Advances in the study of phencyclidine-induced schizophrenia-like animal models and the underlying neural mechanisms.
Journal
Schizophrenia (Heidelberg, Germany)
ISSN: 2754-6993
Titre abrégé: Schizophrenia (Heidelb)
Pays: Germany
ID NLM: 9918367987006676
Informations de publication
Date de publication:
23 Jul 2024
23 Jul 2024
Historique:
received:
16
03
2024
accepted:
12
07
2024
medline:
23
7
2024
pubmed:
23
7
2024
entrez:
22
7
2024
Statut:
epublish
Résumé
Schizophrenia (SZ) is a chronic, severe mental disorder with heterogeneous clinical manifestations and unknown etiology. Research on SZ has long been limited by the low reliability of and ambiguous pathogenesis in schizophrenia animal models. Phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, rapidly induces both positive and negative symptoms of SZ as well as stable SZ-related cognitive impairment in rodents. However, the neural mechanism underlying PCP-induced SZ-like symptoms is not fully understood. Nondopaminergic pathophysiology, particularly excessive glutamate release induced by NMDAR hypofunction in the prefrontal cortex (PFC), may play a key role in the development of PCP-induced SZ-like symptoms. In this review, we summarize studies on the behavioral and metabolic effects of PCP and the cellular and circuitary targets of PCP in the PFC and hippocampus (HIP). PCP is thought to target the ventral HIP-PFC pathway more strongly than the PFC-VTA pathway and thalamocortical pathway. Systemic PCP administration might preferentially inhibit gamma-aminobutyric acid (GABA) neurons in the vHIP and in turn lead to hippocampal pyramidal cell disinhibition. Excitatory inputs from the HIP may trigger sustained, excessive and pathological PFC pyramidal neuron activation to mediate various SZ-like symptoms. In addition, astrocyte and microglial activation and oxidative stress in the cerebral cortex or hippocampus have been observed in PCP-induced models of SZ. These findings perfect the hypoglutamatergic hypothesis of schizophrenia. However, whether these effects direct the consequences of PCP administration and how about the relationships between these changes induced by PCP remain further elucidation through rigorous, causal and direct experimental evidence.
Identifiants
pubmed: 39039065
doi: 10.1038/s41537-024-00485-x
pii: 10.1038/s41537-024-00485-x
doi:
Types de publication
Journal Article
Review
Langues
eng
Pagination
65Informations de copyright
© 2024. The Author(s).
Références
Adell, A. Brain NMDA receptors in schizophrenia and depression. Biomolecules 10, 947 (2020).
pubmed: 32585886
pmcid: 7355879
doi: 10.3390/biom10060947
Wang, X., Liu, J., Dai, Z. & Sui, Y. Andrographolide improves PCP-induced schizophrenia-like behaviors through blocking interaction between NRF2 and KEAP1. J. Pharm. Sci. 147, 9–17 (2021).
doi: 10.1016/j.jphs.2021.05.007
Hamieh, A. M., Babin, D., Sable, E., Hernier, A. M. & Castagne, V. Neonatal phencyclidine and social isolation in the rat: effects of clozapine on locomotor activity, social recognition, prepulse inhibition, and executive functions deficits. Psychopharmacology 238, 517–528 (2021).
pubmed: 33169202
doi: 10.1007/s00213-020-05700-y
Ang, M. J., Lee, S., Kim, J.-C., Kim, S.-H. & Moon, C. Behavioral tasks evaluating schizophrenia-like symptoms in animal models: a recent update. Curr. Neuropharmacol. 19, 641–664 (2021).
pubmed: 32798374
pmcid: 8573744
doi: 10.2174/1570159X18666200814175114
Kikuchi, T. Is memantine effective as an NMDA-receptor antagonist in adjunctive therapy for schizophrenia? Biomolecules 10, 1134 (2020).
pubmed: 32751985
pmcid: 7466074
doi: 10.3390/biom10081134
Bialon, M. & Wasik, A. Advantages and limitations of animal schizophrenia models. Int. J. Mol. Sci. 23, 5968 (2022).
pubmed: 35682647
pmcid: 9181262
doi: 10.3390/ijms23115968
Wu, Q., Huang, J. & Wu, R. Drugs based on NMDAR hypofunction hypothesis in schizophrenia. Front. Neurosci.-Switz. 15, 641047 (2021).
doi: 10.3389/fnins.2021.641047
Wolf, D. H. et al. Effect of mGluR2 positive allosteric modulation on frontostriatal working memory activation in schizophrenia. Mol. Psychiatr. 27, 1226–1232 (2022).
doi: 10.1038/s41380-021-01320-w
Morales-Medina, J. C., Aguilar-Alonso, P., Di Cerbo, A., Iannitti, T. & Flores, G. New insights on nitric oxide: Focus on animal models of schizophrenia. Behav. Brain Res 409, 113304 (2021).
pubmed: 33865887
doi: 10.1016/j.bbr.2021.113304
Perez-Palomar, B., Erdozain, A. M., Erkizia-Santamaria, I., Ortega, J. E. & Meana, J. J. Maternal Immune Activation Induces Cortical Catecholaminergic Hypofunction and Cognitive Impairments in Offspring. J. Neuroimmune Pharm. 18, 348–365 (2023).
doi: 10.1007/s11481-023-10070-1
Thornberg, S. A. & Saklad, S. R. A review of NMDA receptors and the phencyclidine model of schizophrenia. Pharmacotherapy 16, 82–93 (1996).
pubmed: 8700797
doi: 10.1002/j.1875-9114.1996.tb02920.x
Bunney, B. G., Bunney, W. E. & Carlsson, A. Schizophrenia and Glutamate in Psychopharmacology: The Fourth Generation of Progress. 1205 (Raven Press, 2005).
