Overview of Studies in Animal Models of Schizophrenia

doi:10.12300/j.issn.1674-5817.2022.174

Abstract

Abstract:

Schizophrenia (SCZ) is a highly destructive and complex psychiatric disorder illness, accompanied by a variety of positive and negative symptoms along with cognitive impairment, which brings a heavy social burden. Elucidation of the pathogenesis and therapeutic development is challenging because the complex interplay between genetic risk factors and environmental factors in essential neurodevelopmental processes. Therefore, preparing appropriate animal models can help people better understanding the neurobiological basis of SCZ and provide theoretical basis for finding new treatments. In order to provide reference for the application and improvement of SCZ animal models, this commentary reviewed several main modeling methods for animal models of SCZ, including neurodevelopmental models, drug-induced animal models, and genetic models, and the behavioral evaluation, histological analysis and possible molecular mechanisms of SCZ animal models were also outlined.

Key words: Schizophrenia, Animal models, Behavior analysis, Dopamine, γ-aminobutyric acid

CLC Number:

R-332

Ling HU, Zhibin HU, Yunqing HU, Yuqiang DING. Overview of Studies in Animal Models of Schizophrenia[J]. Laboratory Animal and Comparative Medicine, 2023, 43(2): 145-155.

Figures/Tables 1

References 90

1	MCCUTCHEON R A, REIS MARQUES T, HOWES O D. Schizophrenia-an overview[J]. JAMA Psychiatry, 2020, 77(2):201-210. DOI: 10.1001/jamapsychiatry.2019.3360 .
2	CORRELL C U, SCHOOLER N R. Negative symptoms in schizophrenia: a review and clinical guide for recognition, assessment, and treatment[J]. Neuropsychiatr Dis Treat, 2020, 16:519-534. DOI: 10.2147/NDT.S225643 .
3	CONSORTIUM I S, PURCELL S M, WRAY N R, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder[J]. Nature, 2009, 460(7256):748-752. DOI: 10.1038/nature08185 .
4	YEE B K, SINGER P. A conceptual and practical guide to the behavioural evaluation of animal models of the symptomatology and therapy of schizophrenia[J]. Cell Tissue Res, 2013, 354(1):221-246. DOI: 10.1007/s00441-013-1611-0 .
5	GREEN J G, MCLAUGHLIN K A, BERGLUND P A, et al. Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication I: associations with first onset of DSM-IV disorders[J]. Arch Gen Psychiatry, 2010, 67(2):113-123. DOI: 10.1001/archgenpsychiatry.2009.186 .
6	LIPSKA B K, WEINBERGER D R. To model a psychiatric disorder in animals: schizophrenia as a reality test[J]. Neuropsychopharmacology, 2000, 23(3):223-239. DOI:10.1016/ S0893-13.3X(00)00137-8 .
7	HU L, ZHANG L. Adult neural stem cells and schizophrenia[J]. World J Stem Cells, 2022, 14(3):219-230. DOI: 10.4252/wjsc.v14.i3.219 .
8	LAPIZ M S, FULFORD A, MUCHIMAPURA S, et al. Influence of postweaning social isolation in the rat on brain development, conditioned behavior, and neurotransmission[J]. Neurosci Behav Physiol, 2003, 33(1):13-29. DOI: 10.1023/A: 1021171129766 .
9	SHEU J R, HSIEH C Y, JAYAKUMAR T, et al. A critical period for the development of schizophrenia-like pathology by aberrant postnatal neurogenesis[J]. Front Neurosci, 2019, 13:635. DOI: 10.3389/fnins.2019.00635 .
10	LODGE D J, GRACE A A. Gestational methylazoxymethanol acetate administration: a developmental disruption model of schizophrenia[J]. Behav Brain Res, 2009, 204(2):306-312. DOI: 10.1016/j.bbr.2009.01.031 .
11	WALKER D M, CUNNINGHAM A M, GREGORY J K, et al. Long-term behavioral effects of post-weaning social isolation in males and females[J]. Front Behav Neurosci, 2019, 13:66. DOI: 10.3389/fnbeh.2019.00066 .
12	SKELLY M J, CHAPPELL A E, CARTER E, et al. Adolescent social isolation increases anxiety-like behavior and ethanol intake and impairs fear extinction in adulthood: possible role of disrupted noradrenergic signaling[J]. Neuropharmacology, 2015, 97:149-159. DOI: 10.1016/j.neuropharm.2015.05.025 .
13	FABRICIUS K, HELBOE L, FINK-JENSEN A, et al. Pharmacological characterization of social isolation-induced hyperactivity[J]. Psychopharmacology, 2011, 215(2):257-266. DOI: 10.1007/s00213-010-2128-9 .
