Download PDF
Pharmacopsychiatry 2023; 56(02): 57-63
DOI: 10.1055/a-0960-9846
Review

Hippocampal Dysfunction in Schizophrenia and Aberrant Hippocampal Synaptic Plasticity in Rodent Model Psychosis: a Selective Review[1]

Julia C. Bartsch
1   Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany
2   Institute of Physiology I, Westfälische Wilhelms-Universität Münster, Münster, Germany
,
Björn H. Schott
1   Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany
3   Leibniz Institute for Neurobiology, Magdeburg, Germany
4   Department of Psychiatry and Psychotherapy, University Medicine Göttingen, Germany
,
Joachim Behr
1   Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany
5   Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, Brandenburg Medical School, Neuruppin, Germany
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Abstract

Schizophrenia is a complex, heterogeneous psychiatric disorder that affects about 1% of the global population. Hippocampal dysfunction has been linked to both cognitive deficits and positive symptoms in schizophrenia. Here, we briefly review current findings on disrupted hippocampal processing from a clinical perspective before concentrating on preclinical studies of aberrant hippocampal synaptic plasticity using the N-methyl-D-aspartate receptor hypofunction model of psychosis and related findings from genetic models. Taken together, the results put the case for maladaptive hippocampal synaptic plasticity and its extrinsic connections as mechanistic underpinnings of cognitive impairments in schizophrenia.

Key words

schizophrenia - hippocampus - synaptic plasticity - dopamine - long-term potentiation

`1 This work was a contribution at the 16. Hansesymposium, 7.-8.9.2018 in Rostock, Germany.




Publication History

Received: 04 January 2019
Received: 14 May 2019

Accepted: 11 June 2019

Article published online:
01 August 2019

© 2019. Thieme. All rights reserved.

© Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia?. Am J Psychiatry 1996; 153: 321-330
    CrossrefPubMedGoogle Scholar
  • 2 Preston AR, Shohamy D, Tamminga CA. et al. Hippocampal function, declarative memory, and schizophrenia: anatomic and functional neuroimaging considerations. Curr Neurol Neurosci Rep 2005; 5: 249-256
    CrossrefPubMedGoogle Scholar
  • 3 Lisman JE, Grace AA. The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron 2005; 46: 703-713
    CrossrefPubMedGoogle Scholar
  • 4 Bliss TV, Lomo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 1973; 232: 331-356
    CrossrefPubMedGoogle Scholar
  • 5 Hall J, Trent S, Thomas KL. et al. Genetic risk for schizophrenia: convergence on synaptic pathways involved in plasticity. Biol Psychiatry 2015; 77: 52-58
    CrossrefPubMedGoogle Scholar
  • 6 Averbeck BB, Chafee MV. Using model systems to understand errant plasticity mechanisms in psychiatric disorders. Nat Neurosci 2016; 19: 1418-1425
    CrossrefPubMedGoogle Scholar
  • 7 Neill JC, Barnes S, Cook S. et al. Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism. Pharmacol Ther 2010; 128: 419-432
    CrossrefPubMedGoogle Scholar
  • 8 Luby ED, Cohen BD, Rosenbaum G. et al. Study of a new schizophrenomimetic drug—Sernyl. Arch Neurol Psychiatry 1959; 81: 363-363
    CrossrefPubMedGoogle Scholar
  • 9 Hansen KB, Yi F, Perszyk RE. et al. Structure, function, and allosteric modulation of NMDA receptors. J Gen Physiol 2018; 150: 1081-1105
    CrossrefPubMedGoogle Scholar
  • 10 Huettner JE, Bean BP. Block of N-methyl-D-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels. Proc Natl Acad Sci U S A 1988; 85: 1307-1311
    CrossrefPubMedGoogle Scholar
  • 11 Song X, Jensen MØ, Jogini V. et al. Mechanism of NMDA receptor channel block by MK-801 and memantine. Nature 2018; 556: 515-519
    CrossrefPubMedGoogle Scholar
  • 12 Kemp JA, Foster AC, Wong EHF. Non-competitive antagonists of excitatory amino acid receptors. Trends Neurosci 1987; 10: 294-298
    CrossrefPubMedGoogle Scholar
  • 13 Adell A, Jiménez-Sánchez L, López-Gil X. et al. Is the acute NMDA receptor hypofunction a valid model of schizophrenia?. Schizophr Bull 2012; 38: 9-14
    CrossrefPubMedGoogle Scholar
  • 14 Nelson MD, Saykin AJ, Flashman LA. et al. Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging. Arch Gen Psychiatry 1998; 55: 433-433
    CrossrefPubMedGoogle Scholar
  • 15 Brugger SP, Howes OD. Heterogeneity and homogeneity of regional brain structure in schizophrenia: a meta-analysis. JAMA psychiatry 2017; 74: 1104-1111
    CrossrefPubMedGoogle Scholar
  • 16 Kuo SS, Pogue-Geile MF. Variation in fourteen brain structure volumes in schizophrenia: a comprehensive meta-analysis of 246 studies. Neurosci Biobehav Rev 2019; 98: 85-94
    CrossrefPubMedGoogle Scholar
  • 17 Bogerts B, Ashtari M, Degreef G. et al. Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia. Psychiatry Res Neuroimaging 1990; 35: 1-13
    CrossrefPubMedGoogle Scholar
  • 18 Tepest R, Wang L, Miller MI. et al. Hippocampal deformities in the unaffected siblings of schizophrenia subjects. Biol Psychiatry 2003; 54: 1234-1240
    CrossrefPubMedGoogle Scholar
  • 19 Bogerts B. The temporolimbic system theory of positive schizophrenic symptoms. Schizophr Bull 1997; 23: 423-435
    CrossrefPubMedGoogle Scholar
  • 20 Wood SJ, Kennedy D, Phillips LJ. et al. Hippocampal pathology in individuals at ultra-high risk for psychosis: a multi-modal magnetic resonance study. Neuroimage 2010; 52: 62-68
    CrossrefPubMedGoogle Scholar
  • 21 Squire LR, Stark CEL, Clark RE. The medial temporal lobe. Annu Rev Neurosci 2004; 27: 279-306
    CrossrefPubMedGoogle Scholar
  • 22 Zierhut K, Bogerts B, Schott B. et al. The role of hippocampus dysfunction in deficient memory encoding and positive symptoms in schizophrenia. Psychiatry Res Neuroimaging 2010; 183: 187-194
    CrossrefPubMedGoogle Scholar
  • 23 Pirnia T, Woods RP, Hamilton LS. et al. Hippocampal dysfunction during declarative memory encoding in schizophrenia and effects of genetic liability. Schizophr Res 2015; 161: 357-366
    CrossrefPubMedGoogle Scholar
  • 24 Ragland JD, Ranganath C, Harms MP. et al. Functional and neuroanatomic specificity of episodic memory dysfunction in schizophrenia. JAMA Psychiatry 2015; 72: 909-909
    CrossrefPubMedGoogle Scholar
