Introduction
Integrins are heterodimeric (αβ) extracellular matrix (ECM) receptors that mediate cell-matrix and cell-cell adhesion. Integrin β is an essential subunit in heterodimers, and eight different β subunits have been identified that can form a variety of integrin αβ heterodimer combinations with different α subunits, which are important in the developmental maturation of the nervous system. In particular, integrins containing β1 and β3 subunits have been most studied. β-class integrins are closely associated with synapses and play a critical role in the regulation of synaptic function. Integrin β family members also regulate a variety of neurotransmitters, hormones, and protein peptides, such as serotonin (5-HT), glutamate, estrogen, and neurotrophic factors.
Schizophrenia is a polygenic disorder characterized by psychosis, apathy, social withdrawal, and cognitive impairment.Reference Mueser and McGurk 1 It consists of three types of symptoms, negative, positive, and cognitive.Reference Birnbaum and Weinberger 2 Its etiology is currently unknown, but it is associated with developmental processes in the brain and multiple neurotransmitters in the brain, and several different hypotheses have been proposed, including neurodevelopmental and neurochemical hypotheses.Reference Birnbaum and Weinberger 2 Due to the pathogenesis of schizophrenia remains unclear, its treatment presents many challenges.
In schizophrenia-related studies, despite growing evidence of an association between integrin β and schizophrenia, it remains difficult to understand why and how altered integrin β adhesion and signaling can lead to the onset or development of schizophrenia. Here, we discuss the evidence linking integrin β to schizophrenia. We focus on common mechanisms and recurrent signaling pathways in an attempt to connect the dots between integrin β molecular structure, signaling, synaptic function, and schizophrenia and to suggest clinical ideas for exploring the pathogenesis of schizophrenia and studying the treatment related to integrin β and schizophrenia.
Integrin β and DISC1
In earlier years, a study found significantly increased expression of platelet integrin αIIbβIIIa in drug-naive, first-episode schizophrenic patients by comparison with healthy controls.Reference Walsh, Ryan, Hillmann, Condren, Kenny, Dinan and Thakore 3 Subsequently, another study identified polymorphisms in the integrin β3 gene (ITGB3) associated with the age of onset of schizophrenia through statistical analysis of big data.Reference Wang, Liu, Arana, Thompson, Weisman, Devargas, Mao, Su, Camarillo, Escamilla and Xu 4 Disrupted-in-schizophrenia 1 (DISC1) is a major psychiatric disease susceptibility gene associated with the molecular mechanisms of schizophrenia,Reference Matsuzaki and Tohyama 5 and it is involved in many critical neurodevelopmental processes, including neurite growth, neuronal migration, and differentiation.Reference Enomoto, Asai, Namba, Wang, Kato, Tanaka, Tatsumi, Taya, Tsuboi, Kuroda, Kaneko, Sawamoto, Miyamoto, Jijiwa, Murakumo, Sokabe, Seki, Kaibuchi and Takahashi 6 - Reference Miyoshi, Honda, Baba, Taniguchi, Oono, Fujita, Kuroda, Katayama and Tohyama 8 In which, it has been shown that DISC1 regulates cell adhesion by increasing the expression of integrin β1, which promotes neurite growth.Reference Hattori, Shimizu, Koyama, Yamada, Kuwahara, Kumamoto, Matsuzaki, Ito, Katayama and Tohyama 7 Therefore, integrin β can be linked to schizophrenia through DISC1. Integrin β has also been associated with several symptoms of schizophrenia. Integrin β3 knockout mice exhibit diminished preference for social novelty in a novel environment, increased repetitive behaviorReference Carter, Shah, Muller, Crawley, Carneiro and Weele J 9 as well as abnormal anxiety-like behavior,Reference McGeachie, Skrzypiec, Cingolani, Letellier, Pawlak and Goda 10 exaggerated vulnerability under chronic unpredictable stress, and changes in midbrain synaptophysin and dopamine metabolism,Reference Varney, Polston, Jessen and Carneiro 11 which are similar to some of the symptoms present in schizophrenia.