14	SCHUBERT M I, PORKESS M V, DASHDORJ N, et al. Effects of social isolation rearing on the limbic brain: a combined behavioral and magnetic resonance imaging volumetry study in rats[J]. Neuroscience, 2009, 159(1):21-30. DOI: 10.1016/j.neuroscience.2008.12.019 .
15	BERGDOLT L, DUNAEVSKY A. Brain changes in a maternal immune activation model of neurodevelopmental brain disorders[J]. Prog Neurobiol, 2019, 175: 1-19. DOI: 10.1016/j.pneurobio.2018.12.002 .
16	HADAR R, DONG L, DEL-VALLE-ANTON L, et al. Deep brain stimulation during early adolescence prevents microglial alterations in a model of maternal immune activation[J]. Brain Behav Immun, 2017, 63: 71-80. DOI: 10.1016/j.bbi. 2016.12.003 .
17	COIRO P, PADMASHRI R, SURESH A, et al. Impaired synaptic development in a maternal immune activation mouse model of neurodevelopmental disorders[J]. Brain Behav Immun, 2015, 50:249-258. DOI: 10.1016/j.bbi.2015.07.022 .
18	SHORT S J, LUBACH G R, KARASIN A I, et al. Maternal influenza infection during pregnancy impacts postnatal brain development in the Rhesus monkey[J]. Biol Psychiatry, 2010, 67(10):965-973. DOI: 10.1016/j.biopsych.2009.11.026 .
19	DESBONNET L, KONKOTH A, LAIGHNEACH A, et al. Dual hit mouse model to examine the long-term effects of maternal immune activation and post-weaning social isolation on schizophrenia endophenotypes[J]. Behav Brain Res, 2022, 430:113930. DOI: 10.1016/j.bbr.2022.113930 .
20	WILSON C, TERRY A V Jr. Neurodevelopmental animal models of schizophrenia: role in novel drug discovery and development[J]. Clin Schizophr Relat Psychoses, 2010, 4(2):124-137. DOI: 10.3371/CSRP.4.2.4 .
21	MCCUTCHEON R A, ABI-DARGHAM A, HOWES O D. Schizophrenia, dopamine and the Striatum: from biology to symptoms[J]. Trends Neurosci, 2019, 42(3): 205-220. DOI: 10.1016/j.tins.2018.12.004 .
22	BIAŁOŃ M, WĄSIK A. Advantages and limitations of animal schizophrenia models[J]. Int J Mol Sci, 2022, 23(11):5968. DOI: 10.3390/ijms23115968 .
23	NAKAZAWA K, JEEVAKUMAR V, NAKAO K. Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia[J]. NPJ Schizophr, 2017, 3:7. DOI: 10.1038/s41537-016-0003-3 .
24	CERETTA A P C, SCHAFFER L F, DE FREITAS C M, et al. Gabapentin prevents behavioral changes on the amphetamine-induced animal model of schizophrenia[J]. Schizophr Res, 2016, 175(1-3): 230-231. DOI: 10.1016/j.schres.2016.04.044 .
25	ARROYO-GARCÍA L E, TENDILLA-BELTRÁN H, VÁZQUEZ-ROQUE R A, et al. Amphetamine sensitization alters hippocampal neuronal morphology and memory and learning behaviors[J]. Mol Psychiatry, 2021, 26(9):4784-4794. DOI: 10.1038/s41380-020-0809-2 .
26	SAMS-DODD F. A test of the predictive validity of animal models of schizophrenia based on phencyclidine and D-amphetamine[J]. Neuropsychopharmacology, 1998, 18(4):293-304. DOI: 10.1016/S0893-133X(97)00161-9 .
27	ROBINSON T E, KOLB B. Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine[J]. J Neurosci, 1997, 17(21):8491-8497. DOI:10.1523/JNEUROSCI.17- 21-08491.1997 .
28	WALLACH J, KANG H, COLESTOCK T, et al. Pharmacological investigations of the dissociative 'legal highs' diphenidine, methoxphenidine and analogues[J]. PLoS One, 2016, 11(6): e0157021. DOI: 10.1371/journal.pone.0157021 .
29	GRAYSON B, BARNES S A, MARKOU A, et al. Postnatal phencyclidine (PCP) as a neurodevelopmental animal model of schizophrenia pathophysiology and symptomatology: a review[J]. Curr Top Behav Neurosci, 2016, 29:403-428. DOI: 10.1007/7854_2015_403 .