  • 25 Heckers S, Rauch S, Goff D. et al. Impaired recruitment of the hippocampus during conscious recollection in schizophrenia. Nat Neurosci 1998; 1: 318-323
    CrossrefPubMedGoogle Scholar
  • 26 Tamminga CA, Thomas BP, Chin R. et al. Hippocampal novelty activations in schizophrenia: disease and medication effects. Schizophr Res 2012; 138: 157-163
    CrossrefPubMedGoogle Scholar
  • 27 Schott BH, Voss M, Wagner B. et al. Fronto-limbic novelty processing in acute psychosis: disrupted relationship with memory performance and potential implications for delusions. Front Behav Neurosci 2015; 9: 1-13
    CrossrefPubMedGoogle Scholar
  • 28 Ledoux AA, Phillips JL, Labelle A. et al. Decreased fMRI activity in the hippocampus of patients with schizophrenia compared to healthy control participants, tested on a wayfinding task in a virtual town. Psychiatry Res Neuroimaging 2013; 211: 47-56
    CrossrefPubMedGoogle Scholar
  • 29 Holt DJ, Weiss AP, Rauch SL. et al. Sustained activation of the hippocampus in response to fearful faces in schizophrenia. Biol Psychiatry 2005; 57: 1011-1019
    Google Scholar
  • 30 Friston KJ, Liddle PF, Frith CD. et al. The left medial temporal region and schizophrenia: a pet study. Brain 1992; 115: 367-382
    CrossrefPubMedGoogle Scholar
  • 31 Tregellas JR, Smucny J, Harris JG. et al. Intrinsic hippocampal activity as a biomarker for cognition and symptoms in schizophrenia. Am J Psychiatry 2014; 171: 549-556
    CrossrefPubMedGoogle Scholar
  • 32 Lefebvre S, Demeulemeester M, Leroy A. et al. Network dynamics during the different stages of hallucinations in schizophrenia. Hum Brain Mapp 2016; 37: 2571-2586
    CrossrefPubMedGoogle Scholar
  • 33 Li B, Cui LB, Xi YB. et al. Abnormal effective connectivity in the brain is involved in auditory verbal hallucinations in schizophrenia. Neurosci Bull 2017; 33: 281-291
    CrossrefPubMedGoogle Scholar
  • 34 Wolthusen RPF, Coombs G, Boeke EA. et al. Correlation between levels of delusional beliefs and perfusion of the hippocampus and an associated network in a non–help-seeking population. Biol Psychiatry Cogn Neurosci Neuroimaging 2018; 3: 178-186
    PubMedGoogle Scholar
  • 35 Schobel SA, Lewandowski NM, Corcoran CM. et al. Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders. Arch Gen Psychiatry 2009; 66: 938-946
    CrossrefPubMedGoogle Scholar
  • 36 Kühn S, Musso F, Mobascher A. et al. Hippocampal subfields predict positive symptoms in schizophrenia: first evidence from brain morphometry. Transl Psychiatry 2012; 2: e127-e127
    CrossrefPubMedGoogle Scholar
  • 37 Zierhut KC, Graßmann R, Kaufmann J. et al. Hippocampal CA1 deformity is related to symptom severity and antipsychotic dosage in schizophrenia. Brain 2013; 136: 804-814
    CrossrefPubMedGoogle Scholar
  • 38 Lisman JE, Coyle JT, Green RW. et al. Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci 2008; 31: 234-242
    CrossrefPubMedGoogle Scholar
  • 39 Kraguljac NV, White DM, Hadley J. et al. Hippocampal-parietal dysconnectivity and glutamate abnormalities in unmedicated patients with schizophrenia. Hippocampus 2014; 24: 1524-1532
    CrossrefPubMedGoogle Scholar
  • 40 Morgan CJA, Dodds CM, Furby H. et al. Long-term heavy ketamine use is associated with spatial memory impairment and altered hippocampal activation. Front Psychiatry 2014; 5: 149-149
    PubMedGoogle Scholar
  • 41 Grimm O, Gass N, Weber-Fahr W. et al. Acute ketamine challenge increases resting state prefrontal-hippocampal connectivity in both humans and rats. Psychopharmacology (Berl) 2015; 232: 4231-4241
    CrossrefPubMedGoogle Scholar
  • 42 Diederen KMJ, Neggers SFW, Daalman K. et al. Deactivation of the parahippocampal gyrus preceding auditory hallucinations in schizophrenia. Am J Psychiatry 2010; 167: 427-435
    CrossrefPubMedGoogle Scholar
  • 43 Gurin L, Blum S. Delusions and the right hemisphere: a review of the case for the right hemisphere as a mediator of reality-based belief. J Neuropsychiatry Clin Neurosci 2017; 29: 225-235
    CrossrefPubMedGoogle Scholar
  • 44 Wolford G, Miller MB, Gazzaniga M. The left hemisphere’s role in hypothesis formation. J Neurosci 2000; 20: RC64-RC64
    CrossrefPubMedGoogle Scholar
  • 45 Velichkovsky BM, Krotkova OA, Kotov AA. et al. Consciousness in a multilevel architecture: evidence from the right side of the brain. Conscious Cogn 2018; 64: 227-239
