Perturbed synaptic adhesion molecules signaling in neurodevelopmental disorders: The impact of metal neurotoxicity

Abstract

Synaptic adhesion molecules (SAMs) are glycoproteins localized on neuronal surfaces, primarily expressed at synaptic plasma membranes. SAMs play a role in inducing formation, maturation, plasticity, and assembly of synaptic connections, which are vital for normal neurodevelopment. SAMs link the pre- and post-synaptic compartments and assist in inter-synaptic signaling and recognition. An increasing variety of SAMs, including neurexins and neuroligins, immunoglobulin (Ig) domain proteins-like synaptic cell adhesion molecule (SynCAM) and neural cell adhesion molecule, receptor phosphotyrosine kinases and phosphatases, as well as various leucine-rich repeat proteins, have been identified. Neurodevelopmental disorders (NDDs), like autism, attention deficit hyperactivity disorder, intellectual disabilities, and cerebral palsy, have been associated with altered SAMs. NDDs are characterized by a spectrum of challenges stemming from abnormal brain development. The etiology of these disorders involves the interaction between genes and environmental factors, such as metals. This review aims to provide a comprehensive overview of the literature, highlighting the role of SAMs in NDDs and potential mechanisms via which neurotoxic metals may contribute to the pathogenesis of NDDs that could involve perturbations in SAMs. Understanding these interconnections will assist in identifying therapeutic targets for these disorders.

Keywords

neurodevelopmental disorders / neurotoxic metals / synapses and autism / synaptic adhesion molecules

References

[1] Harris KP, Littleton JT. Transmission, development, and plasticity of synapses. Genetics. 2015; 201(2):345-375.

[2] Südhof TC. Towards an understanding of synapse formation. Neuron. 2018; 100(2):276-293.

[3] Rudenko G. Dynamic control of synaptic adhesion and organizing molecules in synaptic plasticity. Neural Plast. 2017; 2017(1):6526151.

[4] Biederer T, Kaeser PS, Blanpied TA. Transcellular nanoalignment of synaptic function. Neuron. 2017; 96(3):680-696.

[5] Lisman JE, Harris KM. Quantal analysis and synaptic anatomy--integrating two views of hippocampal plasticity. Trends Neurosci. 1993; 16(4):141-147.

[6] Evans GJO. The synaptosome as a model system for studying synaptic physiology. Cold Spring Harbor Protocols. 2015; 2015(5):pdb.top074450.

[7] El-Husseini A. Adhesion Molecules at the Synapse. Structural and Functional Organization Of The Synapse. Springer; 2008:173-204.

[8] Scheiffele P. Cell-cell signaling during synapse formation in the CNS. Annu Rev Neurosci. 2003; 26(1):485-508.

[9] Wang M, Fan J, Shao Z. Cellular and molecular mechanisms underlying synaptic subcellular specificity. Brain Sci. 2024; 14(2):155.

[10] Batool S, Raza H, Zaidi J, Riaz S, Hasan S, Syed NI. Synapse formation: from cellular and molecular mechanisms to neurodevelopmental and neurodegenerative disorders. J Neurophysiol. 2019; 121(4):1381-1397.

[11] Scheiffele P, Fan J, Choih J, Fetter R, Serafini T. Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell. 2000; 101(6):657-669.

[12] Biederer T, Sara Y, Mozhayeva M, et al. SynCAM, a synaptic adhesion molecule that drives synapse assembly. Science. 2002; 297(5586):1525-1531.

[13] Verpoort B, de Wit J. Cell adhesion molecule signaling at the synapse: beyond the scaffold. Cold Spring Harbor Perspect Biol. 2024; 16(5):a041501.

[14] Bogaciu CA, Rizzoli SO. Membrane trafficking of synaptic adhesion molecules. J Physiol. 2024; 603(20):5921-5934.

[15] Dalva MB, McClelland AC, Kayser MS. Cell adhesion molecules: signalling functions at the synapse. Nat Rev Neurosci. 2007; 8(3):206-220.

[16] Missler M, Sudhof TC, Biederer T. Synaptic cell adhesion. Cold Spring Harbor Perspect Biol. 2012; 4(4):a005694.

[17] Südhof TC. Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008; 455(7215):903-911.

[18] Körber N, Stein V. In vivo imaging demonstrates dendritic spine stabilization by SynCAM 1. Sci Rep. 2016; 6(1):24241.

[19] Morimura N, Yasuda H, Yamaguchi K, et al. Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice. Nat Commun. 2017; 8(1):15800.

[20] Kim HY, Um JW, Ko J. Proper synaptic adhesion signaling in the control of neural circuit architecture and brain function. Prog Neurobiol. 2021; 200:101983.

[21] Tabuchi K, Blundell J, Etherton MR, et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science. 2007; 318(5847):71-76.

[22] Cheroni C, Caporale N, Testa G. Autism spectrum disorder at the crossroad between genes and environment: contributions, convergences, and interactions in ASD developmental pathophysiology. Mol Autism. 2020; 11(1):69.

[23] Harper KM, Harp SJ, Moy SS. Prenatal stress unmasks behavioral phenotypes in genetic mouse models of neurodevelopmental disorders. Front Behav Neurosci. 2023; 17:1271225.

[24] Ijomone OM, Weishaupt A-K, Michaelis V, Ijomone OK, Bornhorst J. p38- and ERK-MAPK signalling modulate developmental neurotoxicity of nickel and vanadium in the Caenorhabditis elegans model. Kinases and Phosphatases. 2024; 2(1):28-42.

[25] Ijomone OM, Ifenatuoha CW, Aluko OM, Ijomone OK, Aschner M. The aging brain: impact of heavy metal neurotoxicity. Crit Rev Toxicol. 2020; 50(9):801-814.

[26] Ijomone OM, Olung NF, Akingbade GT, Okoh COA, Aschner M. Environmental influence on neurodevelopmental disorders: Potential association of heavy metal exposure and autism. J Trace Elem Med Biol. 2020; 62:126638.

[27] Grandjean P, Landrigan P. Developmental neurotoxicity of industrial chemicals. Lancet. 2006; 368(9553):2167-2178.