30	TSIVION-VISBORD H, PERETS N, SOFER T, et al. Correction: Mesenchymal stem cells derived extracellular vesicles improve behavioral and biochemical deficits in a phencyclidine model of schizophrenia[J]. Transl Psychiatry, 2020, 10(1):327. DOI: 10.1038/s41398-020-01016-9 .
31	GIGG J, MCEWAN F, SMAUSZ R, et al. Synaptic biomarker reduction and impaired cognition in the sub-chronic PCP mouse model for schizophrenia[J]. J Psychopharmacol, 2020, 34(1):115-124. DOI: 10.1177/0269881119874446 .
32	NEUGEBAUER N M, MIYAUCHI M, SATO T, et al. Hippocampal GABA_A antagonism reverses the novel object recognition deficit in sub-chronic phencyclidine-treated rats[J]. Behav Brain Res, 2018, 342:11-18. DOI: 10.1016/j.bbr. 2017.12.033 .
33	MOGHADDAM B, ADAMS B W. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats[J]. Science, 1998, 281(5381):1349-1352. DOI: 10.1126/science , 281.5381.1349.
34	TANQUEIRO S R, MOURO F M, FERREIRA C B, et al. Sustained NMDA receptor hypofunction impairs brain-derived neurotropic factor signalling in the PFC, but not in the hippocampus, and disturbs PFC-dependent cognition in mice[J]. J Psychopharmacol, 2021, 35(6):730-743. DOI: 10.1177/02698811211008560 .
35	MOGHADAM A A, VOSE L R, MIRY O, et al. Pairing of neonatal phencyclidine exposure and acute adolescent stress in male rats as a novel developmental model of schizophrenia[J]. Behav Brain Res, 2021, 409:113308. DOI: 10.1016/j.bbr.2021.113308 .
36	OSHODI T O, BEN-AZU B, ISHOLA I O, et al. Molecular mechanisms involved in the prevention and reversal of ketamine-induced schizophrenia-like behavior by rutin: the role of glutamic acid decarboxylase isoform-67, cholinergic, Nox-2-oxidative stress pathways in mice[J]. Mol Biol Rep, 2021, 48(3):2335-2350. DOI: 10.1007/s11033-021-06264-6 .
37	BECK K, HINDLEY G, BORGAN F, et al. Association of ketamine with psychiatric symptoms and implications for its therapeutic use and for understanding schizophrenia: a systematic review and meta-analysis[J]. JAMA Netw Open, 2020, 3(5): e204693. DOI: 10.1001/jamanetworkopen.2020. 4693 .
38	AZIMI SANAVI M, GHAZVINI H, ZARGARI M, et al. Effects of clozapine and risperidone antipsychotic drugs on the expression of CACNA1C and behavioral changes in rat 'Ketamine model of schizophrenia[J]. Neurosci Lett, 2022, 770:136354. DOI: 10.1016/j.neulet.2021.136354 .
39	XU Y, DENG C, ZHENG Y, et al. Applying vinpocetine to reverse synaptic ultrastructure by regulating BDNF-related PSD-95 in alleviating schizophrenia-like deficits in rat[J]. Compr Psychiatry, 2019, 94:152122. DOI: 10.1016/j.comppsych. 2019.152122 .
40	LI Y N, SHEN R P, WEN G H, et al. Effects of ketamine on levels of inflammatory cytokines IL-6, IL-1β, and TNF-α in the Hippocampus of mice following acute or chronic administration[J]. Front Pharmacol, 2017, 8:139. DOI: 10.3389/fphar.2017.00139 .
41	FUJIKAWA R, YAMADA J, JINNO S. Subclass imbalance of parvalbumin-expressing GABAergic neurons in the hippocampus of a mouse ketamine model for schizophrenia, with reference to perineuronal nets[J]. Schizophr Res, 2021, 229:80-93. DOI: 10.1016/j.schres.2020.11.016 .
42	KRAEUTER A K, MASHAVAVE T, SUVARNA A, et al. Effects of beta-hydroxybutyrate administration on MK-801-induced schizophrenia-like behaviour in mice[J]. Psychopharma-cology, 2020, 237(5):1397-1405. DOI: 10.1007/s00213-020-05467-2 .
43	FAN H R, DU W F, ZHU T, et al. Quercetin reduces cortical GABAergic transmission and alleviates MK-801-induced hyperactivity[J]. EBioMedicine, 2018, 34:201-213. DOI: 10.1016/j.ebiom.2018.07.031 .
44	FLORES-BARRERA E, THOMASES D R, TSENG K Y. MK-801 exposure during adolescence elicits enduring disruption of prefrontal E-I balance and its control of fear extinction behavior[J]. J Neurosci, 2020, 40(25):4881-4887. DOI: 10.1523/JNEUROSCI.0581-20.2020 .
