Abstract
Cognitive deficits in schizophrenia include impairments at automatic, preattentive stages of sensory information processing. These deficits are evident in the prepulse inhibition- (PPI) and habituation of the auditory startle response paradigm, the paired tone paradigm in the EEG, and the peak recovery function of auditory evoked potentials (AEP). Administration of NMDA receptor antagonists reliably disrupts PPI and habituation of the startle, but not gating of AEPs in rodents. In the peak recovery paradigm, patients with schizophrenia and primates treated with NMDA receptor antagonists show reduced maximal response at long interstimulus intervals (ISI), but normal responses at short ISIs. Thus reduced NMDA receptor signalling may underlie alterations in these paradigms observed in schizophrenia. We tested the paradigms mentioned in mouse mutants with reduced expression of the NR1 subunit of the NMDA receptor (N=15) and their wild-type littermates (N=16). The NR1 mutant mice showed impaired habituation and PPI of the auditory startle response, as well as impaired gating in the paired tone paradigm. Deficits between the two gating measures did not correlate, corroborating previous evidence that these paradigms measure distinct processes. In the peak recovery paradigm, the NR1 mutants showed increased responses of the AEPs P1 and N1 at short ISIs but no difference between groups were observed at long ISIs. In conclusion, the NR1 hypomorphic mice modelled sensory and sensorimotor gating and startle habituation deficits observed in schizophrenia, but failed to model alterations in the peak recovery function.
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Acknowledgements
We thank Professor Beverly Koller, Department of Genetics, UNC Chapel Hill, USA, for providing the NMDA receptor mutants.
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None of the authors have to disclose a potential conflict of interest that might bias the presented work in this manuscript. This work was supported by grants from the Swiss National Science Foundation, the National Alliance for Research on Schizophrenia and Depression (NARSAD) to Dr Umbricht and from the ‘National Competence Center for Research (NCCR) ‘Neural Plasticity and Repair’ to Dr Lipp and Dr Fritschy. Dr Umbricht is employed by Novartis, Pharma AG, Switzerland.
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Bickel, S., Lipp, HP. & Umbricht, D. Early Auditory Sensory Processing Deficits in Mouse Mutants with Reduced NMDA Receptor Function. Neuropsychopharmacol 33, 1680–1689 (2008). https://doi.org/10.1038/sj.npp.1301536
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DOI: https://doi.org/10.1038/sj.npp.1301536
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