Wang, C., Inselman, A., Liu, S. & Liu, F. Potential mechanisms for phencyclidine/ketamine-induced brain structural alterations and behavioral consequences. Neurotoxicology 76, 213–219 (2020).
pubmed: 31812709
doi: 10.1016/j.neuro.2019.12.005
ffrench-Mullen, J. M. & Rogawski, M. A. Interaction of phencyclidine with voltage-dependent potassium channels in cultured rat hippocampal neurons: comparison with block of the NMDA receptor-ionophore complex. J. Neurosci. : Off. J. Soc. Neurosci. 9, 4051–4061 (1989).
doi: 10.1523/JNEUROSCI.09-11-04051.1989
Oswald, R. E., Bamberger, M. J. & McLaughlin, J. T. Mechanism of phencyclidine binding to the acetylcholine receptor from Torpedo electroplaque. Mol. Pharm. 25, 360–368 (1984).
Newcomer, J. W. et al. Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacol.: Off. Publ. Am. Coll. Neuropsychopharmacol. 20, 106–118 (1999).
doi: 10.1016/S0893-133X(98)00067-0
Neill, J. C., Harte, M. K., Haddad, P. M., Lydall, E. S. & Dwyer, D. M. Acute and chronic effects of NMDA receptor antagonists in rodents, relevance to negative symptoms of schizophrenia: a translational link to humans. Eur. Neuropsychopharmacol. : J. Eur. Coll. Neuropsychopharmacol. 24, 822–835 (2014).
doi: 10.1016/j.euroneuro.2013.09.011
Thomson, D. M., McVie, A., Morris, B. J. & Pratt, J. A. Dissociation of acute and chronic intermittent phencyclidine-induced performance deficits in the 5-choice serial reaction time task: influence of clozapine. Psychopharmacology 213, 681–695 (2011).
pubmed: 20878519
doi: 10.1007/s00213-010-2020-7
Dutra-Tavares, A. C. et al. Does nicotine exposure during adolescence modify the course of schizophrenia-like symptoms? Behavioral analysis in a phencyclidine-induced mice model. Plos One 16, e0257986 (2021).
pubmed: 34587208
pmcid: 8480744
doi: 10.1371/journal.pone.0257986
Huang, M. et al. Effects of NBI-98782, a selective vesicular monoamine transporter 2 (VMAT2) inhibitor, on neurotransmitter efflux and phencyclidine-induced locomotor activity: Relevance to tardive dyskinesia and antipsychotic action. Pharmacol., Biochem., Behav. 190, 172872 (2020).
pubmed: 32084491
doi: 10.1016/j.pbb.2020.172872
Mouri, A. et al. Mouse strain differences in phencyclidine-induced behavioural changes. Int. J. Neuropsychopharmacol. 15, 767–779 (2012).
pubmed: 21733237
doi: 10.1017/S146114571100085X
Castane, A., Santana, N. & Artigas, F. PCP-based mice models of schizophrenia: differential behavioral, neurochemical and cellular effects of acute and subchronic treatments. Psychopharmacology 232, 4085–4097 (2015).
pubmed: 25943167
doi: 10.1007/s00213-015-3946-6
Turgeon, S. M. & Hoge, S. G. Prior exposure to phencyclidine decreases voluntary sucrose consumption and operant performance for food reward. Pharmacol., Biochem., Behav. 76, 393–400 (2003).
pubmed: 14643837
doi: 10.1016/j.pbb.2003.08.019
Lee, P. R., Brady, D. L., Shapiro, R. A., Dorsa, D. M. & Koenig, J. I. Social interaction deficits caused by chronic phencyclidine administration are reversed by oxytocin. Neuropsychopharmacol. : Off. Publ. Am. Coll. Neuropsychopharmacol. 30, 1883–1894 (2005).
doi: 10.1038/sj.npp.1300722
Adams, B. & Moghaddam, B. Corticolimbic dopamine neurotransmission is temporally dissociated from the cognitive and locomotor effects of phencyclidine. J. Neurosci. : Off. J. Soc. Neurosci. 18, 5545–5554 (1998).
doi: 10.1523/JNEUROSCI.18-14-05545.1998
Jentsch, J. D. et al. Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine. Sci. (N. Y., N. Y) 277, 953–955 (1997).
doi: 10.1126/science.277.5328.953
Broberg, B. V. et al. Assessment of auditory sensory processing in a neurodevelopmental animal model of schizophrenia–gating of auditory-evoked potentials and prepulse inhibition. Behav. Brain Res. 213, 142–147 (2010).
pubmed: 20417666
doi: 10.1016/j.bbr.2010.04.026
Savolainen, K., Ihalainen, J., Hamalainen, E., Tanila, H. & Forsberg, M. M. Phencyclidine-induced cognitive impairments in repeated touchscreen visual reversal learning tests in rats. Behav. Brain Res. 404, 113057 (2021).
pubmed: 33316322
doi: 10.1016/j.bbr.2020.113057
Shan, L. et al. Schizophrenia-like olfactory dysfunction induced by acute and postnatal phencyclidine exposure in rats. Schizophr. Res. 199, 274–280 (2018).