45	CHEN G D, LIN X D, LI G Y, et al. Risperidone reverses the spatial object recognition impairment and hippocampal BDNF-TrkB signalling system alterations induced by acute MK-801 treatment[J]. Biomed Rep, 2017, 6(3):285-290. DOI: 10.3892/br.2017.850 .
46	FARRELL M S, WERGE T, SKLAR P, et al. Evaluating historical candidate genes for schizophrenia[J]. Mol Psychiatry, 2015, 20(5):555-562. DOI: 10.1038/mp.2015.16 .
47	SCHIZOPHRENIA WORKING GROUP OF THE PSYCHIATRIC GENOMICS CONSORTIUM. Biological insights from 108 schizophrenia-associated genetic loci[J]. Nature, 2014, 511(7510):421-427. DOI: 10.1038/nature13595 .
48	TRUBETSKOY V, PARDIÑAS A F, QI T, et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia[J]. Nature, 2022, 604(7906):502-508. DOI: 10.1038/s41586-022-04434-5 .
49	LIU C M, LIU Y L, HWU H G, et al. Genetic associations and expression of extra-short isoforms of disrupted-in-schizophrenia 1 in a neurocognitive subgroup of schizophrenia[J]. J Hum Genet, 2019, 64(7):653-663. DOI: 10.1038/s10038-019-0597-1 .
50	BRADSHAW N, PORTEOUS D J. DISC1-binding proteins in neural development, signalling and schizophrenia[J]. Neuropharmacology, 2012, 62(3):1230-1241. DOI: 10.1016/j.neuropharm.2010.12.027 .
51	PLETNIKOV M V, AYHAN Y, XU Y, et al. Enlargement of the lateral ventricles in mutant DISC1 transgenic mice[J]. Mol Psychiatry, 2008, 13(2):115. DOI: 10.1038/sj.mp.4002144 .
52	ELLISON-WRIGHT I, GLAHN D C, LAIRD A R, et al. The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis[J]. Am J Psychiatry, 2008, 165(8):1015-1023. DOI: 10.1176/appi.ajp.2008.07101562 .
53	UMEDA K, IRITANI S, FUJISHIRO H, et al. Immuno-histochemical evaluation of the GABAergic neuronal system in the prefrontal cortex of a DISC1 knockout mouse model of schizophrenia[J]. Synapse, 2016, 70(12):508-518. DOI: 10.1002/syn.21924 .
54	CUI L, SUN W, YU M, et al. Disrupted-in-schizophrenia1 (DISC1) L100P mutation alters synaptic transmission and plasticity in the hippocampus and causes recognition memory deficits[J]. Mol Brain, 2016, 9(1):89. DOI: 10.1186/ s13041-016-0270-y .
55	VAN L, BOOT E, BASSETT A S. Update on the 22q11.2 deletion syndrome and its relevance to schizophrenia[J]. Curr Opin Psychiatry, 2017, 30(3):191-196. DOI: 10.1097/YCO.0000000000000324 .
56	SUN Z Y, WILLIAMS D J, XU B, et al. Altered function and maturation of primary cortical neurons from a 22q11.2 deletion mouse model of schizophrenia[J]. Transl Psychiatry, 2018, 8(1):85. DOI: 10.1038/s41398-018-0132-8 .
57	KARAYIORGOU M, SIMON T J, GOGOS J A. 22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia[J]. Nat Rev Neurosci, 2010, 11(6):402-416. DOI: 10.1038/nrn2841 .
58	ZINKSTOK J R, BOOT E, BASSETT A S, et al. Neurobiological perspective of 22q11.2 deletion syndrome[J]. Lancet Psychiatry, 2019, 6(11): 951-960. DOI: 10.1016/S2215-0366(19)30076-8 .
59	MOSTAID M S, LLOYD D, LIBERG B, et al. Neuregulin-1 and schizophrenia in the genome-wide association study era[J]. Neurosci Biobehav Rev, 2016, 68:387-409. DOI: 10.1016/j.neubiorev.2016.06.001 .
60	JOSHI D, FULLERTON J M, WEICKERT C S. Elevated ErbB4 mRNA is related to interneuron deficit in prefrontal cortex in schizophrenia[J]. J Psychiatr Res, 2014, 53:125-132. DOI: 10.1016/j.jpsychires.2014.02.014 .
61	KARL T, DUFFY L, SCIMONE A, et al. Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: implications for understanding schizophrenia[J]. Genes Brain Behav, 2007, 6(7):677-687. DOI: 10.1111/j.1601-183X. 2006.00298.x .