Integrin β and synapses
The function of synapses, that is, the connections between neurons, is important for brain function. Abnormalities in synaptic transmission and plasticity during neural development can lead to the development of schizophrenia.Reference Mirnics, Middleton, Lewis and Levitt 12 - Reference Stephan, Baldeweg and Friston 15 And disruption of the glutamatergic signaling pathways associated with synaptic plasticity has also been linked to the etiology of schizophrenia.Reference Pocklington, O’Donovan and Owen 16 In addition, schizophrenia susceptibility genes that play key roles in synaptic function,Reference Yin, Chen, Sathyamurthy, Xiong and Mei 17 such as D2 dopamine receptor (D2 DR), DISC1, neuregulin 1 (NRG1) and its receptor ErbB4, and voltage-gated calcium channels (VGCC) associated with schizophrenia etiology, have been widely reported for their regulation of synaptic plasticity and also interact with postsynaptic N-methyl-D-aspartate acid receptor (NMDAR).Reference Moosmang, Haider, Klugbauer, Adelsberger, Langwieser, Müller, Stiess, Marais, Schulla, Lacinova, Goebbels, Nave, Storm, Hofmann and Kleppisch 18
Not surprisingly, the close association between synapses and schizophrenia is described above, and integrin β is also known to play an important part in synapses (Figure 1). β1 integrins are essential for synapse formation,Reference Nikonenko, Toni, Moosmayer, Shigeri, Muller and Sargent Jones 19 and β1 integrins that aggregate post-synaptically can also function as adhesion proteins to mediate synaptic adhesion.Reference Mortillo, Elste, Ge, Patil, Hsiao, Huntley, Davis and Benson 20 In hippocampal CA1 pyramidal neurons, ablation of α3 or β1 integrins at specific times during embryonic and postnatal life respectively affects the structure and function of excitatory synapses.Reference Kerrisk, Greer and Koleske 21 - Reference Chan, Weeber, Zong, Fuchs, Sweatt and Davis 24 α3β1 integrin regulates synaptic and dendritic stability by binding to the ECM protein laminin α5,Reference Omar, Kerrisk Campbell, Xiao, Zhong, Brunken, Miner, Greer and Koleske 25 and intracellularly it interacts with and activates the Abl2/Arg (Abl-related gene) non-receptor tyrosine kinase, thereby affecting actin remodeling in dendrites and spines.Reference Kerrisk, Greer and Koleske 21 , Reference Warren, Bradley, Gourley, Lin, Simpson, Reichardt, Greer, Taylor and Koleske 22 , Reference Lin, Yeckel and Koleske 26 - Reference Simpson, Bradley, Harburger, Parsons, Calderwood and Koleske 28 β3 integrins affect synaptic strength by regulating the quantal size and content of excitatory synaptic transmission.Reference Cingolani and Goda 29 , Reference Pozo, Cingolani, Bassani, Laurent, Passafaro and Goda 30 Integrin β also modulates synaptic plasticity. Synaptic plasticity in the adult hippocampus requires β1 integrins,Reference Chan, Weeber, Zong, Fuchs, Sweatt and Davis 24 but β3 integrin is dispensable for Hebbian forms of plasticity in the hippocampus.Reference McGeachie, Skrzypiec, Cingolani, Letellier, Pawlak and Goda 10 β1 class integrins also affect neuronal cytoplasmic calcium levels, thereby modulating the lasting synaptic plasticity in forebrain neurons.Reference Lin, Hilgenberg, Smith, Lynch and Gall 31 Postsynaptic plasticity-related gene 1 (PRG-1) also affects synaptic plasticity in a cell-autonomous fashion by activating integrin β1.Reference Liu, Huai, Endle, Schlüter, Fan, Li, Richers, Yurugi, Rajalingam, Ji, Cheng, Rister, Horta, Baumgart, Berger, Laube, Schmitt, Schmeisser, Boeckers, Tenzer, Vlachos, Deller, Nitsch and Vogt 32 Long-term potentiation (LTP) is a form of synaptic plasticity, and deletion of β1 integrins impairs LTP,Reference McGeachie, Skrzypiec, Cingolani, Letellier, Pawlak and Goda 10 , Reference Huang, Shimazu, Woo, Zang, Müller, Lu and Reichardt 33 and in recent years it has also been shown that β1 integrins are involved in a novel form of cognition-related LTP triggered by endocannabinoid signaling in the hippocampus.Reference Wang, Jia, Pham, Palmer, Jung, Cox, Rumbaugh, Piomelli, Gall and Lynch 34 Synaptic homeostasis is also a form of synaptic plasticity, and β3 integrins are required in homeostatic plasticity.Reference Cingolani and Goda 29 In addition, integrins composed of β1 and α3 subunits are involved in the regulation of inhibitory synaptic plasticity.Reference Kawaguchi and Hirano 35 Thus, alterations of integrin β activation and adhesion might therefore underlie some of the structural defects found in schizophrenic patients.
Figure 1. The association among integrin β, schizophrenia, and synapses.