[28] Ruszkiewicz JA, Pinkas A, Miah MR, et al. C. elegans as a model in developmental neurotoxicology. Toxicol Appl Pharmacol. 2018; 354:126-135.

[29] Skogheim TS, Weyde KVF, Engel SM, et al. Metal and essential element concentrations during pregnancy and associations with autism spectrum disorder and attention-deficit/hyperactivity disorder in children. Environ Int. 2021; 152:106468.

[30] Yasuda H, Tsutsui T. Metallomics analysis for early assessment and individualized intervention of neurodevelopmental disorders. Metallomics. 2022; 14(9):mfac067.

[31] Breysse PN ATSDR 2020: Toxicological Profile for Lead. Regulations. Published Dec 23, 2024. https://www.regulations.gov/document/EPA-HQ-OPPT-2024-0085-0176

[32] ATSDR AfTSaDR. Toxicological Profile for Mercury. ATSDR; Published Nov 05 2024. https://wwwn.cdc.gov/TSP/ToxProfiles/ToxProfiles.aspx?id=115&tid=24

[33] Ijomone OK, Ukwubile II, Aneke VO, et al. Glial perturbation in metal neurotoxicity: implications for brain disorders. Neuroglia. 2025; 6(1):4.

[34] Nguyen T. Total number of synapses in the adult human neocortex. Undergraduate J Math Model: One+Two. 2013; 3(1):26.

[35] Piechotta K, Dudanova I, Missler M. The resilient synapse: insights from genetic interference of synaptic cell adhesion molecules. Cell Tissue Res. 2006; 326(2):617-642.

[36] Akins MR, Biederer T. Cell-cell interactions in synaptogenesis. Curr Opin Neurobiol. 2006; 16(1):83-89.

[37] Olsen O, Moore KA, Fukata M, et al. Neurotransmitter release regulated by a MALS–liprin-α presynaptic complex. J Cell Biol. 2005; 170(7):1127-1134.

[38] Zhang H, Lei M, Zhang Y, et al. Phosphorylation of Doc2 by EphB2 modulates Munc13-mediated SNARE complex assembly and neurotransmitter release. Sci Adv. 2024; 10(20):eadi7024.

[39] Südhof TC. The cell biology of synapse formation. J Cell Biol. 2021; 220(7):e202103052.

[40] Liu J, Misra A, Reddy MVVVS, White MA, Ren G, Rudenko G. Structural plasticity of neurexin 1α: implications for its role as synaptic organizer. J Mol Biol. 2018; 430(21):4325-4343.

[41] McMahon SA, Díaz E. Mechanisms of excitatory synapse maturation by trans-synaptic organizing complexes. Curr Opin Neurobiol. 2011; 21(2):221-227.

[42] de Wit J, Ghosh A. Specification of synaptic connectivity by cell surface interactions. Nat Rev Neurosci. 2016; 17(1):4.

[43] Jang S, Lee H, Kim E. Synaptic adhesion molecules and excitatory synaptic transmission. Curr Opin Neurobiol. 2017; 45:45-50.

[44] Ramirez JJ, Bindu DS, Eroglu C. Building and destroying synaptic bridges: how do Hevin/Sparcl1, SPARC, and MDGAs modify trans-synaptic neurexin-neuroligin interactions? Structure. 2021; 29(7):635-637.

[45] Gan KJ, Südhof TC. SPARCL1 promotes excitatory but not inhibitory synapse formation and function independent of neurexins and neuroligins. J Neurosci. 2020; 40(42):8088-8102.

[46] Chanda S, Hale WD, Zhang B, Wernig M, Südhof TC. Unique versus redundant functions of neuroligin genes in shaping excitatory and inhibitory synapse properties. J Neurosci. 2017; 37(29):6816-6836.

[47] Varoqueaux F, Aramuni G, Rawson RL, et al. Neuroligins determine synapse maturation and function. Neuron. 2006; 51(6):741-754.

[48] Lardi-Studler B, Fritschy JM. Matching of pre- and postsynaptic specializations during synaptogenesis. Neuroscientist. 2007; 13(2):115-126.

[49] Bickford ME. Synaptic organization of the dorsal lateral geniculate nucleus. Eur J Neurosci. 2019; 49(7):938-947.

[50] Shepherd GM. Symposium overview and historical perspective: dendrodendritic synapses: past, present, and future. Ann NY Acad Sci. 2009; 1170:215-223.

[51] Südhof TC. Synaptic neurexin complexes: a molecular code for the logic of neural circuits. Cell. 2017; 171(4):745-769.

[52] Harris KM, Weinberg RJ. Ultrastructure of synapses in the mammalian brain. Cold Spring Harbor Perspect Biol. 2012; 4(5):a005587.

[53] Zuber B, Nikonenko I, Klauser P, Muller D, Dubochet J. The mammalian central nervous synaptic cleft contains a high density of periodically organized complexes. Pro Natl Acad Sci. 2005; 102(52):19192-19197.

[54] Nguyen T, Südhof TC. Binding properties of neuroligin 1 and neurexin 1β reveal function as heterophilic cell adhesion molecules. J Biol Chem. 1997; 272(41):26032-26039.

[55] Ullrich B, Ushkaryov YA, Südhof TC. Cartography of neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons. Neuron. 1995; 14(3):497-507.

[56] Taniguchi H, Gollan L, Scholl FG, et al. Silencing of neuroligin function by postsynaptic neurexins. J Neurosci. 2007; 27(11):2815-2824.

[57] Berninghausen O, Rahman MA, Silva JP, Davletov B, Hopkins C, Ushkaryov YA. Neurexin Iβ and neuroligin are localized on opposite membranes in mature central synapses. J Neurochem. 2007; 103(5):1855-1863.

[58] Bottos A, Rissone A, Bussolino F, Arese M. Neurexins and neuroligins: synapses look out of the nervous system. Cell Mol Life Sci. 2011; 68(16):2655-2666.