pubmed: 29510924
doi: 10.1016/j.schres.2018.02.045
Mansbach, R. S. & Geyer, M. A. Effects of phencyclidine and phencyclidine biologs on sensorimotor gating in the rat. Neuropsychopharmacol.: Off. Publ. Am. Coll. Neuropsychopharmacol. 2, 299–308 (1989).
doi: 10.1016/0893-133X(89)90035-3
Bialon, M. et al. 1MeTIQ and olanzapine, despite their neurochemical impact, did not ameliorate performance in fear conditioning and social interaction tests in an MK-801 rat model of schizophrenia. Pharmacol. Rep.: PR 73, 490–505 (2021).
pubmed: 33403530
doi: 10.1007/s43440-020-00209-9
Zhan, J.-Q. et al. Flavonoid fisetin reverses impaired hippocampal synaptic plasticity and cognitive function by regulating the function of AMPARs in a male rat model of schizophrenia. J. Neurochem. 158, 413–428 (2021).
pubmed: 33882624
doi: 10.1111/jnc.15370
Sawahata, M. et al. Microinjection of Reelin into the mPFC prevents MK-801-induced recognition memory impairment in mice. Pharm. Res. 173, 105832 (2021).
doi: 10.1016/j.phrs.2021.105832
Kozela, E. et al. Cannabidiol Improves Cognitive Impairment and Reverses Cortical Transcriptional Changes Induced by Ketamine, in Schizophrenia-Like Model in Rats. Mol. Neurobiol. 57, 1733–1747 (2020).
pubmed: 31823199
doi: 10.1007/s12035-019-01831-2
Azimi Sanavi, M., Ghazvini, H., Zargari, M., Ghalehnoei, H. & Hosseini-Khah, Z. Effects of clozapine and risperidone antipsychotic drugs on the expression of CACNA1C and behavioral changes in rat ‘Ketamine model of schizophrenia. Neurosci. Lett. 770, 136354 (2022).
pubmed: 34801642
doi: 10.1016/j.neulet.2021.136354
Sedky, A. A. & Magdy, Y. Reduction in TNF alpha and oxidative stress by liraglutide: Impact on ketamine-induced cognitive dysfunction and hyperlocomotion in rats. Life Sci. 278, 119523 (2021).
pubmed: 33891942
doi: 10.1016/j.lfs.2021.119523
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. Schizophr. Res. 229, 80–93 (2021).
pubmed: 33229224
doi: 10.1016/j.schres.2020.11.016
Perdikaris, P. & Dermon, C. R. Behavioral and neurochemical profile of MK-801 adult zebrafish model: Forebrain beta2-adrenoceptors contribute to social withdrawal and anxiety-like behavior. Prog. Neuro-Psychoph 115, 110494 (2022).
doi: 10.1016/j.pnpbp.2021.110494
Oliveira, A. W. C. et al. Scopolamine and MK-801 impair recognition memory in a new spontaneous object exploration task in monkeys. Pharmacol., Biochem., Behav. 211, 173300 (2021).
pubmed: 34798097
doi: 10.1016/j.pbb.2021.173300
Seillier, A. & Giuffrida, A. Evaluation of NMDA receptor models of schizophrenia: divergences in the behavioral effects of sub-chronic PCP and MK-801. Behav. Brain Res 204, 410–415 (2009).
pubmed: 19716985
doi: 10.1016/j.bbr.2009.02.007
Wu, B. et al. Prolonged deficits of associative motor learning in cynomolgus monkeys after long-term administration of phencyclidine. Behav. Brain Res 331, 169–176 (2017).
pubmed: 28549649
doi: 10.1016/j.bbr.2017.05.035
Thomas, C. G., Miller, A. J. & Westbrook, G. L. Synaptic and extrasynaptic NMDA receptor NR2 subunits in cultured hippocampal neurons. J. Neurophysiol. 95, 1727–1734 (2006).
pubmed: 16319212
doi: 10.1152/jn.00771.2005
Huang, H. et al. The potential of the P2X7 receptor as a therapeutic target in a sub-chronic PCP-induced rodent model of schizophrenia. J. Chem. Neuroanat. 116, 101993 (2021).
pubmed: 34147620
doi: 10.1016/j.jchemneu.2021.101993
Gigg, J., McEwan, F., Smausz, R., Neill, J. & Harte, M. K. Synaptic biomarker reduction and impaired cognition in the sub-chronic PCP mouse model for schizophrenia. J. Psychopharmacol. (Oxf., Engl.) 34, 115–124 (2020).
doi: 10.1177/0269881119874446
Seillier, A., Martinez, A. A. & Giuffrida, A. Differential effects of Delta9-tetrahydrocannabinol dosing on correlates of schizophrenia in the sub-chronic PCP rat model. Plos One 15, e0230238 (2020).
pubmed: 32163506
pmcid: 7067407
doi: 10.1371/journal.pone.0230238
Morris, B. J., Cochran, S. M. & Pratt, J. A. PCP: from pharmacology to modelling schizophrenia. Curr. Opin. Pharm. 5, 101–106 (2005).
doi: 10.1016/j.coph.2004.08.008
Yonezawa, Y., Kuroki, T., Kawahara, T., Tashiro, N. & Uchimura, H. Involvement of gamma-aminobutyric acid neurotransmission in phencyclidine-induced dopamine release in the medial prefrontal cortex. Eur. J. Pharm. 341, 45–56 (1998).
