Knockout of NMDA-receptors from parvalbumin interneurons sensitizes to schizophrenia-related deficits induced by MK-801

Bygrave, Alexei M.; Masiulis, Simonas; Nicholson, Elizabeth; Berkemann, M; Barkus, Christopher; Sprengel, Rolf; Harrison, Paul J.; Kullmann, Dimitri M.; Bannerman, David M.; Kätzel, Dennis

doi:10.1038/tp.2016.44

Cited by 100 publications

(112 citation statements)

References 50 publications

(92 reference statements)

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“…Our network simulation results also resonate with multiple convergent findings that implicate PV+ cell NMDAR hypofunction at the centre of schizophrenia pathophysiology (Bygrave et al, 2016;Lisman et al, 2008;Nakazawa et al, 2012). For instance, NMDAR blockers have been shown to recapitulate some features of schizophrenia in healthy individuals (Krystal et al, 1994).…”

Section: Discussionsupporting

confidence: 82%

Dendritic NMDA receptors in parvalbumin neurons enable strong and stable neuronal assemblies

Cornford

Mercier

Leite

et al. 2018

Preprint

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Section: Discussionsupporting

confidence: 82%

Dendritic NMDA receptors in parvalbumin neurons enable strong and stable neuronal assemblies

Cornford

Mercier

Leite

et al. 2018

Preprint

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“…In addition, although knockout of Grin1 in PV‐positive interneurons is reported to cause schizophrenia‐related deficits induced by MK‐801 (Bygrave et al . ), all Grin1 cKO mice could walk along a straight line with regular steps (Fig. E ).…”

Section: Resultsmentioning

confidence: 82%

“…Although conventional Grin1 KO mice die within a day of birth (Forrest et al 1994), all three Grin1 cKO mouse lines were viable. In addition, although knockout of Grin1 in PV-positive interneurons is reported to cause schizophrenia-related deficits induced by MK-801 (Bygrave et al 2016), all Grin1 cKO mice could walk along a straight line with regular steps (Fig. 1E).…”

Section: Generation Of Cell Type-specific Conditional Grin1 Knockout mentioning

confidence: 94%

Interneuronal NMDA receptors regulate long‐term depression and motor learning in the cerebellum

Kono

Kakegawa

Yoshida

et al. 2018

The Journal of Physiology

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Key points NMDA receptors (NMDARs) are required for long‐term depression (LTD) at parallel fibre–Purkinje cell synapses, but their cellular localization and physiological functions in vivo are unclear. NMDARs in molecular‐layer interneurons (MLIs), but not granule cells or Purkinje cells, are required for LTD, but not long‐term potentiation induced by low‐frequency stimulation of parallel fibres. Nitric oxide produced by NMDAR activation in MLIs probably mediates LTD induction. NMDARs in granule cells or Purkinje cells are dispensable for motor learning during adaptation of horizontal optokinetic responses. Abstract Long‐term potentiation (LTP) and depression (LTD), which serve as cellular synaptic plasticity models for learning and memory, are crucially regulated by N‐methyl‐d‐aspartate receptors (NMDARs) in various brain regions. In the cerebellum, LTP and LTD at parallel fibre (PF)–Purkinje cell (PC) synapses are thought to mediate certain forms of motor learning. However, while NMDARs are essential for LTD in vitro, their cellular localization remains controversial. In addition, whether and how NMDARs mediate motor learning in vivo remains unclear. Here, we examined the contribution of NMDARs expressed in granule cells (GCs), PCs and molecular‐layer interneurons (MLIs) to LTD/LTP and motor learning by generating GC‐, PC‐ and MLI/PC‐specific knockouts of Grin1, a gene encoding an obligatory GluN1 subunit of NMDARs. While robust LTD and LTP were induced at PF–PC synapses in GC‐ and PC‐specific Grin1 (GC‐Grin1 and PC‐Grin1, respectively) conditional knockout (cKO) mice, only LTD was impaired in MLI/PC‐specific Grin1 (MLI/PC‐Grin1) cKO mice. Application of diethylamine nitric oxide (NO) sodium, a potent NO donor, to the cerebellar slices restored LTD in MLI/PC‐Grin1 cKO mice, suggesting that NO is probably downstream to NMDARs. Furthermore, the adaptation of horizontal optokinetic responses (hOKR), a cerebellar motor learning task, was normally observed in GC‐Grin1 cKO and PC‐Grin1 cKO mice, but not in MLI/PC‐Grin1 cKO mice. These results indicate that it is the NMDARs expressed in MLIs, but not in PCs or GCs, that play important roles in LTD in vitro and motor learning in vivo.

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“…NMDAR antagonists, such as phencyclidine (PCP), induce schizophrenia symptoms, whereas NMDAR agonists are schizophrenia medicines. Mice mutants with reduced NMDAR levels develop symptoms resembling schizophrenia, which can be overcome by treatment with NMDAR agonists (107, 108). This suggests that NMDAR is a candidate pSAg involved in the striatal damage of schizophrenia patients (109).…”

Section: The Candidate Psags Of Npdsmentioning

confidence: 99%

Autoimmune Aspects of Neurodegenerative and Psychiatric Diseases: A Template for Innovative Therapy

Haan¹,

Klein

Hart

2017

Front. Psychiatry

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Neurodegenerative and psychiatric diseases (NPDs) are today’s most important group of diseases, surpassing both atherosclerotic cardiovascular disease and cancer in morbidity incidence. Although NPDs have a dramatic impact on our society because of their high incidence, mortality, and severe debilitating character, remarkably few effective interventions have become available. The current treatments, if available, comprise the lifelong intake of general immunosuppressants to delay disease progression or neurotransmitter antagonists/agonists to dampen undesired behaviors. The long-term usage of such medication, however, coincides with often severe adverse side effects. There is, therefore, an urgent need for safe and effective treatments for these diseases. Here, we discuss that many NPDs coincide with subtle chronic or flaring brain inflammation sometimes escalating with infiltrations of lymphocytes in the inflamed brain parts causing mild to severe or even lethal brain damage. Thus, NPDs show all features of autoimmune diseases. In this review, we postulate that NPDs resemble autoimmune-driven inflammatory diseases in many aspects and may belong to the same disease spectrum. Just like in autoimmune diseases, NPD symptoms basically are manifestations of a chronic self-sustaining inflammatory process with detrimental consequences for the patient. Specific inhibition of the destructive immune responses in the brain, leaving the patient’s immune system intact, would be the ultimate solution to cure patients from the disease. To reach this goal, the primary targets, e.g., the primary self-antigens (pSAgs) of the patient’s chronic (auto)immune response, need to be identified. For a few major NPDs, immunological studies led to the identification of the pSAgs involved in the autoimmune damage of specific brain parts. However, further research is needed to complete the list of pSAgs for all NPDs. Such immunological studies will not only provide crucial insights into NPD pathogenesis but also ultimately enable the development of a new generation of safe and effective immunotherapies for NPDs. Interventions that will dramatically improve the life expectancy and quality of life of individual patients and, moreover, will significantly reduce the health-care costs of the society in general.

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Knockout of NMDA-receptors from parvalbumin interneurons sensitizes to schizophrenia-related deficits induced by MK-801

Cited by 100 publications

References 50 publications

Dendritic NMDA receptors in parvalbumin neurons enable strong and stable neuronal assemblies

Dendritic NMDA receptors in parvalbumin neurons enable strong and stable neuronal assemblies

Interneuronal NMDA receptors regulate long‐term depression and motor learning in the cerebellum

Autoimmune Aspects of Neurodegenerative and Psychiatric Diseases: A Template for Innovative Therapy

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