62	BANERJEE A, MACDONALD M L, BORGMANN-WINTER K E, et al. Neuregulin 1-erbB4 pathway in schizophrenia: from genes to an interactome[J]. Brain Res Bull, 2010, 83(3-4):132-139. DOI: 10.1016/j.brainresbull.2010.04.011 .
63	WANG H T, XU J P, LAZAROVICI P, et al. Dysbindin-1 involvement in the etiology of schizophrenia[J]. Int J Mol Sci, 2017, 18(10):2044. DOI: 10.3390/ijms18102044 .
64	WOLF C, JACKSON M C, KISSLING C, et al. Dysbindin-1 genotype effects on emotional working memory[J]. Mol Psychiatry, 2011, 16(2):145-155. DOI: 10.1038/mp.2009.129 .
65	WEICKERT C S, ROTHMOND D A, HYDE T M, et al. Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients[J]. Schizophr Res, 2008, 98(1-3):105-110. DOI: 10.1016/j.schres.2007.05.041 .
66	KARLSGODT K H, ROBLETO K, TRANTHAM-DAVIDSON H, et al. Reduced dysbindin expression mediates N-methyl-D-aspartate receptor hypofunction and impaired working memory performance[J]. Biol Psychiatry, 2011, 69(1):28-34. DOI: 10.1016/j.biopsych.2010.09.012 .
67	JI Y Y, YANG F, PAPALEO F, et al. Role of dysbindin in dopamine receptor trafficking and cortical GABA function[J]. Proc Natl Acad Sci USA, 2009, 106(46):19593-19598. DOI: 10.1073/pnas.0904289106 .
68	WANG Q Z, JI W D, HE K J, et al. Genetic analysis of common variants in the ZNF804A gene with schizophrenia and major depressive disorder[J]. Psychiatr Genet, 2018, 28(1):1-7. DOI: 10.1097/YPG.0000000000000185 .
69	HUANG Y, HUANG J, ZHOU Q X, et al. ZFP804A mutant mice display sex-dependent schizophrenia-like behaviors[J]. Mol Psychiatry, 2021, 26(6):2514-2532. DOI: 10.1038/s41380-020-00972-4 .
70	LANG B, ZHANG L, JIANG G Y, et al. Control of cortex development by ULK4, a rare risk gene for mental disorders including schizophrenia[J]. Sci Rep, 2016, 6:31126. DOI: 10.1038/srep31126 .
71	HU L, ZHOU B Y, YANG C P, et al. Deletion of schizophrenia susceptibility gene Ulk4 leads to abnormal cognitive behaviors via Akt-GSK-3 signaling pathway in mice[J]. Schizophr Bull, 2022, 48(4):804-813. DOI: 10.1093/schbul/sbac040 .
72	AMANN L C, GANDAL M J, HALENE T B, et al. Mouse behavioral endophenotypes for schizophrenia[J]. Brain Res Bull, 2010, 83(3-4):147-161. DOI: 10.1016/j.brainresbull. 2010. 04.008 .
73	SWERDLOW N R, WEBER M, QU Y, et al. Realistic expectations of prepulse inhibition in translational models for schizophrenia research[J]. Psychopharmacology, 2008, 199(3):331-388. DOI: 10.1007/s00213-008-1072-4 .
74	GEYER M A, MCILWAIN K L, PAYLOR R. Mouse genetic models for prepulse inhibition: an early review[J]. Mol Psychiatry, 2002, 7(10):1039-1053. DOI: 10.1038/sj.mp.4001159 .
75	STERU L, CHERMAT R, THIERRY B, et al. The tail suspension test: a new method for screening antidepressants in mice[J]. Psychopharmacology, 1985, 85(3):367-370. DOI: 10.1007/BF00428203 .
76	LIU M Y, YIN C Y, ZHU L J, et al. Sucrose preference test for measurement of stress-induced anhedonia in mice[J]. Nat Protoc, 2018, 13(7):1686-1698. DOI: 10.1038/s41596-018-0011-z .
77	KOMADA M, TAKAO K, MIYAKAWA T. Elevated plus maze for mice[J]. J Vis Exp, 2008(22):1088. DOI: 10.3791/1088 .
78	O'TUATHAIGH C M, DESBONNET L, WADDINGTON J L. Genetically modified mice related to schizophrenia and other psychoses: seeking phenotypic insights into the pathobiology and treatment of negative symptoms[J]. Eur Neuropsychopharmacol, 2014, 24(5):800-821. DOI: 10.1016/j.euroneuro.2013.08.009 .
79	KEEFE R S E, EESLEY C E, POE M P. Defining a cognitive function decrement in schizophrenia[J]. Biol Psychiatry, 2005, 57(6):688-691. DOI: 10.1016/j.biopsych.2005.01.003 .