Talin and Kindlin act as integrin activators, binding to the cytoplasmic tail of the integrin β subunits thereby activating integrins. LTP is a form of synaptic plasticity, and LTP induction mechanisms require synaptic NMDAR activation and Ca2+ influx to participate in downstream signaling cascades, whereas β1 integrin deficiency impairs LTP; therefore, it can be assumed that β1 integrin has a key role in NMDAR-dependent LTP-induced downstream signaling pathways.Reference Park and Goda 36 PRG-1 affects synaptic plasticity in a cell-autonomous manner by activating integrin β1.Reference Liu, Huai, Endle, Schlüter, Fan, Li, Richers, Yurugi, Rajalingam, Ji, Cheng, Rister, Horta, Baumgart, Berger, Laube, Schmitt, Schmeisser, Boeckers, Tenzer, Vlachos, Deller, Nitsch and Vogt 32 β1 integrin is also involved in a novel form of cognition-related LTP triggered by endogenous cannabinoid signaling in the hippocampus.Reference Wang, Jia, Pham, Palmer, Jung, Cox, Rumbaugh, Piomelli, Gall and Lynch 34 β3 integrins control synaptic strength by influencing alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate receptor (AMPAR). Under basal activity conditions, β3 integrins promote the internalization of GluA2-containing AMPAR, and after chronic activity stripping, β3 integrins are recruited to the cell surface via postsynaptic tumor necrosis factor signaling.Reference Pozo, Cingolani, Bassani, Laurent, Passafaro and Goda 30 The green shaded section contains schizophrenia susceptibility genes (D2 DR, DISC1, NRG1, and ErbB4), which affect synaptic function in multiple ways. Of these, NRG1 can promote GABA release and thus inhibit LTP.Reference Chen, Zhang, Yin, Wen, Ting, Wang, Lu, Zhu, Li, Wu, Wang, Lai, Xiong, Mei and Gao 37 - Reference Wen, Lu, Zhu, Li, Woo, Chen, Yin, Lai, Terry, Vazdarjanova, Xiong and Mei 40 VGCC can interact with postsynaptic NMDARReference Moosmang, Haider, Klugbauer, Adelsberger, Langwieser, Müller, Stiess, Marais, Schulla, Lacinova, Goebbels, Nave, Storm, Hofmann and Kleppisch 18 and regulate synaptic plasticity.
Neuroanatomy of integrin β associated with schizophrenia
Most studies of schizophrenics reveal decreased volume of multiple structures in the brain.Reference Bogerts, Meertz and Schönfeldt-Bausch 41 - Reference Wong and Van Tol 44 One study showed a significant reduction in intracranial and total brain volume of 2.0% and 2.6% in medicated schizophrenia patients by meta-analysis.Reference Haijma, Van Haren, Cahn, Koolschijn, Hulshoff Pol and Kahn 45 β integrins also affect brain volume. Granule cell precursors in the cerebellum of mice with a central nervous system-restricted knockout of the integrin β1 subunit gene stop proliferating and differentiate prematurely, leading to a reduction in the final number of mature granule cells, as well as a reduction in cerebellar size.Reference Blaess, Graus-Porta, Belvindrah, Radakovits, Pons, Littlewood-Evans, Senften, Guo, Li, Miner, Reichardt and Müller 46 Analysis of an ITGβ3 homozygous knockout mouse using MRI imaging revealed an 11% reduction in total brain volume.Reference Ellegood, Henkelman and Lerch 47 Integrin β3 homozygous knockout mice associated with autism also had significantly smaller cerebellum than wild-type mice, with 28 out of 39 cerebellar structures smaller.Reference Steadman, Ellegood, Szulc, Turnbull, Joyner, Henkelman and Lerch 48
Schizophrenia is associated with cortical thickness. Study finds cortical thinning in schizophrenia patients by high-resolution MRI imaging.Reference Xie, Zhang, Tang, Zhang, Yu, Gong, Wang, Evans, Zhang and He 49 , Reference Planchuelo-Gómez, Lubeiro, Núñez-Novo, Gomez-Pilar, de Luis-García, Del Valle, Martín-Santiago, Pérez-Escudero and Molina 50 During cortical development, multiple β-integrins are expressed in the cortex and are closely associated with cortical formation and plasticityReference Schmid and Anton 51 (Table 1). β1 and β5 integrins are widely expressed and persist in the cerebral cortex,Reference Cousin, Leloup, Pénicaud and Price 52 , Reference Pinkstaff, Detterich, Lynch and Gall 53 β6 integrin is expressed in adult cortical primarily on neurons and oligodendrocytes,Reference Cousin, Leloup, Pénicaud and Price 52 and β8 is widely distributed throughout the neuropil.Reference Nishimura, Boylen, Einheber, Milner, Ramos and Pytela 54 Mice lacking β1 integrin have impaired cerebral and cerebellar cortex development, resulting in abnormal cortical neuronal positioning and defects in the laminar structure of the cerebral and cerebellar cortex,Reference Graus-Porta, Blaess, Senften, Littlewood-Evans, Damsky, Huang, Orban, Klein, Schittny and Müller 55 and removal of β1 integrin at the embryonic stage in mice also results in severe cortical lamination defects.Reference Huang, Shimazu, Woo, Zang, Müller, Lu and Reichardt 33 β1 integrin and laminin-mediated glial-meningeal adhesive interactions are closely associated with the normal assembly of the cerebral cortex.Reference Milner and Campbell 56
Table 1. Distribution and Function of Integrin β in the Cerebral Cortex and Phenotype of Integrin β Subunit Deficient Mice
a Not phenotypes associated with schizophrenia.