[59] Shan D, Song Y, Zhang Y, et al. Neurexin dysfunction in neurodevelopmental and neuropsychiatric disorders: a PRIMSA-based systematic review through iPSC and animal models. Front Behav Neurosci. 2024; 18:1297374.

[60] Ichtchenko K, Hata Y, Nguyen T, et al. Neuroligin 1: A splice site-specific ligand for β-neurexins. Cell. 1995; 81(3):435-443.

[61] Wang J, Sudhof T, Wernig M. Distinct mechanisms control the specific synaptic functions of neuroligin 1 and neuroligin 2. EMBO Rep. 2025; 26(3):860-879.

[62] Lisé MF, El-Husseini A. The neuroligin and neurexin families: from structure to function at the synapse. Cell Mol Life Sci. 2006; 63:1833-1849.

[63] Maxeiner S, Benseler F, Brose N, Krasteva-Christ G. Of humans and gerbils—independent diversification of neuroligin-4 into X-and Y-Specific genes in primates and rodents. Front Mol Neurosci. 2022; 15:838262.

[64] Born G, Grayton HM, Langhorst H, et al. Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors. Front Synaptic Neurosci. 2015; 7:3.

[65] Zhang B, Seigneur E, Wei P, Gokce O, Morgan J, Südhof TC. Developmental plasticity shapes synaptic phenotypes of autism-associated neuroligin-3 mutations in the calyx of Held. Mol Psychiatry. 2017; 22(10):1483-1491.

[66] Boucard AA, Chubykin AA, Comoletti D, Taylor P, Südhof TC. A splice code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to α- and β-neurexins. Neuron. 2005; 48(2):229-236.

[67] Reissner C, Klose M, Fairless R, Missler M. Mutational analysis of the neurexin/neuroligin complex reveals essential and regulatory components. Proc Natl Acad Sci. 2008; 105(39):15124-15129.

[68] Araç D, Boucard AA, Özkan E, et al. Structures of neuroligin-1 and the neuroligin-1/neurexin-1β complex reveal specific protein-protein and protein-Ca2+ interactions. Neuron. 2007; 56(6):992-1003.

[69] Graf ER, Kang Y, Hauner AM, Craig AM. Structure function and splice site analysis of the synaptogenic activity of the neurexin-1β LNS domain. J Neurosci. 2006; 26(16):4256-4265.

[70] Iijima T, Wu K, Witte H, et al. SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1. Cell. 2011; 147(7):1601-1614.

[71] Lalo U, Koh W, Lee CJ, Pankratov Y. The tripartite glutamatergic synapse. Neuropharmacology. 2021; 199:108758.

[72] Heller JP, Rusakov DA. The nanoworld of the tripartite synapse: insights from super-resolution microscopy. Front Cell Neurosci. 2017; 11:374.

[73] Chelini G, Pantazopoulos H, Durning P, Berretta S. The tetrapartite synapse: a key concept in the pathophysiology of schizophrenia. Eur Psychiatry. 2018; 50:60-69.

[74] Stasenko SV, Kazantsev VB. Spiking neural network with tetrapartite synapse. Springer. 2023; 1120:83-92.

[75] Singh SK, Stogsdill JA, Pulimood NS, et al. Astrocytes assemble thalamocortical synapses by bridging NRX1α and NL1 via hevin. Cell. 2016; 164(1-2):183-196.

[76] Carstens KE, Phillips ML, Pozzo-Miller L, Weinberg RJ, Dudek SM. Perineuronal nets suppress plasticity of excitatory synapses on CA2 pyramidal neurons. J Neurosci. 2016; 36(23):6312-6320.

[77] Hug L, Mpai R. Optimization of experimental conditions to characterize perineuronal nets in the human cerebellum. McGill Science Undergraduate Res J. 2024; 19(1):1-5.

[78] Cao X, Tabuchi K. Functions of synapse adhesion molecules neurexin/neuroligins and neurodevelopmental disorders. Neurosci Res. 2017; 116:3-9.

[79] Ribeiro LF, Verpoort B, de Wit J. Trafficking mechanisms of synaptogenic cell adhesion molecules. Mol Cell Neurosci. 2018; 91:34-47.

[80] Zhang JS, Honkaniemi J, Yang T, Yeo TT, Longo FM. LAR tyrosine phosphatase receptor: a developmental isoform is present in neurites and growth cones and its expression is regional-and cell-specific. Mol Cell Neurosci. 1998; 10(5-6):271-286.

[81] Boxer EE, Aoto J. Neurexins and their ligands at inhibitory synapses. Front Synaptic Neurosci. 2022; 14:1087238.

[82] Schreiner D, Scheiffele P. Neuroligins and neurexins. In: Rubenstein J, Rakic P, Chen B, Kwan KY, Cline HT, Cardin J, eds., Synapse Development and Maturation. Elsevier; 2020:193-212

[83] Hirano S, Takeichi M. Cadherins in brain morphogenesis and wiring. Physiol Rev. 2012; 92(2):597-634.

[84] Nguyen L, Hippenmeyer S. Cellular and molecular control of neuronal migration. Springer; 2014.

[85] Takahashi H, Craig AM. Protein tyrosine phosphatases PTPδ, PTPσ, and LAR: presynaptic hubs for synapse organization. Trends Neurosci. 2013; 36(9):522-534.

[86] Michetti C, Falace A, Benfenati F, Fassio A. Synaptic genes and neurodevelopmental disorders: from molecular mechanisms to developmental strategies of behavioral testing. Neurobiol Dis. 2022; 173:105856.

[87] Blum D, Lopes LV. Stabilizing synapses. Science. 2021; 374(6568):684-685.

[88] Sanes JR, Lichtman JW. Development of the vertebrate neuromuscular junction. Annu Rev Neurosci. 1999; 22(1):389-442.

[89] Garcia N, Lanuza MA, Tomàs M, et al. PKA and PKC balance in synapse elimination during neuromuscular junction development. Cells. 2021; 10(6):1384.

[90] Chen C, Regehr WG. Developmental remodeling of the retinogeniculate synapse. Neuron. 2000; 28(3):955-966.