doi: 10.1016/S0014-2999(97)01435-0
Kehr, J. et al. Effects of cariprazine on extracellular levels of glutamate, GABA, dopamine, noradrenaline and serotonin in the medial prefrontal cortex in the rat phencyclidine model of schizophrenia studied by microdialysis and simultaneous recordings of locomotor activity. Psychopharmacology 235, 1593–1607 (2018).
pubmed: 29637288
pmcid: 5920013
doi: 10.1007/s00213-018-4874-z
Moghaddam, B. & Adams, B. W. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Sci. (N. Y., N. Y) 281, 1349–1352 (1998).
doi: 10.1126/science.281.5381.1349
Lorrain, D. S., Baccei, C. S., Bristow, L. J., Anderson, J. J. & Varney, M. A. Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience 117, 697–706 (2003).
pubmed: 12617973
doi: 10.1016/S0306-4522(02)00652-8
Amargos-Bosch, M., Lopez-Gil, X., Artigas, F. & Adell, A. Clozapine and olanzapine, but not haloperidol, suppress serotonin efflux in the medial prefrontal cortex elicited by phencyclidine and ketamine. Int J. Neuropsychopharmacol. 9, 565–573 (2006).
pubmed: 16316487
doi: 10.1017/S1461145705005900
Nelson, C. L., Burk, J. A., Bruno, J. P. & Sarter, M. Effects of acute and repeated systemic administration of ketamine on prefrontal acetylcholine release and sustained attention performance in rats. Psychopharmacology 161, 168–179 (2002).
pubmed: 11981597
doi: 10.1007/s00213-002-1004-7
Coyle, J. T. Schizophrenia: Basic and Clinical. Adv. Neurobiol. 15, 255–280 (2017).
pubmed: 28674984
doi: 10.1007/978-3-319-57193-5_9
Lin, C.-H., Chen, Y.-M. & Lane, H.-Y. Novel Treatment for the Most Resistant Schizophrenia: Dual Activation of NMDA Receptor and Antioxidant. Curr. drug targets 21, 610–615 (2020).
pubmed: 31660823
doi: 10.2174/1389450120666191011163539
Lin, C.-H. & Lane, H.-Y. Early Identification and Intervention of Schizophrenia: Insight From Hypotheses of Glutamate Dysfunction and Oxidative Stress. Front Psychiatry 10, 93 (2019).
pubmed: 30873052
pmcid: 6400883
doi: 10.3389/fpsyt.2019.00093
Nakazawa, K. & Sapkota, K. The origin of NMDA receptor hypofunction in schizophrenia. Pharm. Therapeut 205, 107426 (2020).
doi: 10.1016/j.pharmthera.2019.107426
Tan, Y. et al. Phencyclidine-induced cognitive deficits in mice are ameliorated by subsequent repeated intermittent administration of (R)-ketamine, but not (S)-ketamine: Role of BDNF-TrkB signaling. Pharmacol., Biochem., Behav. 188, 172839 (2020).
pubmed: 31866390
doi: 10.1016/j.pbb.2019.172839
Snigdha, S. et al. Phencyclidine (PCP)-induced disruption in cognitive performance is gender-specific and associated with a reduction in brain-derived neurotrophic factor (BDNF) in specific regions of the female rat brain. J. Mol. Neurosci.: MN 43, 337–345 (2011).
pubmed: 20852970
doi: 10.1007/s12031-010-9447-5
Li, Y.-X., Ye, Z.-H., Chen, T., Jia, X.-F. & He, L. The effects of donepezil on phencyclidine-induced cognitive deficits in a mouse model of schizophrenia. Pharmacol., Biochem., Behav. 175, 69–76 (2018).
pubmed: 30218672
doi: 10.1016/j.pbb.2018.09.006
Man, L. et al. Cognitive impairments and low BDNF serum levels in first-episode drug-naive patients with schizophrenia. Psychiatr Res. 263, 1–6 (2018).
doi: 10.1016/j.psychres.2018.02.034
Yang, Y. et al. Brain-derived neurotrophic factor is associated with cognitive impairments in first-episode and chronic schizophrenia. Psychiatr. Res. 273, 528–536 (2019).
doi: 10.1016/j.psychres.2019.01.051
Zhang, X. Y. et al. Low BDNF is associated with cognitive impairment in chronic patients with schizophrenia. Psychopharmacology 222, 277–284 (2012).
pubmed: 22274000
doi: 10.1007/s00213-012-2643-y
Zhang, Y. et al. Brain-derived neurotrophic factor as a biomarker for cognitive recovery in acute schizophrenia: 12-week results from a prospective longitudinal study. Psychopharmacology 235, 1191–1198 (2018).
pubmed: 29392373
doi: 10.1007/s00213-018-4835-6
Chen, Y., Li, S., Zhang, T., Yang, F. & Lu, B. Corticosterone antagonist or TrkB agonist attenuates schizophrenia-like behavior in a mouse model combining Bdnf-e6 deficiency and developmental stress. Iscience 25, 104609 (2022).
pubmed: 35789832
pmcid: 9250029
doi: 10.1016/j.isci.2022.104609
Grace, A. A. Ventral hippocampus, interneurons, and schizophrenia: a new understanding of the pathophysiology of schizophrenia and its implications for treatment and prevention. Curr. Dir. Psychol. Sci. 19, 232–237 (2010).
doi: 10.1177/0963721410378032
Jimenez-Sanchez, L. et al. Activation of AMPA Receptors Mediates the Antidepressant Action of Deep Brain Stimulation of the Infralimbic Prefrontal Cortex. Cereb. cortex (N. Y., N.Y: 1991) 26, 2778–2789 (2016).