Dysfunctional dendrites are a key feature of many developmental neurological disorders. Dendrites in prefrontal cortex (PFC) pyramidal cells are hypodense and small in schizophrenia. β integrins can also affect dendritic and axonal function. Study shows that neuronal α7β1 integrin can mediate neurite growth in the alternatively spliced region of human Tenascin-C.Reference Mercado, Nur-e-Kamal, Liu, Gross, Movahed and Meiners 57 Integrins can regulate actin reorganization in dendritic spines through NMDAR, thereby affecting dendritic spine plasticity.Reference Shi and Ethell 58 Integrin β1 can regulate the size and complexity of hippocampal dendritic arbors through the β1- Arg-p190RhoGAP signaling cascade.Reference Warren, Bradley, Gourley, Lin, Simpson, Reichardt, Greer, Taylor and Koleske 22 Integrin β1 also interacts with intercellular adhesion molecule-5 (ICAM-5) by regulating the ectodomain cleavage of ICAM-5, which in turn regulates dendritic spine morphology and synaptic maturation.Reference Ning, Tian, Smirnov, Vihinen, Llano, Vick, Davis, Rivera and Gahmberg 59 Integrin β3 organizes dendritic complexity of cerebral cortical pyramidal neurons along a tangential gradient.Reference Swinehart, Bland, Holley, Lopuch, Casey, Handwerk and Vidal 60
Integrin β associated with neurotransmitters in schizophrenia
Neurotransmitters have been the most active area of research on the etiology of schizophrenia. It has been shown earlier that platelet glutamate receptors may be hypersensitive in schizophrenic patients,Reference Berk, Plein and Csizmadia 75 and the results support decreased glutamate function in schizophrenia.Reference Kim, Kornhuber, Schmid-Burgk and Holzmüller 76 , Reference Tsai, Passani, Slusher, Carter, Baer, Kleinman and Coyle 77 Several studies have shown that neurotransmitters such as dopamine, serotonin, and glutamate are involved in the development of schizophrenia.Reference Howes and Kapur 78 - Reference Zamanpoor 81 Some symptoms of schizophrenia may be due to hypofunction of NMDARs, especially in the PFC.Reference Balu 82 In addition, metabotropic glutamate (mGlu) receptors have long been used as important therapeutic targets for schizophrenia.Reference Vinson and Conn 83 - Reference Dogra and Conn 85 It has recently been shown that ITGB3, the gene encoding the ECM receptor integrin β3, can interact with mGluR5 to regulate the functional expression of synaptic mGluR5 and directly affect neuronal excitability.Reference Jaudon, Thalhammer, Zentilin and Cingolani 86 Neurotransmitter imbalances play an important role in cognitive deficits in schizophrenia,Reference Clegg, Wingerd, Hikita and Tolhurst 87 and depression and anxiety are also associated with imbalances in central nervous system 5-HT levels. And there is a close link between integrin β and several of those neurotransmitters.
Integrin β regulates glutamate
NMDARs and AMPARs are subtypes of ionotropic glutamate receptors, and mice with reduced NMDA receptor expression exhibit manifestations similar to schizophrenia.Reference Mohn, Gainetdinov, Caron and Koller 88 Integrins can exert regulation of synaptic NMAD-type glutamate receptor operation by activating Src kinase,Reference Lin, Arai, Lynch and Gall 89 and the activated local kinase cascade response enhances the function of synaptic NMDA receptors in the mature hippocampus, a response that is closely associated with β1 integrins.Reference Bernard-Trifilo, Kramár, Torp, Lin, Pineda, Lynch and Gall 90 The interplay between Reelin and β1 integrins is required also for the developmental switch in NMDAR subunit composition from GluN2B to GluN2A.Reference Jaudon, Thalhammer and Cingolani 91 - Reference Iafrati, Orejarena, Lassalle, Bouamrane, Gonzalez-Campo and Chavis 93 AMPA-type glutamate receptor activation increases α5 and β1 integrin surface expression, adhesive function, and signaling.Reference Lin, Lynch and Gall 94 Postsynaptic β3 integrins directly interact with GluA2 AMPAR subunits through their respective C-termini and regulate AMPAR abundance and composition to control synaptic strength.Reference