    CrossrefPubMedGoogle Scholar
  • 46 Tamminga CA, Southcott S, Sacco C. et al. Glutamate dysfunction in hippocampus: relevance of dentate gyrus and CA3 signaling. Schizophr Bull 2012; 38: 927-935
    CrossrefPubMedGoogle Scholar
  • 47 Abraham WC, Mason SE. Effects of the NMDA receptor/channel antagonists CPP and MK801 on hippocampal field potentials and long-term potentiation in anesthetized rats. Brain Res 1988; 462: 40-46
    CrossrefPubMedGoogle Scholar
  • 48 Wiescholleck V, Manahan-Vaughan D. Persistent deficits in hippocampal synaptic plasticity accompany losses of hippocampus-dependent memory in a rodent model of psychosis. Front Integr Neurosci 2013; 7: 12-12
    CrossrefPubMedGoogle Scholar
  • 49 Manahan-Vaughan D, Von Haebler D, Winter C. et al. A single application of MK801 causes symptoms of acute psychosis, deficits in spatial memory, and impairment of synaptic plasticity in rats. Hippocampus 2008; 18: 125-134
    CrossrefPubMedGoogle Scholar
  • 50 Wiescholleck V, Manahan-Vaughan D. PDE4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues MK801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis. Transl Psychiatry 2012; 2: e89-e89
    CrossrefPubMedGoogle Scholar
  • 51 Manahan-Vaughan D, Wildförster V, Thomsen C. Rescue of hippocampal LTP and learning deficits in a rat model of psychosis by inhibition of glycine transporter-1 (GlyT1). Eur J Neurosci 2008; 28: 1342-1350
    CrossrefPubMedGoogle Scholar
  • 52 Wöhrl R, Eisenach S, Manahan-Vaughan D. et al. Acute and long-term effects of MK-801 on direct cortical input evoked homosynaptic and heterosynaptic plasticity in the CA1 region of the female rat. Eur J Neurosci 2007; 26: 2873-2883
    CrossrefPubMedGoogle Scholar
  • 53 Bartsch JC, Fidzinski P, Huck JH. et al. Enhanced dopamine-dependent hippocampal plasticity after single MK-801 application. Neuropsychopharmacology 2015; 987-995
    CrossrefPubMedGoogle Scholar
  • 54 Buck N, Cali S, Behr J. Enhancement of long-term potentiation at CA1-subiculum synapses in MK-801-treated rats. Neurosci Lett 2006; 392: 5-9
    CrossrefPubMedGoogle Scholar
  • 55 Bhat S, Dao DT, Terrillion CE. et al. CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease. Prog Neurobiol 2012; 99: 1-14
    CrossrefPubMedGoogle Scholar
  • 56 Schott BH, Assmann A, Schmierer P. et al. Epistatic interaction of genetic depression risk variants in the human subgenual cingulate cortex during memory encoding. Transl Psychiatry 2014; 4: e372-e372
    CrossrefPubMedGoogle Scholar
  • 57 Graef JD, Newberry K, Newton A. et al. Effect of acute NR2B antagonist treatment on long-term potentiation in the rat hippocampus. Brain Res 2015; 1609: 31-39
    CrossrefPubMedGoogle Scholar
  • 58 Preskorn SH, Baker B, Kolluri S. et al. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective n-methyl-d-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol 2008; 28: 631-637
    CrossrefPubMedGoogle Scholar
  • 59 Lewis DA, Levitt P. Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci 2002; 25: 409-432
    CrossrefPubMedGoogle Scholar
  • 60 Lim AL, Taylor DA, Malone DT. Consequences of early life MK-801 administration: long-term behavioural effects and relevance to schizophrenia research. Behav Brain Res 2012; 227: 276-286
    CrossrefPubMedGoogle Scholar
  • 61 Uttl L, Petrasek T, Sengul H. et al. Chronic MK-801 application in adolescence and early adulthood: a spatial working memory deficit in adult Long-Evans rats but no changes in the hippocampal NMDA receptor subunits. Front Pharmacol 2018; 9: 1-13
    CrossrefPubMedGoogle Scholar
  • 62 O’Mara SM, Commins S, Anderson M. Synaptic plasticity in the hippocampal area CA1-subiculum projection: implications for theories of memory. Hippocampus 2000; 10: 447-456
    CrossrefPubMedGoogle Scholar
  • 63 Lodge DJ, Grace AA. Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia. J Neurosci 2007; 27: 11424-11430
    CrossrefPubMedGoogle Scholar
  • 64 Lisman JE, Otmakhova NA. Storage, recall, and novelty detection of sequences by the hippocampus: elaborating on the SOCRATIC model to account for normal and aberrant effects of dopamine. Hippocampus 2001; 11: 551-568
    CrossrefPubMedGoogle Scholar
  • 65 Breitenstein C, Korsukewitz C, Flöel A. et al. Tonic dopaminergic stimulation impairs associative learning in healthy subjects. Neuropsychopharmacology 2006; 31: 2552-2564