Lopez-Gil, X. et al. Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of Ketamine. Acs Chem. Neurosci. 10, 3318–3326 (2019).
pubmed: 31244055
doi: 10.1021/acschemneuro.9b00288
Beard, E., Lengacher, S., Dias, S., Magistretti, P. J. & Finsterwald, C. Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives. Front Physiol. 12, 825816 (2021).
pubmed: 35087428
doi: 10.3389/fphys.2021.825816
Fattorini, G. et al. GLT-1 expression and Glu uptake in rat cerebral cortex are increased by phencyclidine. Glia 56, 1320–1327 (2008).
pubmed: 18615569
doi: 10.1002/glia.20700
Kondziella, D. et al. Glial-neuronal interactions are impaired in the schizophrenia model of repeated MK801 exposure. Neuropsychopharmacol.: Off. Publ. Am. Coll. Neuropsychopharmacol. 31, 1880–1887 (2006).
doi: 10.1038/sj.npp.1300993
Cahill, M. K. et al. Network-level encoding of local neurotransmitters in cortical astrocytes. Nature 629, 146–153 (2024).
pubmed: 38632406
pmcid: 11062919
doi: 10.1038/s41586-024-07311-5
Mu, Y. et al. Glia Accumulate Evidence that Actions Are Futile and Suppress Unsuccessful Behavior. Cell 178, 27–43.e19 (2019).
pubmed: 31230713
doi: 10.1016/j.cell.2019.05.050
Ma, Z., Stork, T., Bergles, D. E. & Freeman, M. R. Neuromodulators signal through astrocytes to alter neural circuit activity and behaviour. Nature 539, 428–432 (2016).
pubmed: 27828941
pmcid: 5161596
doi: 10.1038/nature20145
Katz, M. et al. Glutamate spillover in C. elegans triggers repetitive behavior through presynaptic activation of MGL-2/mGluR5. Nat. Commun. 10, 1882 (2019).
pubmed: 31015396
pmcid: 6478929
doi: 10.1038/s41467-019-09581-4
Bindocci, E. et al. Three-dimensional Ca
Di Castro, M. A. et al. Local Ca
pubmed: 21909085
doi: 10.1038/nn.2929
Wang, Y. et al. Accurate quantification of astrocyte and neurotransmitter fluorescence dynamics for single-cell and population-level physiology. Nat. Neurosci. 22, 1936–1944 (2019).
pubmed: 31570865
pmcid: 6858541
doi: 10.1038/s41593-019-0492-2
Paukert, M. et al. Norepinephrine controls astroglial responsiveness to local circuit activity. Neuron 82, 1263–1270 (2014).
pubmed: 24945771
pmcid: 4080721
doi: 10.1016/j.neuron.2014.04.038
Guttenplan, K. A. et al. Neurotoxic reactive astrocytes induce cell death via saturated lipids. Nature 599, 102–107 (2021).
pubmed: 34616039
doi: 10.1038/s41586-021-03960-y
Zhang, L. et al. Alleviating symptoms of neurodegenerative disorders by astrocyte-specific overexpression of TMEM164 in mice. Nat. Metab. 5, 1787–1802 (2023).
pubmed: 37679556
doi: 10.1038/s42255-023-00887-8
Zhu, S. et al. Chronic phencyclidine induces inflammatory responses and activates GSK3beta in mice. Neurochem Res 39, 2385–2393 (2014).
pubmed: 25270429
doi: 10.1007/s11064-014-1441-9
He, J. et al. Chronic administration of quetiapine attenuates the phencyclidine-induced recognition memory impairment and hippocampal oxidative stress in rats. Neuroreport 29, 1099–1103 (2018).
pubmed: 30036204
doi: 10.1097/WNR.0000000000001078
Tran, H.-Q. et al. Clozapine attenuates mitochondrial burdens and abnormal behaviors elicited by phencyclidine in mice via inhibition of p47 phox; Possible involvements of phosphoinositide 3-kinase/Akt signaling. J. Psychopharmacol. (Oxf., Engl.) 32, 1233–1251 (2018).
doi: 10.1177/0269881118795244
Ohnishi, T. et al. Investigation of betaine as a novel psychotherapeutic for schizophrenia. Ebiomedicine 45, 432–446 (2019).
pubmed: 31255657
pmcid: 6642071
doi: 10.1016/j.ebiom.2019.05.062
Gundlach, A. L., Largent, B. L. & Snyder, S. H. Phencyclidine (PCP) receptors: autoradiographic localization in brain with the selective ligand, [3H]TCP. Brain Res. 386, 266–279 (1986).
pubmed: 3022881
doi: 10.1016/0006-8993(86)90163-0
Maragos, W. F., Greenamyre, J. T., Chu, D. C., Penney, J. B. & Young, A. B. A study of cortical and hippocampal NMDA and PCP receptors following selective cortical and subcortical lesions. Brain Res 538, 36–45 (1991).
pubmed: 1850317
doi: 10.1016/0006-8993(91)90373-4
Weinberger, D. R. Cell biology of the hippocampal formation in schizophrenia. Biol. Psychiatr. 45, 395–402 (1999).
doi: 10.1016/S0006-3223(98)00331-X
Jodo, E. et al. Activation of medial prefrontal cortex by phencyclidine is mediated via a hippocampo-prefrontal pathway. Cereb. cortex (N.Y., N.Y. : 1991) 15, 663–669 (2005).