Pozo, Cingolani, Bassani, Laurent, Passafaro and Goda 30 , Reference Cingolani, Thalhammer, Yu, Catalano, Ramos, Colicos and Goda 95 β1 integrins and ERK1/2 can mediate astrocyte-derived Pentraxin 3 (PTX3)-induced recruitment of synaptic AMPA glutamate receptors, thereby promoting synaptic maturation.Reference Fossati, Pozzi, Canzi, Mirabella, Valentino, Morini, Ghirardini, Filipello, Moretti, Gotti, Annis, Mosher, Garlanda, Bottazzi, Taraboletti, Mantovani, Matteoli and Menna 96 Binding of β1 integrin to vascular cell adhesion molecule 1 triggers glutamine, which stimulates glutamate release from Th17 cells.Reference Birkner, Wasser, Ruck, Thalman, Luchtman, Pape, Schmaul, Bitar, Krämer-Albers, Stroh, Meuth, Zipp and Bittner 97
Integrin β regulates 5-HT
There is a strong association between β-integrin and whole blood serotonin levels, genomic scans identified ITGB3 (encoding integrin β3) as a quantitative trait loci for whole blood serotonin,Reference Weiss, Veenstra-Vanderweele, Newman, Kim, Dytch, MS, Cheng, Ober, Cook and Abney 98 and common variation in ITGB3 is associated with serotonin concentrated in males.Reference Weiss, Abney, Parry, Scanu, Cook and Ober 99 A strong association between single-nucleotide polymorphisms (SNPs) in ITGB3 and serotonin levels was found in two outbred samples,Reference Weiss, Kosova, Delahanty, Jiang, Cook, Ober and Sutcliffe 100 after which experiments showed that it was the SNP rs2317385, located at the 5’ end of the ITGB3 gene, that significantly influenced 5-HT blood levels.Reference Napolioni, Lombardi, Sacco, Curatolo, Manzi, Alessandrelli, Militerni, Bravaccio, Lenti, Saccani, Schneider, Melmed, Pascucci, Puglisi-Allegra, Reichelt, Rousseau, Lewin and Persico 101 ITGB3 haplotypes were also significantly associated with the distribution of platelet serotonin levels.Reference Coutinho, Sousa, Martins, Correia, Morgadinho, Bento, Marques, Ataíde, Miguel, Moore, Oliveira and Vicente 102
The transporter protein of 5-hydroxytryptamine (SERT) is a membrane protein that transports 5HT from the synaptic gap to presynaptic neurons, and knockout mice lacking integrin β3 showed reduced platelet SERT activity.Reference Carneiro, Cook, Murphy and Blakely 103 SLC6A4 is the gene encoding the 5-HT transporter, and it has been demonstrated through open genomic resources that the expression of SLC6A4 and ITGB3 is correlated in several tissues in humans and mice.Reference Weiss, Ober and Cook 104 The 5-HT transporter and integrin β3 genes interact to regulate 5-HT uptake in the mouse central nervous system.Reference Whyte, Jessen, Varney and Carneiro 105 Changes in integrin β3 subunit expression can also regulate the rate of SERT-mediated 5-HT transport.Reference Mazalouskas, Jessen, Varney, Sutcliffe, Veenstra-Vander Weele, Cook and Carneiro 106 In recent years, a study has shown an important association between integrin β and both neuropsychiatric disorders by using knock-in mice of the Itgb3 variant to phenocopies the human Pro33 variant, which produces hyperactive αvβ3 receptors in mice, and found decreased 5-HT system function and multiple behavioral deficits in mice.Reference Dohn, Kooker, Bastarache, Jessen, Rinaldi, Varney, Mazalouskas, Pan, Oliver, Velez Edwards, Sutcliffe, Denny and Carneiro 107 In a study based on samples from patients with autism spectrum disorder, the promoter variant rs55827077 of ITGB3 was found to increase platelet integrin β3 protein expression and elevated blood levels of 5-HT.Reference Gabriele, Canali, Lintas, Sacco, Tirindelli, Ricciardello and Persico 108 Integrin β3 is also associated with a mode of action with selective serotonin reuptake inhibitors (SSRIs) antidepressants,Reference Oved, Morag, Pasmanik-Chor, Rehavi, Shomron and Gurwitz 109 and reduced expression of integrin β3 subunits reduces the effective dose of SSRIs by affecting the population size of active SERT molecules.Reference Mazalouskas, Jessen, Varney, Sutcliffe, Veenstra-Vander Weele, Cook and Carneiro 106
Integrin β and BDNF