80	CLARK R E, MARTIN S J. Interrogating rodents regarding their object and spatial memory[J]. Curr Opin Neurobiol, 2005, 15(5):593-598. DOI: 10.1016/j.conb.2005.08.014 .
81	JAARO-PELED H. Gene models of schizophrenia: DISC1 mouse models[J]. Prog Brain Res, 2009, 179:75-86. DOI: 10.1016/S0079-6123(09)17909-8 .
82	BRENNAMAN L H, KOCHLAMAZASHVILI G, STOENICA L, et al. Transgenic mice overexpressing the extracellular domain of NCAM are impaired in working memory and cortical plasticity[J]. Neurobiol Dis, 2011, 43(2):372-378. DOI: 10.1016/j.nbd.2011.04.008 .
83	JAUHAR S, JOHNSTONE M, MCKENNA P J. Schizophrenia[J]. Lancet, 2022, 399(10323):473-486. DOI: 10.1016/S0140-6736(21)01730-X .
84	JOHNSTONE E C, CROW T J, FRITH C D, et al. Mechanism of the antipsychotic effect in the treatment of acute schizophrenia[J]. Lancet, 1978, 1(8069):848-851. DOI: 10.1016/ s0140-6736(78)90193-9 .
85	EMAMIAN E S, HALL D, BIRNBAUM M J, et al. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia[J]. Nat Genet, 2004, 36(2):131-137. DOI: 10.1038/ ng1296
86	ARGUELLO P A, GOGOS J A. A signaling pathway AKTing up in schizophrenia[J]. J Clin Invest, 2008, 118(6):2018-2021. DOI: 10.1172/JCI35931 .
87	TAKAYANAGI Y, SASABAYASHI D, TAKAHASHI T, et al. Reduced cortical thickness in schizophrenia and schizotypal disorder[J]. Schizophr Bull, 2020, 46(2):387-394. DOI: 10.1093/schbul/sbz051 .
88	HELLER C, WEISS T, DEL RE E C, et al. Smaller subcortical volumes and enlarged lateral ventricles are associated with higher global functioning in young adults with 22q11.2 deletion syndrome with prodromal symptoms of schizophrenia[J]. Psychiatry Res, 2021, 301:113979. DOI: 10.1016/j.psychres.2021.113979 .
89	BENES F M, LIM B, MATZILEVICH D, et al. Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars[J]. Proc Natl Acad Sci USA, 2007, 104(24):10164-10169. DOI: 10.1073/pnas.0703806104 .
90	FATEMI S H, FOLSOM T D, THURAS P D. GABA_A and GABA_B receptor dysregulation in superior frontal cortex of subjects with schizophrenia and bipolar disorder[J]. Synapse, 2017, 71(7):e21973. DOI: 10.1002/syn.21973 .

模型类型 Type of model	操作方式 Operation	行为学表型 Behavioral phenotype	组织学表型 Histological phenotype	参考文献 Reference
神经发育学模型 Neurodevelopmental model	出生前注射甲基氧化偶氮甲醇	对多巴胺通路激动剂安非他明的运动反应增加，社交活动减少，感觉运动门控缺陷，记忆障碍，焦虑增加	内侧前额叶体积减少，侧脑室和第三脑室体积增加，边缘和皮层区域的中间神经元标志物减少，腹侧被盖区多巴胺神经元活性增加	[10]
	出生后社会隔离	自发运动增加，对新奇事物的反应增强，感觉运动门控障碍，认知障碍，焦虑和攻击性增加	前额叶体积减少，树突棘密度降低，海马中PV阳性的中间神经元降低	[11-13]
	母体免疫激活	感觉运动门控异常、社交行为异常、焦虑样和抑郁样行为增加等阴性症状，同时出现对多巴胺通路激动剂安非他明的运动反应增加等阳性症状	树突棘的密度下降，树突的复杂性下降，抑制性神经元的数量也减少。磁共振成像研究发现母体免疫激活的后代脑室扩大和脑区体积减少	[15-16,18]