Aghajanian, G. K. & Marek, G. J. Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Res. Brain Res. Rev. 31, 302–312 (2000).
pubmed: 10719157
doi: 10.1016/S0165-0173(99)00046-6
Suzuki, Y., Jodo, E., Takeuchi, S., Niwa, S. & Kayama, Y. Acute administration of phencyclidine induces tonic activation of medial prefrontal cortex neurons in freely moving rats. Neuroscience 114, 769–779 (2002).
pubmed: 12220577
doi: 10.1016/S0306-4522(02)00298-1
Kargieman, L., Santana, N., Mengod, G., Celada, P. & Artigas, F. Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine. P Natl Acad. Sci. USA 104, 14843–14848 (2007).
doi: 10.1073/pnas.0704848104
Lopez-Gil, X. et al. Importance of inter-hemispheric prefrontal connection in the effects of non-competitive NMDA receptor antagonists. Int. J. Neuropsychopharmacol. 15, 945–956 (2012).
pubmed: 21733285
doi: 10.1017/S1461145711001064
Llado-Pelfort, L. et al. Effects of Hallucinogens on Neuronal Activity. Curr. Top. Behav. Neurosci. 36, 75–105 (2018).
pubmed: 28238186
doi: 10.1007/7854_2017_473
Katayama, T. et al. Activation of medial prefrontal cortex neurons by phencyclidine is mediated via AMPA/kainate glutamate receptors in anesthetized rats. Neuroscience 150, 442–448 (2007).
pubmed: 17935894
doi: 10.1016/j.neuroscience.2007.09.007
Homayoun, H., Jackson, M. E. & Moghaddam, B. Activation of metabotropic glutamate 2/3 receptors reverses the effects of NMDA receptor hypofunction on prefrontal cortex unit activity in awake rats. J. Neurophysiol. 93, 1989–2001 (2005).
pubmed: 15590730
doi: 10.1152/jn.00875.2004
Jodo, E. The role of the hippocampo-prefrontal cortex system in phencyclidine-induced psychosis: a model for schizophrenia. J. Physiol., Paris 107, 434–440 (2013).
pubmed: 23792022
doi: 10.1016/j.jphysparis.2013.06.002
Perez, S. M., Shah, A., Asher, A. & Lodge, D. J. Hippocampal deep brain stimulation reverses physiological and behavioural deficits in a rodent model of schizophrenia. Int. J. Neuropsychopharmacol. 16, 1331–1339 (2013).
pubmed: 23190686
doi: 10.1017/S1461145712001344
Callicott, J. H. et al. Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. Am. J. Psychiatry 160, 2209–2215, (2003).
pubmed: 14638592
doi: 10.1176/appi.ajp.160.12.2209
Barch, D. M., Sheline, Y. I., Csernansky, J. G. & Snyder, A. Z. Working memory and prefrontal cortex dysfunction: specificity to schizophrenia compared with major depression. Biol. Psychiatr. 53, 376–384 (2003).
doi: 10.1016/S0006-3223(02)01674-8
Bikovsky, L. et al. Deep brain stimulation improves behavior and modulates neural circuits in a rodent model of schizophrenia. Exp. Neurol. 283, 142–150 (2016).
pubmed: 27302677
pmcid: 5319857
doi: 10.1016/j.expneurol.2016.06.012
Jessen, F. et al. Reduced hippocampal activation during encoding and recognition of words in schizophrenia patients. Am. J.Psychiatry 160, 1305–1312 (2003).
pubmed: 12832246
doi: 10.1176/appi.ajp.160.7.1305
Ewing, S. G. & Winter, C. The ventral portion of the CA1 region of the hippocampus and the prefrontal cortex as candidate regions for neuromodulation in schizophrenia. Med. Hypotheses 80, 827–832 (2013).
pubmed: 23583328
doi: 10.1016/j.mehy.2013.03.026
Miller, E. J., Saint Marie, L. R., Breier, M. R. & Swerdlow, N. R. Pathways from the ventral hippocampus and caudal amygdala to forebrain regions that regulate sensorimotor gating in the rat. Neuroscience 165, 601–611 (2010).
pubmed: 19854244
doi: 10.1016/j.neuroscience.2009.10.036
Sotres-Bayon, F., Sierra-Mercado, D., Pardilla-Delgado, E. & Quirk, G. J. Gating of fear in prelimbic cortex by hippocampal and amygdala inputs. Neuron 76, 804–812 (2012).
pubmed: 23177964
pmcid: 3508462
doi: 10.1016/j.neuron.2012.09.028
Dienel, S. J., Enwright, J. F. 3rd, Hoftman, G. D. & Lewis, D. A. Markers of glutamate and GABA neurotransmission in the prefrontal cortex of schizophrenia subjects: Disease effects differ across anatomical levels of resolution. Schizophr. Res 217, 86–94 (2020).
pubmed: 31296415
doi: 10.1016/j.schres.2019.06.003
Abdallah, C. G. et al. The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects. Neuropsychopharmacol.: Off. Publ. Am. Coll. Neuropsychopharmacol. 43, 2154–2160 (2018).