    CrossrefPubMedGoogle Scholar
  • 66 Winton-Brown T, Schmidt A, Roiser JP. et al. Altered activation and connectivity in a hippocampal-basal ganglia-midbrain circuit during salience processing in subjects at ultra high risk for psychosis. Transl Psychiatry 2017; 7: 1-8
    CrossrefPubMedGoogle Scholar
  • 67 Blot K, Kimura SI, Bai J. et al. Modulation of hippocampus-prefrontal cortex synaptic transmission and disruption of executive cognitive functions by MK-801. Cereb Cortex 2015; 25: 1348-1361
    CrossrefPubMedGoogle Scholar
  • 68 Gass N, Becker R, Sack M. et al. Antagonism at the NR2B subunit of NMDA receptors induces increased connectivity of the prefrontal and subcortical regions regulating reward behavior. Psychopharmacology (Berl) 2018; 235: 1055-1068
    CrossrefPubMedGoogle Scholar
  • 69 Schizophrenia Working Group of the Psychiatric Genomics Consortium . Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511: 421-427
    CrossrefPubMedGoogle Scholar
  • 70 Purcell SM, Moran JL, Fromer M. et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 2014; 506: 185-190
    CrossrefPubMedGoogle Scholar
  • 71 Fromer M, Pocklington AJ, Kavanagh DH. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 2014; 506: 179-184
    CrossrefPubMedGoogle Scholar
  • 72 Kirov G, Pocklington AJ, Holmans P. et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry 2012; 17: 142-153
    CrossrefPubMedGoogle Scholar
  • 73 Earls LR, Bayazitov IT, Fricke RG. et al. Dysregulation of presynaptic calcium and synaptic plasticity in a mouse model of 22q11 deletion syndrome. J Neurosci 2010; 30: 15843-15855
    CrossrefPubMedGoogle Scholar
  • 74 Stefansson H, Petursson H, Sigurdsson E. et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71: 877-892
    CrossrefPubMedGoogle Scholar
  • 75 Bjarnadottir M, Misner DL, Haverfield-Gross S. et al. Neuregulin1 (NRG1) signaling through Fyn modulates NMDA receptor phosphorylation: differential synaptic function in NRG1+/− knock-outs compared with wild-type mice. J Neurosci 2007; 27: 4519-4529
    CrossrefPubMedGoogle Scholar
  • 76 Fazzari P, Snellinx A, Sabanov V. et al. Cell autonomous regulation of hippocampal circuitry via Aph1b-γ-secretase/neuregulin 1 signalling. Elife 2014; 3: 1-16
    CrossrefPubMedGoogle Scholar
  • 77 Straub RE, Jiang Y, MacLean CJ. et al. Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet 2002; 71: 337-348
    CrossrefPubMedGoogle Scholar
  • 78 Tang TTT, Yang F, Chen BS. et al. Dysbindin regulates hippocampal LTP by controlling NMDA receptor surface expression. Proc Natl Acad Sci USA 2009; 106: 21395-21400
    CrossrefPubMedGoogle Scholar
  • 79 Tindi JO, Chávez AE, Cvejic S. et al. ANKS1B gene product AIDA-1 controls hippocampal synaptic transmission by regulating GluN2B subunit localization. J Neurosci 2015; 35: 8986-8996
    CrossrefPubMedGoogle Scholar
  • 80 Schell MJ, Molliver ME, Snyder SH.. D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc Natl Acad Sci U S A 1995; 92: 3948-3952
    CrossrefPubMedGoogle Scholar
  • 81 Mothet JP, Parent AT, Wolosker H. et al. D-Serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci 2002; 97: 4926-4931
    CrossrefPubMedGoogle Scholar
  • 82 Basu AC, Tsai GE, Ma CL. et al. Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior. Mol Psychiatry 2009; 14: 719-727
    CrossrefPubMedGoogle Scholar
  • 83 Balu DT, Li Y, Puhl MD. et al. Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction. Proc Natl Acad Sci 2013; 110: E2400-E2409
    PubMedGoogle Scholar
  • 84 MacKay MAB, Kravtsenyuk M, Thomas R. et al. D-Serine: potential therapeutic agent and/or biomarker in schizophrenia and depression?. Front Psychiatry 2019; 10: 18-23
    PubMedGoogle Scholar
  • 85 Balu DT, Li Y, Takagi S. et al. An mGlu5-positive allosteric modulator rescues the neuroplasticity deficits in a genetic model of NMDA receptor hypofunction in schizophrenia. Neuropsychopharmacology 2016; 41: 2052-2061
    CrossrefPubMedGoogle Scholar
  • 86 Finke C, Kopp UA, Pajkert A. et al. Structural hippocampal damage following anti-N-methyl-D-aspartate receptor encephalitis. Biol Psychiatry 2016; 79: 727-734
    CrossrefPubMedGoogle Scholar
  • 87 Finke C, Kopp UA, Prüss H. et al. Cognitive deficits following anti-NMDA receptor encephalitis. J Neurol Neurosurg Psychiatry 2012; 83: 195-198
    CrossrefPubMedGoogle Scholar