Brain-derived neurotrophic factor (BDNF) is a secreted peptide that is widely expressed in the nervous system and plays a key role in neuronal survival and synaptic plasticity. The role played by BDNF in schizophrenia has been extensively studied, and many studies have shown that serum BDNF levels are lower in schizophrenic patientsReference Turkmen, Yazici, Erdogan, Suda and Yazici 110 - Reference Vinogradov, Fisher, Holland, Shelly, Wolkowitz and Mellon 116 except that a few studies have found higher BDNF levels,Reference Gama, Andreazza, Kunz, Berk, Belmonte-de-Abreu and Kapczinski 117 , Reference Reis, Nicolato, Barbosa, Teixeira do Prado, Romano-Silva and Teixeira 118 but what can be confirmed is that BDNF levels are altered in patients with schizophrenia.Reference Favalli, Li, Belmonte-de-Abreu, Wong and Daskalakis 119 , Reference Pandya, Kutiyanawalla and Pillai 120 Meta-analysis demonstrated a firm correlation between serum BDNF levels and the course of severe schizophrenia and major depression, suggesting that BDNF is a potential circulating biomarker for schizophrenia or depression.Reference Peng, Li, Lv, Zhang and Zhan 121 In recent years, studies have supported that serum BDNF levels are lower in patients with first-episode schizophrenia than in healthy controlsReference Singh, Verma, Raghav, Sarkar, Sood and Jain 122 , Reference Li, Chen, Xiu, Li and Zhang 123 and that abnormal signaling of BDNF increases an individual’s susceptibility to schizophrenia by affecting brain function.Reference Singh, Verma, Raghav, Sarkar, Sood and Jain 122 Lower BDNF levels are also associated with decreased cognitive performance in schizophrenia subjects.Reference Hori, Yoshimura, Katsuki, Atake, Igata, Konishi and Nakamura 124 , Reference Yang, Liu, Wang, Hei, Wang, Li, Li, Wu and Zhao 125
The relationship between integrin β and BDNF has not been well documented by research, but a few studies have indicated an association. Integrins bound to arginine-glycine-aspartate (RGD) matrix sequences can increase the expression of mRNAs for BDNF and its receptors TrkB and TrkC in hippocampal slices through effects on voltage-sensitive calcium channels, and although the specific integrin involved is unclear, it is likely to be related to integrin β1.Reference Gall, Pinkstaff, Lauterborn, Xie and Lynch 126 Neurotrophins promote the survival of newborn hippocampal neurons by promoting spontaneous GABA-dependent activity, and this survival effect requires integrin β1 signaling.Reference Murase, Owens and McKay 127 Integrin β1 is also involved in signaling of the glial cell line-derived neurotrophic factor (GDNF) and may function as a signaling receptor for GDNF.Reference Cao, Yu, Li, Sun, Yuan, Wang and Gao 128
Integrin β and estrogen
Estrogen can function in schizophrenia by modulating the excitatory transmitter glutamate (Figure 2). In cultured hippocampal neurons, estrogen enhances glutamate release from presynaptic sites through activation of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK).Reference Yokomaku, Numakawa, Numakawa, Suzuki, Matsumoto, Adachi, Nishio, Taguchi and Hatanaka 129 Several studies have shown that 17 β-estradiol (E2) enhances glutamatergic synaptic transmission in the hippocampus through mechanisms that increase presynaptic glutamate release probabilityReference Smejkalova and Woolley 130 , Reference Oberlander and Woolley 131 and postsynaptic sensitivity to glutamate.Reference Oberlander and Woolley 131 Estrogen and integrin β are tightly related in many ways. Estrogen’s effects on excitatory synaptic transmission entail transactivation of the BDNF receptors TrkB and β1 integrin, and β1 integrin function has a decisive role.Reference Wang, Kantorovich, Babayan, Hou, Gall and Lynch 132 Estradiol activates integrin α5β1 to promote the attachment of striatal neurons to fibronectin, and activated integrin α5β1 also contributes to synapse formation of human-induced pluripotent stem cell-derived dopaminergic (DA) neurons.Reference Nishimura, Doi, Samata, Murayama, Tahara, Onoe and Takahashi 133
Figure 2. Schematic representation of the mechanism by which estrogen affects glutamatergic synaptic transmission.
