction in mPFC leads to social deficits in neuroligin 3 R451C knockin mice. Neuron. https://doi.org/10.1016/j.neuron.2018.02.001
Tabuchi K, Blundell J, Etherton MR et al (2007) A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318:71–76. https://doi.org/10.1126/science.1146221
Jung SY, Kim J, Bin KO et al (2010) Input-specific synaptic plasticity in the amygdala is regulated by neuroligin-1 via postsynaptic NMDA receptors. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1001084107
Kim J, Jung S-Y, Lee YK et al (2008) Neuroligin-1 is required for normal expression of LTP and associative fear memory in the amygdala of adult animals. Proc Natl Acad Sci USA 105:9087–9092. https://doi.org/10.1073/pnas.0803448105
Troyano-Rodriguez E, Wirsig-Wiechmann CR, Ahmad M (2019) Neuroligin-2 determines inhibitory synaptic transmission in the lateral septum to optimize stress-induced neuronal activation and avoidance behavior. Biol Psychiatry. https://doi.org/10.1016/j.biopsych.2019.01.022
Zeisel A, Hochgerner H, Lönnerberg P et al (2018) Molecular architecture of the mouse nervous system. Cell 174:999–1014.e22. https://doi.org/10.1016/j.cell.2018.06.021
Gilbert M, Smith J, Roskams AJ, Auld VJ (2001) Neuroligin 3 is a vertebrate gliotactin expressed in the olfactory ensheathing glia, a growth-promoting class of macroglia. Glia 34:151–164. https://doi.org/10.1002/glia.1050
The Tabula Muris Consortium (2018) Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 562:367–372. https://doi.org/10.1038/s41586-018-0590-4
Stogsdill JA, Ramirez J, Liu D et al (2017) Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis. Nature 551:192–197. https://doi.org/10.1038/nature24638
Bourgeron T (2015) From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nat Rev Neurosci 16:551–563. https://doi.org/10.1038/nrn3992
Sindi IA, Tannenberg RK, Dodd PR (2014) A role for the neurexin-neuroligin complex in Alzheimer’s disease. Neurobiol Aging 35:746–756
Venkatesh HS, Johung TB, Caretti V et al (2015) Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell 161:803–816. https://doi.org/10.1016/j.cell.2015.04.012
Acknowledgements
This research was supported by Shenzhen-Hong Kong Institute of Brain Science (2019SHIBS0004) (to B. Zhang). We would like to thank Dr. Justin Trotter (Stanford University) for discussion and feedback, and Drs. Zhihui Liu (Stanford University) and Lulu Chen (University of California, Irvine) for the reading of the early manuscript.
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Qin, L., Guo, S., Han, Y. et al. Functional mosaic organization of neuroligins in neuronal circuits. Cell. Mol. Life Sci. 77, 3117–3127 (2020). https://doi.org/10.1007/s00018-020-03478-y
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DOI: https://doi.org/10.1007/s00018-020-03478-y