	胚胎期和青春期进行刺激	根据胚胎期和青春期的刺激确定	根据胚胎期和青春期的刺激确定	[15,19]
药物诱导模型 Drug-induced model	多巴胺通路激动剂安非他命	运动过度，空间工作记忆障碍，感觉运动门控缺陷，潜在抑制缺陷	NMDA受体表达异常，树突形态改变，伏隔核和纹状体中多巴胺的释放增加	[24-26]
	氯胺酮	损害空间工作记忆，引起焦虑样行为、社会行为改变，运动过度，感觉运动门控障碍	多个脑区BDNF蛋白的表达水平降低，炎性细胞因子失衡，海马区域PV阳性神经元的数量下降	[37-41]
	苯环己哌啶	记忆和学习障碍，社交能力受损，活动升高，感觉运动门控异常	前额叶皮层多巴胺、谷氨酸、5羟色胺以及去甲肾上腺素释放增加，γ-氨基丁酸释放降低，BDNF/TrkB的水平下调	[30-34]
	MK-801	运动过度，感觉运动门控缺陷，社交能力下降，条件性恐惧记忆异常	运动过度，感觉运动门控缺陷，社交能力下降，条件性恐惧记忆的异常	[42-45]
遗传模型 Genetic model	DISC1	识别记忆、社交和焦虑行为缺陷，感觉运动门控异常等	脑室增大，皮质厚度和脑容量减少，皮层中γ-氨基丁酸能神经元密度降低，NMDA受体亚基和PSD-95的表达减少	[50-54]
	22q11.2缺失综合征	感觉运动门控异常，恐惧条件反射异常，空间记忆受损等	皮层和皮层下灰质体积改变，脑室增大，树突棘密度和树突复杂性减少，多巴胺和γ-氨基丁酸系统紊乱	[56-58]
	NRG1	活动和探索行为增加，在自发交替测试中工作记忆异常，感觉运动门控异常	脑中功能性的NMDA受体水平降低，海马锥体神经元上的树突棘密度减少	[61-62]
	Dysbindin	多动，学习和记忆缺陷，冲动和强迫行为增加	多巴胺释放增加，细胞表面D2受体过表达	[66-67]
	Ulk4	感觉运动门控异常，工作和空间记忆异常	Akt-Gsk3β信号通路异常，Gsk3β活性增加	[71]

模型类型 Type of model	操作方式 Operation	行为学表型 Behavioral phenotype	组织学表型 Histological phenotype	参考文献 Reference
神经发育学模型 Neurodevelopmental model	出生前注射甲基氧化偶氮甲醇	对多巴胺通路激动剂安非他明的运动反应增加，社交活动减少，感觉运动门控缺陷，记忆障碍，焦虑增加	内侧前额叶体积减少，侧脑室和第三脑室体积增加，边缘和皮层区域的中间神经元标志物减少，腹侧被盖区多巴胺神经元活性增加	[10]
	出生后社会隔离	自发运动增加，对新奇事物的反应增强，感觉运动门控障碍，认知障碍，焦虑和攻击性增加	前额叶体积减少，树突棘密度降低，海马中PV阳性的中间神经元降低	[11-13]
	母体免疫激活	感觉运动门控异常、社交行为异常、焦虑样和抑郁样行为增加等阴性症状，同时出现对多巴胺通路激动剂安非他明的运动反应增加等阳性症状	树突棘的密度下降，树突的复杂性下降，抑制性神经元的数量也减少。磁共振成像研究发现母体免疫激活的后代脑室扩大和脑区体积减少	[15-16,18]
	胚胎期和青春期进行刺激	根据胚胎期和青春期的刺激确定	根据胚胎期和青春期的刺激确定	[15,19]
药物诱导模型 Drug-induced model	多巴胺通路激动剂安非他命	运动过度，空间工作记忆障碍，感觉运动门控缺陷，潜在抑制缺陷	NMDA受体表达异常，树突形态改变，伏隔核和纹状体中多巴胺的释放增加	[24-26]
	氯胺酮	损害空间工作记忆，引起焦虑样行为、社会行为改变，运动过度，感觉运动门控障碍	多个脑区BDNF蛋白的表达水平降低，炎性细胞因子失衡，海马区域PV阳性神经元的数量下降	[37-41]
	苯环己哌啶	记忆和学习障碍，社交能力受损，活动升高，感觉运动门控异常	前额叶皮层多巴胺、谷氨酸、5羟色胺以及去甲肾上腺素释放增加，γ-氨基丁酸释放降低，BDNF/TrkB的水平下调	[30-34]
	MK-801	运动过度，感觉运动门控缺陷，社交能力下降，条件性恐惧记忆异常	运动过度，感觉运动门控缺陷，社交能力下降，条件性恐惧记忆的异常	[42-45]
遗传模型 Genetic model	DISC1	识别记忆、社交和焦虑行为缺陷，感觉运动门控异常等	脑室增大，皮质厚度和脑容量减少，皮层中γ-氨基丁酸能神经元密度降低，NMDA受体亚基和PSD-95的表达减少	[50-54]
	22q11.2缺失综合征	感觉运动门控异常，恐惧条件反射异常，空间记忆受损等	皮层和皮层下灰质体积改变，脑室增大，树突棘密度和树突复杂性减少，多巴胺和γ-氨基丁酸系统紊乱	[56-58]
	NRG1	活动和探索行为增加，在自发交替测试中工作记忆异常，感觉运动门控异常	脑中功能性的NMDA受体水平降低，海马锥体神经元上的树突棘密度减少	[61-62]
	Dysbindin	多动，学习和记忆缺陷，冲动和强迫行为增加	多巴胺释放增加，细胞表面D2受体过表达	[66-67]
	Ulk4	感觉运动门控异常，工作和空间记忆异常	Akt-Gsk3β信号通路异常，Gsk3β活性增加	[71]

[1]	Committee of Experts on Medical Animal Experiments, Chinese Research Hospital Association. Guidelines for the Selection of Animal Models and Preclinical Drug Trials for Spontaneous Intracerebral Hemorrhage (2024 Edition) [J]. Laboratory Animal and Comparative Medicine, 2024, 44(1): 3-30.