E2 binds to the estrogen receptor ER and activates the classical MAPK pathway, causing phosphorylation and activation of the MAPK kinase B-Raf, the MAPK kinases MEK1/2 and the ERK1/2. E2 activates the PI3K signaling pathway, causing activation of phosphoinositide-dependent kinases (PDK1/2) and subsequently AKT/protein kinase B.Reference Belcher and Zsarnovszky 139 Both signaling pathways can enhance glutamatergic synaptic transmission. The mechanisms involved include increased presynaptic glutamate release probabilityReference Smejkalova and Woolley 130 , Reference Oberlander and Woolley 131 and postsynaptic sensitivity to glutamate.Reference Oberlander and Woolley 131 In addition, E2 is involved in the activation of integrin β1 by acting on Src family kinases and Ras/Rap GTPases. Activated integrin β1 can drive downstream small GTPases that enable local polymerization of filamentous actin (F-actin) from actin monomers (G-actin), thereby affecting AMPAR. Activation of small GTPases can transactivate TrkB, and it has also been speculated that the aforementioned cytoskeletal reorganization also affects TrkB activation.Reference Wang, Kantorovich, Babayan, Hou, Gall and Lynch 132
Estrogen is additionally involved in the regulation of hippocampal synaptic plasticity.Reference Rune and Frotscher 134 - Reference Spencer-Segal, Tsuda, Mattei, Waters, Romeo, Milner, BS and Ogawa 136 Moreover, E2 acts as a novel neuromodulator in the forebrain, affecting synaptic plasticity and cognitive function.Reference Lu, Sareddy, Wang, Wang, Li, Dong, Zhang, Liu, O’Connor, Xu, Vadlamudi and Brann 137 Recently, it has been indicated that E2 receptor α induces a new form of LTP that is NMAD receptor dependent and involves AMPAR transport to the synapse.Reference Clements and Harvey 138
Integrin β and CHL1
Close homologue of L1 (CHL1) belongs to the immunoglobulin (Ig) superfamily cell adhesion molecules, a gene encoding neuronal cell adhesion protein that regulates the proliferation, migration, differentiation, and survival of neuronal cells.Reference Huang, Zhu, Zhao, Wu, Wu, Schachner, Xiao and Fan 140 - Reference Chen, Mantei, Dong and Schachner 142 CHL1 has been significantly associated with schizophrenia. Patients with schizophrenia present with timing impairmentsReference Braus 143 - Reference Volz, Nenadic, Gaser, Rammsayer, Häger and Sauer 146 as well as deficits in spatiotemporal integration,Reference Herzog and Brand 147 , Reference Velasques, Machado, Paes, Cunha, Sanfim, Budde, Cagy, Anghinah, Basile, Piedade and Ribeiro 148 and CHL1 knockout mice exhibit the same symptoms.Reference Buhusi, Scripa, Williams and Buhusi 149 Furthermore, the rs2272522 polymorphism of the CHL1 locus is significantly associated with schizophrenia in the Qatari population,Reference Shaltout, Alali, Bushra, Alkaseri, Jose, Al-Khainji, Saleh, Salama Dahir, Shaltout, Al-Abdullah and Rizk 150 and CHL1-deficient mice were also identified as a model for schizophrenia-like learning and attention impairments.Reference Buhusi, Obray, Guercio, Bartlett and Buhusi 151 Domestic studies have shown that CHL1 interacts with DISC1 to regulate the development of neurite outgrowth and that disruption of this interaction may contribute to increased risk of schizophrenia.Reference Ren, Zhao, Xu and Ye 152
Integrin β is tightly associated with CHL1 as well. CHL1 interacts with β1-containing integrins to potentiate integrin-mediated cell migration.Reference Buhusi, Midkiff, Gates, Richter, Schachner and Maness 153 A direct link between ITGB3 and CHL1 was postulated to be involved in the regulation of serotonin uptake.Reference Oved, Morag, Pasmanik-Chor, Rehavi, Shomron and Gurwitz 109 Subsequently, a significant correlation between the gene expression levels of CHL1 and ITGB3 in Munich Antidepressant Response Signature lymphoblastoid cell lines was found, supporting the connection between CHL1 and ITGB3.Reference Probst-Schendzielorz, Scholl, Efimkina, Ersfeld, Viviani, Serretti, Fabbri, Gurwitz, Lucae, Ising, Paul, Lehmann, Steffens, Crisafulli, Calabrò, Holsboer and Stingl 154
Integrin β and Reelin
Reelin is an ECM protein that is synthesized and secreted by cortical GABAergic interneurons and is involved in several aspects of brain development and function, such as neuronal migration, synaptogenesis, and synaptic plasticity. Several studies have shown that Reelin and its mRNA levels are significantly reduced in several brain regions in schizophrenia patients compared to controls,Reference Jaudon, Thalhammer and Cingolani 91 , Reference Impagnatiello, Guidotti, Pesold, Dwivedi, Caruncho, Pisu, Uzunov, Smalheiser, Davis, Pandey, Pappas, Tueting, Sharma and Costa 155 - Reference Sethi and Zaia 160 and that Reelin downregulation is accompanied by a downregulation of GAD67.Reference Guidotti, Grayson and Caruncho 158 , Reference Lubbers, Smit, Spijker and van den Oever 161 Reelin can be involved in the regulation of glutamatergic synaptic maturation and plasticity by regulating synaptic NMDA receptor subunit composition and surface transport.Reference Groc, Choquet, Stephenson, Verrier, Manzoni and Chavis 92 In addition, adult brain Reelin levels directly affect cognitive function and dendritic spine density.Reference Guidotti, Grayson and Caruncho 158