[91] Cong Q, Soteros BM, Wollet M, Kim JH, Sia GM. The endogenous neuronal complement inhibitor SRPX2 protects against complement-mediated synapse elimination during development. Nature Neurosci. 2020; 23(9):1067-1078.

[92] Horstkorte R, Fuss B. Cell adhesion molecules. In: Brady S, Siegal G, Albers RW, Price D, eds., Basic Neurochemistry: Principles of Molecular, Cellular, and Medical Neurobiology. Elsevier; 2012:165-179

[93] Taylor SC, Ferri SL, Grewal M, et al. The role of synaptic cell adhesion molecules and associated scaffolding proteins in social affiliative behaviors. Biol Psychiatry. 2020; 88(6):442-451.

[94] Ozkan ED, Creson TK, Kramár EA, et al. Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons. Neuron. 2014; 82(6):1317-1333.

[95] Gaugler T, Klei L, Sanders SJ, et al. Most genetic risk for autism resides with common variation. Nature Genet. 2014; 46(8):881-885.

[96] Sanders SJ, He X, Willsey AJ, et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron. 2015; 87(6):1215-1233.

[97] Hu Z, Yang Y, Zhao Y, et al. APOE hypermethylation is associated with autism spectrum disorder in a Chinese population. Exp Ther Med. 2018; 15(6):4749-4754.

[98] Noborn F, Sterky FH. Role of neurexin heparan sulfate in the molecular assembly of synapses – expanding the neurexin code? FEBS J. 2023; 290(2):252-265.

[99] Philbrook A, Ramachandran S, Lambert CM, et al. Neurexin directs partner-specific synaptic connectivity in C. elegans. eLife. 2018; 7:e35692.

[100] Hart MP. Stress-Induced neuron remodeling reveals differential interplay between neurexin and environmental factors in Caenorhabditis elegans. Genetics. 2019; 213(4):1415-1430.

[101] Jiang X, Sando R, Südhof TC. Multiple signaling pathways are essential for synapse formation induced by synaptic adhesion molecules. Proc Natl Acad Sci. 2021; 118(3):e2000173118.

[102] Fuccillo MV, Földy C, Gökce Ö, et al. Single-cell mRNA profiling reveals cell-type-specific expression of neurexin isoforms. Neuron. 2015; 87(2):326-340.

[103] Nguyen TM, Schreiner D, Xiao L, Traunmüller L, Bornmann C, Scheiffele P. An alternative splicing switch shapes neurexin repertoires in principal neurons versus interneurons in the mouse hippocampus. eLife. 2016; 5:e22757.

[104] Rudenko G. Neurexins—Versatile molecular platforms in the synaptic cleft. Curr Opin Struct Biol. 2019; 54:112-121.

[105] Liakath-Ali K, Südhof TC. The perils of navigating activity-dependent alternative splicing of neurexins. Front Mol Neurosci. 2021; 14:659681.

[106] Han KA, Kim YJ, Yoon TH, et al. LAR-RPTPs directly interact with neurexins to coordinate bidirectional assembly of molecular machineries. J Neurosci. 2020; 40(44):8438-8462.

[107] Roppongi RT, Dhume SH, Padmanabhan N, et al. LRRTMs organize synapses through differential engagement of neurexin and PTPσ. Neuron. 2020; 106(1):108-125. e12.

[108] Kim JYV, Megat S, Moy JK, et al. Neuroligin 2 regulates spinal GABAergic plasticity in hyperalgesic priming, a model of the transition from acute to chronic pain. Pain. 2016; 157(6):1314-1324.

[109] Hata Y, Butz S, Sudhof T. CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins. J Neurosci. 1996; 16(8):2488-2494.

[110] Irie M, Hata Y, Takeuchi M, et al. Binding of neuroligins to PSD-95. Science. 1997; 277(5331):1511-1515.

[111] Levy AM, Gomez-Puertas P, Tümer Z. Neurodevelopmental disorders associated with PSD-95 and its interaction partners. Int J Mol Sci. 2022; 23(8):4390.

[112] Ichtchenko K, Nguyen T, Südhof TC. Structures, alternative splicing, and neurexin binding of multiple neuroligins. J Biol Chem. 1996; 271(5):2676-2682.

[113] Bemben MA, Shipman SL, Nicoll RA, Roche KW. The cellular and molecular landscape of neuroligins. Trends Neurosci. 2015; 38(8):496-505.

[114] Kasem E, Kurihara T, Tabuchi K. Neurexins and neuropsychiatric disorders. Neurosci Res. 2018; 127:53-60.

[115] Nguyen TA, Lehr AW, Roche KW. Neuroligins and neurodevelopmental disorders: X-Linked genetics. Front Synaptic Neurosci. 2020; 12:33.

[116] Vieira MM, Jeong J, Roche KW. The role of NMDA receptor and neuroligin rare variants in synaptic dysfunction underlying neurodevelopmental disorders. Curr Opin Neurobiol. 2021; 69:93-104.

[117] Wang J, Gong J, Li L, et al. Neurexin gene family variants as risk factors for autism spectrum disorder. Autism Research. 2018; 11(1):37-43.

[118] Gerik-Celebi HB, Bolat H, Unsel-Bolat G. Rare heterozygous genetic variants of NRXN and NLGN gene families involved in synaptic function and their association with neurodevelopmental disorders. Dev Neurobiol. 2024; 84(3):158-168.

[119] Rowen L, Young J, Birditt B, et al. Analysis of the human neurexin genes: alternative splicing and the generation of protein diversity. Genomics. 2002; 79(4):587-597.

[120] Tromp A, Mowry B, Giacomotto J. Neurexins in autism and schizophrenia-a review of patient mutations, mouse models and potential future directions. Mol Psychiatry. 2021; 26(3):747-760.

[121] Armstrong EC, Caruso A, Servadio M, et al. Assessing the developmental trajectory of mouse models of neurodevelopmental disorders: social and communication deficits in mice with neurexin 1α deletion. Genes Brain Behav. 2020; 19(4):e12630.

