Brain in flames – animal models of psychosis: utility and limitations

Figures & data

Table 1 Behavioral abnormalities that match schizophrenia symptoms and their treatment

Model	Positive symptoms	Negative symptoms	Cognitive symptoms	Antipsychotic treatment	MN treatment
DISC1 (129S6/SvEv mouse strain)	Hyperlocomotion, PPI deficits.^Citation27	Increased immobility in the forced swimming and tail suspension test.^Citation27	No deficits in the Y-maze test for working memory.^Citation27	ND	ND
NMDA antagonists	Hyperlocomotion, PPI deficit (not sustained, only upon repeated administration of any of the NMDA antagonists), and latent inhibition deficits.^Citation37^–^Citation56	Social withdrawal, forced swimming immobility, increased anxiety-like behavior.^Citation37^–^Citation56	Deficits in: novel object recognition, attentional set shifting, and T-maze delayed alternation and reversal learning along with working memory and visuospatial memory deficits in the Morris’s water maze.^Citation37^–^Citation56	TAP had no effect on the negative symptoms. Haloperidol reverses hyperlocomotion and novel object recognition deficits. AAP reverses all the mentioned deficits.^Citation37^–^Citation56	Pretreatment with MN, prior to NMDA-antagonist injection, prevents the outbreak of positive cognitive and negative manifestations. Treatment with MN post NMDA-antagonist administration reverts the latter symptoms.^Citation38,Citation46,Citation64^–^Citation66
nVHL	PPI deficits, drug-induced hyperlocomotion, increased aggression, higher risk taking behavior, and disrupted latent inhibition.^Citation83,Citation85^–^Citation88	Social withdrawal enhanced immobility in forced swimming test when administered PCP.^Citation84	Deficits in working and spatial memory.^Citation85,Citation89,Citation90	AAP have no effect on social withdrawal but reversed amphetamine-induced hyperlocomotion.^Citation86,Citation91 TAP restored increased aggression.^Citation88 AAP are able to rescue PPI deficits, but not TAP.^Citation88	MN treatment prior to lesion prevented the phenotype outbreak completely.^Citation95 Chronic MN treatment starting at P42 rescued all behavioral abnormalities in the LPS induced nVHL.^Citation102
PolyI:C	Drug-induced hyper-locomotion, deficits in PPI, and latent inhibition.^Citation116,Citation117	Social withdrawal, decreased sucrose preference, increased immobility in the forced swimming test, and tail suspension test.^Citation122,Citation144^–^Citation146	Deficits in: working memory, intentional set shifting along with spatial memory deficits, and impaired object-in-place recognition memory.^Citation119,Citation145,Citation147,Citation148	AAP reverses deficits in working memory and latent inhibition, the latter also rescued by TAP. No tests have been carried for screening on the negative symptoms.^Citation143,Citation149	MN restored PPI deficits and social withdrawal. No test has been carried out on other behavioral abnormalities.^Citation16,Citation158
LPS	Psychostimulant-induced hyperactivity, PPI deficits.^Citation175,Citation181,Citation182	Increased despair in the forced swimming test. Decreased social behavior and increased anxiety.^Citation176^–^Citation178,Citation180	Impaired object-recognition memory and spatial learning.^Citation175,Citation179	TAP and AAP reverse the PPI deficits and chlorpromazine the drug-induced hyperactivity.^Citation171,Citation183	ND

Notes: The table summarizes the main behavioral abnormalities that best match positive, negative, and cognitive symptoms of schizophrenia displayed by the animal models described in this review. Moreover, the table reports the effect of present antipsychotic treatment and anti-inflammatory minocycline intervention on the behavioral manifestations.

Abbreviations: MN, minocycline; DISC1, disrupted in schizophrenia-1; NMDA, N-methyl-D-aspartate; PCP, phencyclidine; TAP, typical antipsychotics; AAP, atypical antipsychotics; nVHL, neonatal ventral hippocampal lesion; PPI, prepulse inhibition; P42, postnatal day 42; ND, not determined; LPS, lipopolysaccharide.

van den BuuseMModeling the positive symptoms of schizophrenia in genetically modified mice: pharmacology and methodology aspectsSchizophr Bull201036224627010.1093/schbul/sbp13219900963

 PubMed Web of Science ®Google Scholar

BondiCMatthewsMMoghaddamBGlutamatergic animal models of schizophreniaCurr Pharm Des201218121593160422280432

 PubMed Web of Science ®Google Scholar

RungJPCarlssonAMarkinhuhtaKRCarlssonMLThe dopaminergic stabilizers (−)-OSU6162 and ACR16 reverse (+)-MK-801-induced social withdrawal in ratsProg Neuropsychopharmacol Biol Psychiatry200529583383910.1016/j.pnpbp.2005.03.00315913873

 PubMed Web of Science ®Google Scholar

MoghaddamBJacksonMEGlutamatergic animal models of schizophreniaAnn N Y Acad Sci20031003113113710.1196/annals.1300.06514684441

 PubMed Web of Science ®Google Scholar

NodaYYamadaKFurukawaHNabeshimaTEnhancement of immobility in a forced swimming test by subacute or repeated treatment with phencyclidine: a new model of schizophreniaBr J Pharmacol1995116253125378581295