Integrin β is linked to Reelin in multiple aspects. α3β1 integrin interacts with Reelin to regulate neuronal migration and normal cortical lamination and promote neuronal adhesion to fibronectin.Reference Jaudon, Thalhammer and Cingolani 91 , Reference Sekine, Kawauchi, Kubo, Honda, Herz, Hattori, Kinashi and Nakajima 162 , Reference Dulabon, Olson, Taglienti, Eisenhuth, McGrath, Walsh, Kreidberg and Anton 163 The interaction among the amyloid precursor protein, Reelin, and α3β1 integrin promotes neurite outgrowth.Reference Hoe, Lee, Carney, Lee, Markova, Lee, Howell, Hyman, Pak, Bu and Rebeck 164 Reelin activates α5β1 integrin to affect the correct neuronal positioning in the mature cortex.Reference Sekine, Kawauchi, Kubo, Honda, Herz, Hattori, Kinashi and Nakajima 162 In addition, Reelin initiates a series of kinase cascade reactions to promote neurodevelopmental processes by directly binding to its receptors APOER2, VLDLR, and α3β1 integrin and activating the downstream adapter protein DAB1.Reference Lubbers, Smit, Spijker and van den Oever 161 , Reference Folsom and Fatemi 165
Integrin β and MMP9
Matrix metalloproteinase-9 (MMP9) is an extracellular protease that has been revealed in several studies to play a critical role in regulating hippocampal synaptic physiology, plasticity, and long-term memory.Reference Nagy, Bozdagi, Matynia, Balcerzyk, Okulski, Dzwonek, Costa, Silva, Kaczmarek and Huntley 166 , Reference Bozdagi, Nagy, Kwei and Huntley 167 It has been found that tissue inhibitor of matrix metalloproteinases-1, an endogenous inhibitor of MMP9, interacts with MMP9 to affect plasticity in the PFC,Reference Okulski, Jay, Jaworski, Duniec, Dzwonek, Konopacki, Wilczynski, Sánchez-Capelo, Mallet and Kaczmarek 168 and the dysfunction of the PFC is tightly associated with the development of psychiatric disorders such as schizophrenia.Reference Egan and Weinberger 169 , Reference Kalia 170 A later study found increased MMP9 activity in mild cognitive impairment and that MMP9 led to a decrease in mature nerve growth factor.Reference Bruno, Mufson, Wuu and Cuello 171 In addition, a functional-1562 C/T polymorphism of the MMP9 gene was found to be relevant in the pathogenesis of schizophrenia by comparison with healthy controls.Reference Rybakowski 172 , Reference Rybakowski, Skibinska, Kapelski, Kaczmarek and Hauser 173
In the study of the relationship between MMP9 and integrin β, it was found that MMP9-driven LTP requires the mediation of β1-containing integrins and the activation of their downstream coenzyme protein signaling pathways.Reference Wang, Bozdagi, Nikitczuk, Zhai, Zhou and Huntley 174 Furthermore, MMP9 mediates surface transport of NMDAR through an integrin β1-dependent pathway.Reference Michaluk, Mikasova, Groc, Frischknecht, Choquet and Kaczmarek 175 Taken together, the interaction between integrin β and MMP9 may have an important association with schizophrenia.
Discussion
A strong correlation between integrin β and schizophrenia can be demonstrated by linking the etiology and clinical symptoms of schizophrenia to the role of integrin β in neurodevelopment, transmitter regulation, signaling, and the role it plays in states of anxiety and stress. However, we lack experimental evidence, and the pathways or mechanisms through which integrin β is involved in the effects on schizophrenia are not well understood. To date, most of our knowledge of the β integrin family in the brain has been on β1- and β3-containing integrins, and there is a lack of adequate interpretation of the physiological role of other β integrin subtypes in specific circuit-related brain functions in different brain regions,Reference Park and Goda 36 and it is not clear whether these integrin subtypes are associated with schizophrenia or play a role in other brain disorders. In addition, the ECM ligands of integrins have been less studied, whereas alterations in the components of the ECM are important for brain function, and past clinical studies have demonstrated a correlation between abnormal ECM function and neuropsychiatric disorders with some degree of causality, one of the most prominent being schizophrenia. Therefore, the identification of the ECM ligand for integrin β is also helpful to study the correlation with schizophrenia. In conclusion, it remains much to be learned about the diverse functions of members of the β integrin family and the ways in which they are involved in the pathogenesis of schizophrenia, and investigating the role of different β subtypes in specific signaling pathways and potential ECM ligands could provide new clinical directions for studying the pathogenesis and treatment of schizophrenia.
Acknowledgments
This work was supported by the 2021 National Innovation and Entrepreneurship Training program for College Students in China (grant no. 202110632050).
Author Contributions
Methodology: H.L.; resources: B.H., H.L.; supervision: Y.W.; writing—original draft: B.H.; writing—review and editing: Y.W., Y.H.
Disclosure
Binshan He, Yuhan Wang, Huang Li, and Yuanshuai Huang do not have anything to disclose.