[122] Grayton HM, Missler M, Collier DA, Fernandes C. Altered social behaviours in neurexin 1α knockout mice resemble core symptoms in neurodevelopmental disorders. PLoS One. 2013; 8(6):e67114.

[123] Hodge R. Human Sex-Specific Synaptic Adhesion Proteins NLGN4X and NLGN4Y Regulate the Dual Innervation of Dendritic Spines. Thomas Jefferson University; 2021.

[124] Craig AM, Kang Y. Neurexin-neuroligin signaling in synapse development. Curr Opin Neurobiol. 2007; 17(1):43-52.

[125] Trobiani L, Meringolo M, Diamanti T, et al. The neuroligins and the synaptic pathway in autism spectrum disorder. Neurosci Biobehav Rev. 2020; 119:37-51.

[126] Zhao JY, Duan XL, Yang L, et al. Activity-dependent synaptic recruitment of neuroligin 1 In spinal dorsal horn contributed to inflammatory pain. Neuroscience. 2018; 388:1-10.

[127] Ali H, Marth L, Krueger-Burg D. Neuroligin-2 as a central organizer of inhibitory synapses in health and disease. Sci Signaling. 2020; 13(663):eabd8379.

[128] Budreck EC, Scheiffele P. Neuroligin-3 is a neuronal adhesion protein at GABAergic and glutamatergic synapses. Eur J Neurosci. 2007; 26(7):1738-1748.

[129] Bemben MA, Nguyen QA, Wang T, Li Y, Nicoll RA, Roche KW. Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses. Proc Natl Acad Sci. 2015; 112(8):2551-2556.

[130] Nakanishi M, Nomura J, Ji X, et al. Functional significance of rare neuroligin 1 variants found in autism. PLoS Genet. 2017; 13(8):e1006940.

[131] Redin C, Gérard B, Lauer J, et al. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. J Med Genet. 2014; 51(11):724-736.

[132] Geisheker MR, Heymann G, Wang T, et al. Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Nature Neurosci. 2017; 20(8):1043-1051.

[133] Quartier A, Courraud J, Thi Ha T, et al. Novel mutations in NLGN3 causing autism spectrum disorder and cognitive impairment. Hum Mutat. 2019; 40(11):2021-2032.

[134] Parente DJ, Garriga C, Baskin B, et al. Neuroligin 2 nonsense variant associated with anxiety, autism, intellectual disability, hyperphagia, and obesity. Am J Med Genet, Part A. 2017; 173(1):213-216.

[135] De Jaco A, Lin MZ, Dubi N, et al. Neuroligin trafficking deficiencies arising from mutations in the α/β-hydrolase fold protein family. J Biol Chem. 2010; 285(37):28674-28682.

[136] Marro SG, Chanda S, Yang N, et al. Neuroligin-4 regulates excitatory synaptic transmission in human neurons. Neuron. 2019; 103(4):617-626.e6.

[137] Nguyen TA, Wu K, Pandey S, et al. A cluster of autism-associated variants on X-linked NLGN4X functionally resemble NLGN4Y. Neuron. 2020; 106(5):759-768.e7.

[138] Gilman SR, Iossifov I, Levy D, Ronemus M, Wigler M, Vitkup D. Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron. 2011; 70(5):898-907.

[139] Sanders SJ, Ercan-Sencicek AG, Hus V, et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. Jun 9 2011; 70(5):863-885.

[140] Jamain S, Quach H, Betancur C, et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genet. 2003; 34(1):27-29.

[141] Kopp N, Amarillo I, Martinez-Agosto J, Quintero-Rivera F. Pathogenic paternally inherited NLGN4X deletion in a female with autism spectrum disorder: Clinical, cytogenetic, and molecular characterization. Am J Med Genet, Part A. 2021; 185(3):894-900.

[142] Doherty P, Williams E, Walsh FS. A soluble chimeric form of the L1 glycoprotein stimulates neurite outgrowth. Neuron. 1995; 14(1):57-66.

[143] Yamagata M, Duan X, Sanes JR. Cadherins interact with synaptic organizers to promote synaptic differentiation. Front Mol Neurosci. 2018; 11:142.

[144] Rivero O, Selten MM, Sich S, et al. Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition. Transl Psychiatry. 2015; 5(10):e655.

[145] Tamura K, Shan WS, Hendrickson WA, Colman DR, Shapiro L. Structure-function analysis of cell adhesion by neural (N-) cadherin. Neuron. 1998; 20(6):1153-1163.

[146] Benson D. Making memories stick: cell-adhesion molecules in synaptic plasticity. Trends Cell Biol. 2000; 10(11):473-482.

[147] Pettitt J. The cadherin superfamily. In: WormBoo: The Online Review of C. Elegans Biologyk. 2005:1-9.

[148] Basu R, Taylor MR, Williams ME. The classic cadherins in synaptic specificity. Cell Adh Migr. 2015; 9(3):193-201.

[149] Accogli A, Calabretta S, St-Onge J, et al. De novo pathogenic variants in N-cadherin cause a syndromic neurodevelopmental disorder with corpus callosum, axon, cardiac, ocular, and genital defects. Am J Hum Genet. 2019; 105(4):854-868.

[150] Halperin D, Stavsky A, Kadir R, et al. CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice. Nat Commun. 2021; 12(1):6187.

[151] Liu D, Cao H, Kural KC, Fang Q, Zhang F. Integrative analysis of shared genetic pathogenesis by autism spectrum disorder and obsessive-compulsive disorder. Biosci Rep. 2019; 39(12):BSR20191942.

[152] László ZI, Lele Z. Flying under the radar: CDH2 (N-cadherin), an important hub molecule in neurodevelopmental and neurodegenerative diseases. Front Neurosci. 2022; 16:972059.

[153] Piprek RP, Kolasa M, Podkowa D, Kloc M, Kubiak JZ. N-cadherin is critical for the survival of germ cells, the formation of steroidogenic cells, and the architecture of developing mouse gonads. Cells. 2019; 8(12):1610.