doi: 10.1038/s41386-018-0136-3
Fan, Z.-L. et al. Optogenetic inhibition of ventral hippocampal neurons alleviates associative motor learning dysfunction in a rodent model of schizophrenia. Plos One 14, e0227200 (2019).
pubmed: 31891640
pmcid: 6938361
doi: 10.1371/journal.pone.0227200
Grunze, H. C. et al. NMDA-dependent modulation of CA1 local circuit inhibition. J. Neurosci.: Off. J. Soc. Neurosci. 16, 2034–2043 (1996).
doi: 10.1523/JNEUROSCI.16-06-02034.1996
Freund, T. F. & Katona, I. Perisomatic inhibition. Neuron 56, 33–42 (2007).
pubmed: 17920013
doi: 10.1016/j.neuron.2007.09.012
Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B. & Seeburg, P. H. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12, 529–540 (1994).
pubmed: 7512349
doi: 10.1016/0896-6273(94)90210-0
Straub, R. E. et al. Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression. Mol. Psychiatr. 12, 854–869 (2007).
doi: 10.1038/sj.mp.4001988
Kumari, V., Soni, W., Mathew, V. M. & Sharma, T. Prepulse inhibition of the startle response in men with schizophrenia: effects of age of onset of illness, symptoms, and medication. Arch. Gen. Psychiatr. 57, 609–614 (2000).
pubmed: 10839340
doi: 10.1001/archpsyc.57.6.609
Kocsis, B. Differential role of NR2A and NR2B subunits in N-methyl-D-aspartate receptor antagonist-induced aberrant cortical gamma oscillations. Biol. Psychiatr. 71, 987–995 (2012).
doi: 10.1016/j.biopsych.2011.10.002
Sullivan, E. M., Timi, P., Hong, L. E. & O’Donnell, P. Reverse translation of clinical electrophysiological biomarkers in behaving rodents under acute and chronic NMDA receptor antagonism. Neuropsychopharmacol.: Off. Publ. Am. Coll. Neuropsychopharmacol. 40, 719–727 (2015).
doi: 10.1038/npp.2014.228
Noda, Y., Kamei, H., Mamiya, T., Furukawa, H. & Nabeshima, T. Repeated phencyclidine treatment induces negative symptom-like behavior in forced swimming test in mice: imbalance of prefrontal serotonergic and dopaminergic functions. Neuropsychopharmacol. : Off. Publ. Am. Coll. Neuropsychopharmacol. 23, 375–387 (2000).
doi: 10.1016/S0893-133X(00)00138-X
Nath, M., Bhardwaj, S. K., Srivastava, L. K. & Wong, T. P. Altered excitatory and decreased inhibitory transmission in the prefrontal cortex of male mice with early developmental disruption to the ventral hippocampus. Cereb. cortex (N. Y., N.Y: 1991) 33, 865–880 (2023).
Gaskin, P. L., Toledo-Rodriguez, M., Alexander, S. P. & Fone, K. C. Down-regulation of hippocampal genes regulating dopaminergic, GABAergic, and glutamatergic function following combined neonatal phencyclidine and post-weaning social isolation of rats as a neurodevelopmental model for schizophrenia. Int. J. Neuropsychopharmacol. 19, pyw062 (2016).
pubmed: 27382048
pmcid: 5137279
doi: 10.1093/ijnp/pyw062
Hervig, M. E., Thomsen, M. S., Kallo, I. & Mikkelsen, J. D. Acute phencyclidine administration induces c-Fos-immunoreactivity in interneurons in cortical and subcortical regions. Neuroscience 334, 13–25 (2016).
pubmed: 27476436
doi: 10.1016/j.neuroscience.2016.07.028
Santana, N., Troyano-Rodriguez, E., Mengod, G., Celada, P. & Artigas, F. Activation of thalamocortical networks by the N-methyl-D-aspartate receptor antagonist phencyclidine: reversal by clozapine. Biol. Psychiatr. 69, 918–927 (2011).
doi: 10.1016/j.biopsych.2010.10.030
Troyano-Rodriguez, E. et al. Phencyclidine inhibits the activity of thalamic reticular gamma-aminobutyric acidergic neurons in rat brain. Biol. Psychiatr. 76, 937–945 (2014).
doi: 10.1016/j.biopsych.2014.05.019
Jodo, E. et al. Differences in responsiveness of mediodorsal thalamic and medial prefrontal cortical neurons to social interaction and systemically administered phencyclidine in rats. Neuroscience 170, 1153–1164 (2010).
pubmed: 20727386
doi: 10.1016/j.neuroscience.2010.08.017
Kuroda, M., Yokofujita, J. & Murakami, K. An ultrastructural study of the neural circuit between the prefrontal cortex and the mediodorsal nucleus of the thalamus. Prog. Neurobiol. 54, 417–458 (1998).
pubmed: 9522395
doi: 10.1016/S0301-0082(97)00070-1
Bubser, M. et al. Disinhibition of the mediodorsal thalamus induces fos-like immunoreactivity in both pyramidal and GABA-containing neurons in the medial prefrontal cortex of rats, but does not affect prefrontal extracellular GABA levels. Synap. (N. Y., N. Y.) 30, 156–165 (1998).