[2]	Shuwu XIE, Ruling SHEN, Jinxing LIN, Chun FAN. Progress in Establishment and Application of Laboratory Animal Models Related to Development of Male Infertility Drugs [J]. Laboratory Animal and Comparative Medicine, 2023, 43(5): 504-511.
[3]	Rui ZHANG, Meiyu LÜ, Jianjun ZHANG, Jinlian LIU, Yan CHEN, Zhiqiang HUANG, Yao LIU, Lanhua ZHOU. Research Progress on Establishing and Evaluation of Acne Animal Models [J]. Laboratory Animal and Comparative Medicine, 2023, 43(4): 398-405.
[4]	Jiahui YU, Qian GONG, Lenan ZHUANG. Animal Models of Pulmonary Arterial Hypertension and Their Application in Drug Research [J]. Laboratory Animal and Comparative Medicine, 2023, 43(4): 381-397.
[5]	Feng WEI, Weiwei CHENG, Yafu YIN. Characteristics and Application of Transgenic Mouse Models in Alzheimer's Disease [J]. Laboratory Animal and Comparative Medicine, 2022, 42(5): 432-439.
[6]	Zhejin SHENG, Limei LI. Research Progress in Animal Model of Alzheimer's Disease [J]. Laboratory Animal and Comparative Medicine, 2022, 42(4): 342-350.
[7]	Yaohua HU, Jumei ZHAO, Changhong SHI. Application of Animal Models in the Functional Studies of Eph Family Proteins [J]. Laboratory Animal and Comparative Medicine, 2022, 42(4): 351-357.
[8]	Xiao LI, Haipeng YAN, Zhenghui XIAO. Construction Methods and Influencing Factors on Animal Model of Sepsis [J]. Laboratory Animal and Comparative Medicine, 2022, 42(3): 207-212.
[9]	Hui LI. A Comparative Biological Study of Language [J]. Laboratory Animal and Comparative Medicine, 2022, 42(3): 255-261.
[10]	LIN Jiang, LUO Fei, LIU Peng, HAN Siyin, CHEN Zhenxing, LIANG Zhongxiu, LAN Taijin. Research Progress Related to Candidate Treatment Methods and Modeling Factors for Diabetic Animal Models with Skin Injury [J]. Laboratory Animal and Comparative Medicine, 2021, 41(6): 515-520.
[11]	LI Feng, LI Shun, REN Xiaonan, ZHOU Xiaohui. A Brief Review on Development and Application of Animal Models of Emerging Infectious Diseases Caused by Three Genus Viruses [J]. Laboratory Animal and Comparative Medicine, 2020, 40(3): 173-.
[12]	GAO Shiping, LI Feng, ZHA Sifan. High-fat Diet Induced Cynomolgus Monkey Model of Non-alcoholic Fatty Liver Disease [J]. Laboratory Animal and Comparative Medicine, 2020, 40(2): 123-127.
[13]	XIA Mengxiong, HAN Haihui, LIANG Qianqian, ZHAI Weitao, XU Hao. Research Progress on Animal Models of Osteoarthritis [J]. Laboratory Animal and Comparative Medicine, 2020, 40(2): 159-165.
[14]	DONG Guoju, LIU Jiangang, Guan Jie. The Research Progress of Pathological Characteristics of Animal Models with Heart Failure with Ejection Fraction Preservation [J]. Laboratory Animal and Comparative Medicine, 2020, 40(1): 74-79.
[15]	WANG Cong, CHEN Xiao-xue, YANG Shao-ling, WANG Feng-ling, FAN Lin-yan, HE Qian-qian. Comparative Analysis of Rabbit Carotid Atherosclerosis Models Established by Collar And Air-drying Method [J]. Laboratory Animal and Comparative Medicine, 2019, 39(3): 208-212.