[154] Oliver C, González CA, Alvial G, Flores CA, Rodríguez EM, Bátiz LF. Disruption of CDH2/N-cadherin-based adherens junctions leads to apoptosis of ependymal cells and denudation of brain ventricular walls. J Neuropathol Exp Neurol. 2013; 72(9):846-860.

[155] Rebman JK, Kirchoff KE, Walsh GS. Cadherin-2 is required cell autonomously for collective migration of facial branchiomotor neurons. PLoS One. 2016; 11(10):e0164433.

[156] McGregor NW, Lochner C, Stein DJ, Hemmings SMJ. Polymorphisms within the neuronal cadherin (CDH2) gene are associated with obsessive-compulsive disorder (OCD) in a South African cohort. Metab Brain Dis. 2016; 31:191-196.

[157] Smith KR, Jones KA, Kopeikina KJ, et al. Cadherin-10 maintains excitatory/inhibitory ratio through interactions with synaptic proteins. J Neurosci. 2017; 37(46):11127-11139.

[158] Williams ME, Wilke SA, Daggett A, et al. Cadherin-9 regulates synapse-specific differentiation in the developing hippocampus. Neuron. 2011; 71(4):640-655.

[159] Lilja J, Ivaska J. Integrin activity in neuronal connectivity. J Cell Sci. 2018; 131(12):jcs212803.

[160] Moreno-Layseca P, Icha J, Hamidi H, Ivaska J. Integrin trafficking in cells and tissues. Nature Cell Biol. 2019; 21(2):122-132.

[161] Kadry YA, Calderwood DA. Chapter 22: structural and signaling functions of integrins. Biochim Biophys Acta (BBA) - Biomembranes. 2020; 1862(5):183206.

[162] Dohn MR, Kooker CG, Bastarache L, et al. The gain-of-function integrin β3 Pro33 variant alters the serotonin system in the mouse brain. J Neurosci. 2017; 37(46):11271-11284.

[163] Yamaguchi Y, Pasquale EB. Eph receptors in the adult brain. Curr Opin Neurobiol. 2004; 14(3):288-296.

[164] Aoto J, Chen L. Bidirectional ephrin/Eph signaling in synaptic functions. Brain Res. 2007; 1184:72-80.

[165] Klein R. Bidirectional modulation of synaptic functions by Eph/ephrin signaling. Nature Neurosci. 2009; 12(1):15-20.

[166] Cramer KS, Miko IJ. Eph-ephrin signaling in nervous system development. F1000Research. 2016; 5:413.

[167] Kania A, Klein R. Mechanisms of ephrin-Eph signalling in development, physiology and disease. Nat Rev Mol Cell Biol. 2016; 17(4):240-256.

[168] Sheleg M, Yochum CL, Wagner GC, Zhou R, Richardson JR. Ephrin-A5 deficiency alters sensorimotor and monoaminergic development. Behav Brain Res. 2013; 236(1):139-147.

[169] Wurzman R, Forcelli PA, Griffey CJ, Kromer LF. Repetitive grooming and sensorimotor abnormalities in an ephrin-A knockout model for autism spectrum disorders. Behav Brain Res. 2015; 278:115-128.

[170] Arnall S, Cheam LY, Smart C, et al. Abnormal strategies during visual discrimination reversal learning in ephrin-A2(-/-) mice. Behav Brain Res. 2010; 209(1):109-113.

[171] Rutz HLH, Rothblat LA. Intact and impaired executive abilities in the BTBR mouse model of autism. Behav Brain Res. 2012; 234(1):33-37.

[172] Jomova K, Makova M, Alomar SY, et al. Essential metals in health and disease. Chemico-Biol Interact. 2022; 367:110173.

[173] Bradbury MWB. Chapter 20: An approach to study of transport of trace metals at the blood-brain barrier. In: Armin E, Rainer L, Hans-Joachim R, eds., Circumventricular Organs and Brain Fluid Environment. Elsevier; 1992:133-138vol. Progress in Brain Research.

[174] Pellowski D, Ebert F, Bornhorst J, Schwerdtle T. Zinc-modulated bidirectional copper transfer across the blood-brain barrier in a porcine brain capillary endothelial cell culture model system. J Trace Elem Med Biol. 2024; 86:127547.

[175] Martinez-Finley EJ, Chakraborty S, Fretham SJB, Aschner M. Cellular transport and homeostasis of essential and nonessential metals. Metallomics. 2012; 4(7):593-605.

[176] Lucchini RG, Aschner M, Bellinger DC, Caito SW. Neurotoxicology of metals. In: Nordberg Gunnar F, Bruce A, eds., Handbook on the Toxicology of Metals. Elsevier; 2015:299-311

[177] Zahoor SM, Ishaq S, Ahmed T. Neurotoxic effects of metals on blood brain barrier impairment and possible therapeutic approaches. Vitam Horm. 2024; 126:1-24.

[178] Tjälve H, Henriksson J. Uptake of metals in the brain via olfactory pathways. Neurotoxicology. 1999; 20(2-3):181-195.

[179] Tjälve H, Tallkvist J. The olfactory pathway as a route of entry of metals into the brain. Metal Ions and Neurodegenerative Disorders. World Scientific; 2003:67-98.

[180] Chalansonnet M, Carabin N, Boucard S, et al. Study of potential transfer of aluminum to the brain via the olfactory pathway. Toxicol Lett. 2018; 283:77-85.

[181] Althomali RH, Abbood MA, Saleh EAM, et al. Exposure to heavy metals and neurocognitive function in adults: a systematic review. Environ Sci Eur. 2024; 36(1):18.

[182] Neal AP, Guilarte TR. Mechanisms of lead and manganese neurotoxicity. Toxicol Res. 2013; 2(2):99-114.

[183] Verkhratsky A, Nedergaard M. Physiology of astroglia. Physiol Rev. 2018; 98(1):239-389.

[184] Valles SL, Singh SK, Campos-Campos J, et al. Functions of astrocytes under normal conditions and after a brain disease. Int J Mol Sci. 2023; 24(9):8434.

[185] Verkhratsky A, Rose CR. Na(+)-dependent transporters: the backbone of astroglial homeostatic function. Cell Calcium. 2020; 85:102136.