doi: 10.1002/(SICI)1098-2396(199810)30:2<156::AID-SYN5>3.0.CO;2-B
Floresco, S. B. & Grace, A. A. Gating of hippocampal-evoked activity in prefrontal cortical neurons by inputs from the mediodorsal thalamus and ventral tegmental area. J. Neurosci. : Off. J. Soc. Neurosci. 23, 3930–3943 (2003).
doi: 10.1523/JNEUROSCI.23-09-03930.2003
Grayson, B. et al. Postnatal Phencyclidine (PCP) as a Neurodevelopmental Animal Model of Schizophrenia Pathophysiology and Symptomatology: A Review. Curr. Top. Behav. Neurosci. 29, 403–428 (2016).
pubmed: 26510740
doi: 10.1007/7854_2015_403
Moghadam, A. A., Vose, L. R., Miry, O., Zhang, X.-L. & Stanton, P. K. Pairing of neonatal phencyclidine exposure and acute adolescent stress in male rats as a novel developmental model of schizophrenia. Behav. Brain Res 409, 113308 (2021).
pubmed: 33872663
doi: 10.1016/j.bbr.2021.113308
Feigenson, K. A., Kusnecov, A. W. & Silverstein, S. M. Inflammation and the two-hit hypothesis of schizophrenia. Neurosci. Biobehav R. 38, 72–93 (2014).
doi: 10.1016/j.neubiorev.2013.11.006
Gomes, F. V., Rincon-Cortes, M. & Grace, A. A. Adolescence as a period of vulnerability and intervention in schizophrenia: Insights from the MAM model. Neurosci. Biobehav R. 70, 260–270 (2016).
doi: 10.1016/j.neubiorev.2016.05.030
Murray, R. M., Bhavsar, V., Tripoli, G. & Howes, O. 30 Years on: How the Neurodevelopmental Hypothesis of Schizophrenia Morphed Into the Developmental Risk Factor Model of Psychosis. Schizophrenia Bull. 43, 1190–1196 (2017).
doi: 10.1093/schbul/sbx121
Selemon, L. D. & Zecevic, N. Schizophrenia: a tale of two critical periods for prefrontal cortical development. Transl. Psychiat. 5, e623 (2015).
doi: 10.1038/tp.2015.115
Kalopita, K., Armakolas, A., Philippou, A., Zarros, A. & Angelogianni, P. Ketamine-induced neurotoxicity in neurodevelopment: A synopsis of main pathways based on recent in vivo experimental findings. J. Anaesthesiol., Clin. Pharmacol. 37, 37–42 (2021).
pubmed: 34103820
doi: 10.4103/joacp.JOACP_415_19
Pratt, J., Winchester, C., Dawson, N. & Morris, B. Advancing schizophrenia drug discovery: optimizing rodent models to bridge the translational gap. Nat. Rev. Drug Discov. 11, 560–579 (2012).
pubmed: 22722532
doi: 10.1038/nrd3649
Goff, D. C. & Coyle, J. T. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am. J. psychiatry 158, 1367–1377 (2001).
pubmed: 11532718
doi: 10.1176/appi.ajp.158.9.1367
Javitt, D. C. Glutamatergic theories of schizophrenia. Isr. J. Psychiatry Relat. Sci. 47, 4–16 (2010).
pubmed: 20686195
Hanson, J. E. et al. Therapeutic potential of N-methyl-D-aspartate receptor modulators in psychiatry. Neuropsychopharmacol.: Off. Publ. Am. Coll. Neuropsychopharmacol. 49, 51–66 (2024).
doi: 10.1038/s41386-023-01614-3
Zheng, W. et al. Adjunctive memantine for schizophrenia: a meta-analysis of randomized, double-blind, placebo-controlled trials. Psychol. Med. 48, 72–81 (2018).
pubmed: 28528597
doi: 10.1017/S0033291717001271
Zheng, W. et al. Adjunctive memantine for major mental disorders: A systematic review and meta-analysis of randomized double-blind controlled trials. Schizophr. Res. 209, 12–21 (2019).
pubmed: 31164254
doi: 10.1016/j.schres.2019.05.019
Schaefer, M. et al. Acute and Long-term Memantine Add-on Treatment to Risperidone Improves Cognitive Dysfunction in Patients with Acute and Chronic Schizophrenia. Pharmacopsychiatry 53, 21–29 (2020).
pubmed: 31390660
doi: 10.1055/a-0970-9310
Magdaleno-Madrigal, V. M. et al. Short-term deep brain stimulation of the thalamic reticular nucleus modifies aberrant oscillatory activity in a neurodevelopment model of schizophrenia. Neuroscience 357, 99–109 (2017).
pubmed: 28576730
doi: 10.1016/j.neuroscience.2017.05.035
Ewing, S. G. & Grace, A. A. Deep brain stimulation of the ventral hippocampus restores deficits in processing of auditory evoked potentials in a rodent developmental disruption model of schizophrenia. Schizophr. Res 143, 377–383 (2013).
pubmed: 23269227
doi: 10.1016/j.schres.2012.11.023
Corripio, I. et al. Clinical improvement in a treatment-resistant patient with schizophrenia treated with deep brain stimulation. Biol. Psychiat. 80, e69–70 (2016).
pubmed: 27113497
doi: 10.1016/j.biopsych.2016.03.1049
Zain, M. A. et al. Phencyclidine dose optimisation for induction of spatial learning and memory deficits related to schizophrenia in C57BL/6 mice. Exp. Anim. Tokyo 67, 421–429 (2018).
doi: 10.1538/expanim.18-0006