 PubMed Web of Science ®Google Scholar

KobayashiKImagamaSOhgomoriTMinocycline selectively inhibits M1 polarization of microgliaCell Death Dis201343e52510.1038/cddis.2013.5423470532

 PubMed Web of Science ®Google Scholar

ZhangLShirayamaYIyoMHashimotoKMinocycline attenuates hyper-locomotion and prepulse inhibition deficits in mice after administration of the NMDA receptor antagonist dizocilpineNeuropsychopharmacology20073292004201010.1038/sj.npp.130131317228338

 PubMed Web of Science ®Google Scholar

BenesFMBerrettaSGABAergic interneurons: implications for understanding schizophrenia and bipolar disorderNeuropsychopharmacology2001250112710.1016/S0893-133X(01)00225-111377916

 PubMed Web of Science ®Google Scholar

BringasMEMorales-MedinaJCFlores-VivaldoYClozapine administration reverses behavioral, neuronal, and nitric oxide disturbances in the neonatal ventral hippocampus ratNeuropharmacology20126241848185710.1016/j.neuropharm.2011.12.00822207157

 PubMed Web of Science ®Google Scholar

RueterLEBallardMEGallagherKBBassoAMCurzonPKohlhaasKLChronic low dose risperidone and clozapine alleviate positive but not negative symptoms in the rat neonatal ventral hippocampal lesion model of schizophreniaPsychopharmacology (Berl)20041763–431231910.1007/s00213-004-1897-415179541

 PubMed Web of Science ®Google Scholar

FloresGAlquicerGSilva-GómezABAlterations in dendritic morphology of prefrontal cortical and nucleus accumbens neurons in post-pubertal rats after neonatal excitotoxic lesions of the ventral hippocampusNeuroscience200513346347010.1016/j.neuroscience.2005.02.02115878241

 PubMed Web of Science ®Google Scholar

Le PenGKewJAlberatiDBorroniEHeitzMPMoreauJLPrepulse inhibition deficits of the startle reflex in neonatal ventral hippocampal-lesioned rats: reversal by glycine and a glycine transporter inhibitorBiol Psychiatry200354031162117010.1016/S0006-3223(03)00374-314643083

 PubMed Web of Science ®Google Scholar

BeckerAGreckschGHaloperidol and clozapine affect social behaviour in rats postnatally lesioned in the ventral hippocampusPharmacol Biochem Behav20037611810.1016/S0091-3057(03)00139-413679211

 PubMed Web of Science ®Google Scholar

HoriTSubramaniamSSrivastavaLKQuirionRBehavioral and neurochemical alterations following repeated phencyclidine administration in rats with neonatal ventral hippocampal lesionsNeuropharmacology2000392478249110.1016/S0028-3908(00)00059-910974332

 PubMed Web of Science ®Google Scholar

Le PenGGrottickAJHigginsGAMartinJRJenckFMoreauJLSpatial and associative learning deficits induced by neonatal excitotoxic hippocampal damage in rats: further evaluation of an animal model of schizophreniaBehav Pharmacol2000113–425726811103880

 PubMed Web of Science ®Google Scholar

Le PenGMoreauJLDisruption of prepulse inhibition of startle reflex in a neurodevelopmental model of schizophrenia: reversal by clozapine, olanzapine and risperidone but not by haloperidolNeuropsychopharmacology200227111110.1016/S0893-133X(01)00383-912062902

 PubMed Web of Science ®Google Scholar

ZhuFZhengYDingY-QMinocycline and risperidone prevent microglia activation and rescue behavioral deficits induced by neonatal intrahippocampal injection of lipopolysaccharide in ratsPLoS One201494e9396610.1371/journal.pone.009396624705495

 PubMed Web of Science ®Google Scholar

ZuckermanLRehaviMNachmanRWeinerIImmune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: a novel neurodevelopmental model of schizophreniaNeuropsychopharmacology200328101778178910.1038/sj.npp.130024812865897

 PubMed Web of Science ®Google Scholar

OzawaKHashimotoKKishimotoTShimizuEIshikuraHIyoMImmune activation during pregnancy in mice leads to dopaminergic hyper-function and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophreniaBiol Psychiatry200659654655410.1016/j.biopsych.2005.07.03116256957

 PubMed Web of Science ®Google Scholar

WinterCDjodari-IraniASohrRPrenatal immune activation leads to multiple changes in basal neurotransmitter levels in the adult brain: implications for brain disorders of neurodevelopmental origin such as schizophreniaInt J Neuropsychopharmacol200912451352410.1017/S146114570800920618752727

 PubMed Web of Science ®Google Scholar

ZhangZvan PraagHMaternal immune activation differentially impacts mature and adult-born hippocampal neurons in male miceBrain Behav Immun201545607010.1016/j.bbi.2014.10.01025449671

 PubMed Web of Science ®Google Scholar

HowlandJGCazakoffBNZhangYAltered object-in-place recognition memory, prepulse inhibition, and locomotor activity in the offspring of rats exposed to a viral mimetic during pregnancyNeuroscience201220118419810.1016/j.neuroscience.2011.11.01122119062