[186] Li B, Xia M, Zorec R, Parpura V, Verkhratsky A. Astrocytes in heavy metal neurotoxicity and neurodegeneration. Brain Res. 2021; 1752:147234.

[187] Milatovic D, Yin Z, Gupta RC, et al. Manganese induces oxidative impairment in cultured rat astrocytes. Toxicol Sci. 2007; 98(1):198-205.

[188] Yubolphan R, Phuagkhaopong S, Sangpairoj K, Sibmooh N, Power C, Vivithanaporn P. Intracellular nickel accumulation induces apoptosis and cell cycle arrest in human astrocytic cells. Metallomics. 2020; 13(1):mfaa006.

[189] Baraibar AM, de Pascual R, Carretero VJ, Liccardi N, Juárez NH, Hernández-Guijo JM. Aluminum alters excitability by inhibiting calcium, sodium, and potassium currents in bovine chromaffin cells. J Neurochem. 2023; 165(2):162-176.

[190] Busselberg D, Platt B, Michael D, Carpenter DO, Haas HL. Mammalian voltage-activated calcium channel currents are blocked by Pb2+, Zn2+, and Al3+. J Neurophysiol. 1994; 71(4):1491-1497.

[191] Julka D, Gill KD. Altered calcium homeostasis: a possible mechanism of aluminium-induced neurotoxicity. Biochim Biophys Acta (BBA)-Mol Basis Dis. 1996; 1315(1):47-54.

[192] Carmona A, Roudeau S, Ortega R. Molecular mechanisms of environmental metal neurotoxicity: a focus on the interactions of metals with synapse structure and function. Toxics. 2021; 9(9):198.

[193] Sadiq S, Ghazala Z, Chowdhury A, Büsselberg D. Metal toxicity at the synapse: presynaptic, postsynaptic, and long-term effects. J Toxicol. 2012; 2012:132671.

[194] Minami A, Takeda A, Nishibaba D, Takefuta S, Oku N. Cadmium toxicity in synaptic neurotransmission in the brain. Brain Res. 2001; 894(2):336-339.

[195] Marchetti C. Interaction of metal ions with neurotransmitter receptors and potential role in neurodiseases. BioMetals. 2014; 27(6):1097-1113.

[196] Chandravanshi LP, Agrawal P, Darwish HW, Trigun SK. Impairments of spatial memory and N-methyl-D-aspartate receptors and their postsynaptic signaling molecules in the hippocampus of developing rats induced by As, Pb, and Mn mixture exposure. Brain Sci. 2023; 13(12):1715.

[197] Khedr NF, Talkan OFA. New insights into arsenic, lead, and iron neurotoxicity: activation of MAPK signaling pathway and oxidative stress. J Biochem Mol Toxicol. 2022; 36(6):e23040.

[198] Zhao F, Wang Z, Liao Y, Wang G, Jin Y. Alterations of NMDA and AMPA receptors and their signaling apparatus in the hippocampus of mouse offspring induced by developmental arsenite exposure. J Toxicol Sci. 2019; 44(11):777-788.

[199] Del Pino J, Zeballos G, Anadon MJ, et al. Muscarinic M1 receptor partially modulates higher sensitivity to cadmium-induced cell death in primary basal forebrain cholinergic neurons: a cholinesterase variants dependent mechanism. Toxicology. Jun 15 2016; 361-362:1-11.

[200] Moyano P, de Frias M, Lobo M, et al. Cadmium induced ROS alters M1 and M3 receptors, leading to SN56 cholinergic neuronal loss, through AChE variants disruption. Toxicology. 2018; 394:54-62.

[201] Gorini F, Muratori F, Morales MA. The role of heavy metal pollution in neurobehavioral disorders: a focus on autism. Review Journal of Autism and Developmental Disorders. 2014; 1:354-372.

[202] Frye RE, Cakir J, Rose S, et al. Early life metal exposure dysregulates cellular bioenergetics in children with regressive autism spectrum disorder. Transl Psychiatry. 2020; 10(1):223.

[203] Chou C-H, Harper C Toxicological profile for arsenic. CDC STACK. Published 08/01/2007. https://stacks.cdc.gov/view/cdc/11481

[204] Ashizawa A, Faroon O, Ingerman L, Jenkins K, Tucker P, Wright S. Toxicological Profile for Cadmium. Agency for Toxic Substances and Disease Registry (US); 2012.

[205] Al-Farsi YM, Waly MI, Al-Sharbati MM, et al. Levels of heavy metals and essential minerals in hair samples of children with autism in Oman: a case-control study. Biol Trace Elem Res. 2013; 151(2):181-186.

[206] Nayak S, Sahu S, John J, Patra S. Hair and urine lead, cadmium, nickel, and arsenic levels in children with attention-deficit hyperactivity disorder: A case–control study in a tertiary care hospital in eastern India. Precision Med Sci. 2023; 12(3):153-158.

[207] Beaudin SA, Strupp BJ, Strawderman M, Smith DR. Early postnatal manganese exposure causes lasting impairment of selective and focused attention and arousal regulation in adult rats. Environ Health Perspect. 2017; 125(2):230-237.

[208] Schneider JS, Decamp E, Clark K, Bouquio C, Syversen T, Guilarte TR. Effects of chronic manganese exposure on working memory in non-human primates. Brain Res. 2009; 1258:86-95.

[209] Ouisselsat M, Maidoumi S, Elmaouaki A, Lekouch N, Pineau A, Sedki A. Hair trace elements and mineral content in Moroccan children with autism spectrum disorder: a case-control study. Biol Trace Elem Res. 2023; 201(6):2701-2710.

[210] Ma J, Wu J, Li H, Wang J, Han J, Zhang R. Association between essential metal elements and the risk of autism in Chinese Han population. Biol Trace Elem Res. 2022; 200(2):505-515.

[211] Pavăl D. A dopamine hypothesis of autism spectrum disorder. Dev Neurosci. 2017; 39(5):355-360.

[212] Ijomone OM, Aluko OM, Okoh COA, Martins Jr. AC, Aschner M. Role for calcium signaling in manganese neurotoxicity. J Trace Elem Med Biol. 2019; 56:146-155.

