The role of abnormal NMDA receptor-mediated transmission in specific neuronal populations in the post-adolescent onset of psychosis
Final Report Abstract
A vast body of evidence supports a causal role of NMDAR-mediated glutamatergic dysfunction in triggering psychosis. However, the neuronal substrate and mechanisms are yet unknown. Previous genetic models of NMDAR hypofunction restricted to parvalbumin-positive interneurons indicate the necessity of an early postnatal impairment to trigger schizophrenia-like abnormalities, whereas the substrates of NMDAR-mediated psychosis at adolescent/adult stages are unknown. We analyzed the effect of the inducible ablation of NMDARs in ErbB4-expressing cells in mice during late adolescence using a pharmacogenetic approach. Interestingly, the tamoxifeninducible NMDAR deletion during this late developmental stage did not induce behavioral alterations resembling depression, schizophrenia or anxiety. Our data indicate that post-adolescent NMDAR deletion, even in a wider cell population than parvalbumin-positive interneurons, is not sufficient to generate behavioral abnormalities resembling psychiatric disorders. Other neuronal substrates may underlie post-adolescent NMDAR-driven psychosis. NMDAR agonists such as D-serine and rapastinel represent promising therapeutic alternatives in the treatment of psychosis with a more favourable side-effect profile than NMDAR antagonists also during neurodevelopment. Surprisingly, targeting microglia activation by minocycline aggravates perinatal neurotoxicity induced by NMDAR blockade, questioning ist uility as early intervention. Perinatal hypoxia as environmental risk factor induces long-term functional impairment of parvalbumin-positive interneurons and is influenced differentially by subunit- versus global NMDAR antagonists.
Publications
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(2016) Minocycline exacerbates apoptotic neurodegeneration induced by the NMDA receptor antagonist MK-801 in the early postnatal mouse brain. Eur Arch Psychiatry Clin Neurosci, 266:673-677
Inta I, Vogt MA, Vogel AS, Bettendorf M, Gass P, Inta D
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(2017) Modulation of NMDA receptors activity as a novel treatment option for depression: Current clinical evidence and therapeutic potential of Rapastinel (GLYX-13). Neuropsychiatr Dis Treat 13:973-980
Vasilescu AN, Schweinfurth N, Borgwardt S, Gass P, Lang UE, Inta D, Eckart S
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(2017) Puberty marks major changes in the hippocampal and cortical c-Fos activation pattern induced by NMDA receptor antagonists. Neuropharmacology 112:181-187
Inta I, Domonkos E, Pfeiffer N, Sprengel R, Bettendorf M, Lang UE, Inta D, Gass P
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(2018) Altered expression of schizophrenia-related genes in mice lacking mGlu5 receptors. Eur Arch Psychiatry Clin Neurosci. 268(1):77-87
Luoni A, Gass P, Brambilla P, Ruggeri M, Riva MA, Inta D
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(2018) Antagonism at the NR2B subunit of NMDA receptors induces increased connectivity of the prefrontal and subcortical regions regulating reward behavior. Psychopharmacology. 235:1055-1068
Gass N, Becker R, Markus Sack S, Schwarz AJ, Reinwald J, Alejandro Cosa- Linan A, Zheng L, Clemm von Hohenberg C, Inta D, Meyer-Lindenberg A, Weber-Fahr W, Gass P, Sartorius A
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(2018) Chronic treatment with fluoxetine or clozapine of socially isolated rats prevents subsector-specific reduction of parvalbumin-immunoreactive cells in the hippocampus. Neuroscience. 371:384-394
Filipovic D, Stanisavljevic A, Jasnic N, Bernardi R.E., Inta D, Peric I, Gass P
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(2018) Molecular and cellular dissection of NMDA receptor subtypes as antidepressant targets. Neurosci Biobehav Rev 84:352-358
Lang E, Mallien AS, Vasilescu AN, Hefter D, Luoni A, Riva MA, Borgwardt S, Sprengel R, Lang UE, Gass P, Inta D
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(2019) Altered prepulse inhibition of the acoustic startle response in BDNF-deficient mice in a model of early postnatal hypoxia: implications for schizophrenia. Eur Arch Psychiatry Clin Neurosci,269(4):439-447
Lima-Ojeda JM, Mallien AS, Brandwein C, Lang UE, Hefter D, Inta D
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(2021) Cre-Activation in ErbB4-Positive Neurons of Floxed Grin1/NMDA Receptor Mice Is Not Associated With Major Behavioral Impairment. Front Psychiatry. 12:750106
Mallien AS, Pfeiffer N, Vogt MA, Chourbaji S, Sprengel R, Gass P, Inta D
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(2021) Rapastinel alleviates the neurotoxic effect induced by NMDA receptor blockade in the early postnatal mouse brain. Eur Arch Psychiatry Clin Neurosci 271:1587-1591
Vasilescu AN, Mallien AS, Pfeiffer N, Lange UE, Gass P, Inta D