 PubMed Web of Science ®Google Scholar

NyffelerMMeyerUYeeBKFeldonJKnueselIMaternal immune activation during pregnancy increases limbic GABAA receptor immunoreactivity in the adult offspring: implications for schizophreniaNeuroscience20061431516210.1016/j.neuroscience.2006.07.02917045750

 PubMed Web of Science ®Google Scholar

ZhangYCazakoffBNThaiCAHowlandJGPrenatal exposure to a viral mimetic alters behavioural flexibility in male, but not female, ratsNeuropharmacology20126231299130710.1016/j.neuropharm.2011.02.02221376064

 PubMed Web of Science ®Google Scholar

KhanDFernandoPCicvaricALong-term effects of maternal immune activation on depression-like behavior in the mouseTransl Psychiatry20144e36310.1038/tp.2013.13224548878

 PubMed Web of Science ®Google Scholar

MeyerUKnueselINyffelerMFeldonJChronic clozapine treatment improves prenatal infection-induced working memory deficits without influencing adult hippocampal neurogenesisPsychopharmacology (Berl)2010208453154310.1007/s00213-009-1754-620041229

 PubMed Web of Science ®Google Scholar

KhanDFernandoPCicvaricALong-term effects of maternal immune activation on depression-like behavior in the mouseTransl Psychiatry20144e36310.1038/tp.2013.13224548878

 PubMed Web of Science ®Google Scholar

MissaultSVan den EyndeKVanden BergheWThe risk for behavioural deficits is determined by the maternal immune response to prenatal immune challenge in a neurodevelopmental modelBrain Behav Immun20144213814610.1016/j.bbi.2014.06.01324973728

 PubMed Web of Science ®Google Scholar

Van BerckelBNBossongMGBoellaardRMicroglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography studyBiol Psychiatry200864982082210.1016/j.biopsych.2008.04.02518534557

 PubMed Web of Science ®Google Scholar

ZhuFZhengYLiuYZhangXZhaoJMinocycline alleviates behavioral deficits and inhibits microglial activation in the offspring of pregnant mice after administration of polyriboinosinic-polyribocytidilic acidPsychiatry Res2014219368068610.1016/j.psychres.2014.06.04625042426

 PubMed Web of Science ®Google Scholar

KirstenTBTaricanoMMaiorkaPCPalermo-NetoJBernardiMMPrenatal lipopolysaccharide reduces social behavior in male offspringNeuroimmunomodulation201017424025110.1159/00029004020203530

 PubMed Web of Science ®Google Scholar

Basta-kaimASzczêsnyELeoekiewiczMMaternal immune activation leads to age-related behavioral and immunological changes in male rat offspring – the effect of antipsychotic drugsPharmacol Rep20126461400141023406750

 PubMed Web of Science ®Google Scholar

GraciarenaMDepinoAMPitossiFJPrenatal inflammation impairs adult neurogenesis and memory related behavior through persistent hippocampal TGFbeta1 downregulationBrain Behav Immun20102481301130910.1016/j.bbi.2010.06.00520600816

 PubMed Web of Science ®Google Scholar

FoleyKAMacFabeDFVazAOssenkoppK-PKavaliersMSexually dimorphic effects of prenatal exposure to propionic acid and lipopolysaccharide on social behavior in neonatal, adolescent, and adult rats: implications for autism spectrum disordersInt J Dev Neurosci201439687810.1016/j.ijdevneu.2014.04.00124747144

 PubMed Web of Science ®Google Scholar

ChlodzinskaNGajerskaMBartkowskaKTurlejskiKDjavadianRLLipopolysaccharide injected to pregnant mice affects behavior of their offspring in adulthoodActa Neurobiol Exp (Wars)201171451952722237497

 PubMed Web of Science ®Google Scholar

LinY-LLinS-YWangSPrenatal lipopolysaccharide exposure increases anxiety-like behaviors and enhances stress-induced corticosterone responses in adult ratsBrain Behav Immun201226345946810.1016/j.bbi.2011.12.00322198119

 PubMed Web of Science ®Google Scholar

Basta-KaimABudziszewskaBLeskiewiczMHyperactivity of the hypothalamus-pituitary-adrenal axis in lipopolysaccharide-induced neurodevelopmental model of schizophrenia in rats: effects of antipsychotic drugsEur J Pharmacol20116502–358659510.1016/j.ejphar.2010.09.08321034739

 PubMed Web of Science ®Google Scholar

GolanHMLevVHallakMSorokinYHuleihelMSpecific neurodevelopmental damage in mice offspring following maternal inflammation during pregnancyNeuropharmacology200548690391710.1016/j.neuropharm.2004.12.02315829260

 PubMed Web of Science ®Google Scholar

GraciarenaMRocaVMathieuPDepinoAMPitossiFJDifferential vulnerability of adult neurogenesis by adult and prenatal inflammation: role of TGF-beta1Brain Behav Immun201334172810.1016/j.bbi.2013.05.00723732461

 PubMed Web of Science ®Google Scholar