[213] Ijomone OM, Miah MR, Peres TV, Nwoha PU, Aschner M. Null allele mutants of trt-1, the catalytic subunit of telomerase in Caenorhabditis elegans, are less sensitive to Mn-induced toxicity and DAergic degeneration. Neurotoxicology. 2016; 57:54-60.

[214] Peres TV, Schettinger MRC, Chen P, et al. Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies. BMC Pharmacol Toxicol. 2016; 17(1):57.

[215] Torti SV, Torti FM. Iron: the cancer connection. Mol Aspects Med. 2020; 75:100860.

[216] Georgieff MK. Iron deficiency in pregnancy. Am J Obstet Gynecol. 2020; 223(4):516-524.

[217] Georgieff MK. The role of iron in neurodevelopment: fetal iron deficiency and the developing hippocampus. Biochem Soc Trans. 2008; 36(Pt 6):1267-1271.

[218] Chen L, Guo X, Hou C, et al. The causal association between iron status and the risk of autism: a Mendelian randomization study. Front Nutr. 2022; 9:957600.

[219] Latif A, Heinz P, Cook R. Iron deficiency in autism and Asperger syndrome. Autism. 2002; 6:103-114.

[220] Hare DJ, Arora M, Jenkins NL, Finkelstein DI, Doble PA, Bush AI. Is early-life iron exposure critical in neurodegeneration? Nat Rev Neurol. 2015; 11:536-544.

[221] Lepeta K, Lourenco MV, Schweitzer BC, et al. Synaptopathies: synaptic dysfunction in neurological disorders - a review from students to students. J Neurochem. 2016; 138(6):785-805.

[222] Südhof TC, Malenka RC. Understanding synapses: past, present, and future. Neuron. 2008; 60(3):469-476.

[223] LeDoux J. Synaptic Self: How Our Brains Become Who We Are. Penguin; 2003.

[224] Garí M, Grzesiak M, Krekora M, et al. Prenatal exposure to neurotoxic metals and micronutrients and neurodevelopmental outcomes in early school age children from Poland. Environ Res. 2022; 204(Pt B):112049.

[225] Liu CH, Huang CY, Huang CC. Occupational neurotoxic diseases in Taiwan. Saf Health Work. 2012; 3(4):257-267.

[226] Gunderson JT, Peppriell AE, Krout IN, Vorojeikina D, Rand MD. Neuroligin-1 is a mediator of methylmercury neuromuscular toxicity. Toxicol Sci. 2021; 184(2):236-251.

[227] Hunter JW, Mullen GP, McManus JR, Heatherly JM, Duke A, Rand JB. Neuroligin-deficient mutants of C. elegans have sensory processing deficits and are hypersensitive to oxidative stress and mercury toxicity. Dis Models & Mech. 2010; 3(5-6):366-376.

[228] Tu H, Fan C, Chen X, et al. Effects of cadmium, manganese, and lead on locomotor activity and neurexin 2a expression in zebrafish. Environ Toxicol Chem. 2017; 36(8):2147-2154.

[229] Luo J, Qiu Z, Chen J, et al. Maternal and early life arsenite exposure impairs neurodevelopment and increases the expression of PSA-NCAM in hippocampus of rat offspring. Toxicology. 2013; 311(3):99-106.

[230] Dey PM, Gochfeld M, Reuhl KR. Developmental methylmercury administration alters cerebellar PSA-NCAM expression and Golgi sialyltransferase activity. Brain Res. 1999; 845(2):139-151.

[231] Marchand G, Fliniaux I, Titran P, et al. Cadmium induces physiological and behavioral changes associated with 180 kDa NCAM lower expression and higher polysialic acid, in the African clawed Xenopus laevis tadpoles. Ecotoxicol Environ Safety. 2024; 273:116119.

[232] Wilson DT, Polunas MA, Zhou R, Halladay AK, Lowndes HE, Reuhl KR. Methylmercury alters Eph and ephrin expression during neuronal differentiation of P19 embryonal carcinoma cells. Neurotoxicology. 2005; 26(4):661-674.

[233] Dey PM, Burger J, Gochfeld M, Reuhl KR. Developmental lead exposure disturbs expression of synaptic neural cell adhesion molecules in herring gull brains. Toxicology. 2000; 146(2-3):137-147.

[234] Burger J, Gochfeld M. Lead and neurobehavioral development in gulls: a model for understanding effects In the laboratory and the field. Neurotoxicology. 1997; 18(2):495-506.

[235] Bonfanti L, Theodosis DT. Polysialic acid and activity-dependent synapse remodeling. Cell Adh Migr. 2009; 3(1):43-50.

[236] Senkov O, Tikhobrazova O, Dityatev A. PSA-NCAM: synaptic functions mediated by its interactions with proteoglycans and glutamate receptors. Int J Biochem Cell Biol. 2012; 44(4):591-595.

[237] Wilson DT. Effects of Methylmercury on Ephs and ephrins During Central Nervous System Development. Rutgers The State University of New Jersey, School of Graduate Studies; 2003.

[238] Reuben KE, Parish A. Dissociation in Autism Spectrum Disorders: An Under-Recognized Symptom. In: Christensen E, ed. Perspectives of Dissociativeidentity Response: Ethical, Historical, and Cultural Issues. HWC Press; 2022:151-183.

[239] Murphy KJ, Regan CM. Low-level lead exposure in the early postnatal period results in persisting neuroplastic deficits associated with memory consolidation. J Neurochem. 1999; 72(5):2099-2104.

[240] Heidmets L, Zharkovsky T, Jurgenson M, Jaako-Movits K, Zharkovsky A. Early post-natal, low-level lead exposure increases the number of PSA-NCAM expressing cells in the dentate gyrus of adult rat hippocampus. Neurotoxicology. 2006; 27(1):39-43.

RIGHTS & PERMISSIONS

2025 The Author(s). Ibrain published by Affiliated Hospital of Zunyi Medical University (AHZMU) and Wiley-VCH GmbH.