Abstract
Schizophrenia is a disabling psychiatric disease characterized by symptoms including hallucinations, delusions, social withdrawal, loss of pleasure, and inappropriate affect. Although schizophrenia is marked by dysfunction in dopaminergic and glutamatergic signaling, it is not presently clear how these dysfunctions give rise to symptoms. The aberrant salience hypothesis of schizophrenia argues that abnormal attribution of motivational salience to stimuli is one of the main contributors to both positive and negative symptoms of schizophrenia. The proposed mechanisms for this hypothesis are overactive striatal dopaminergic and hypoactive glutamatergic signaling. The current study assessed salience attribution in mice (n = 72) using an oddball paradigm in which an infrequent stimulus either co-occurred with shock (conditioned group) or was presented alone (non-conditioned group). Behavioral response (freezing) and electroencephalogram (whole brain and amygdala) were used to assess salience attribution. Mice with pyramidal cell-selective knockout of ionotropic glutamate receptors (GluN1) were used to reproduce a prominent physiological change involved in schizophrenia. Non-conditioned knockout mice froze significantly more in response to the unpaired stimulus than non-conditioned wild-type mice, suggesting that this irrelevant cue acquired motivational salience for the knockouts. In accordance with this finding, low-frequency event-related spectral perturbation was significantly increased in non-conditioned knockout mice relative to both conditioned knockout and non-conditioned wild-type mice. These results suggest that pyramidal cell-selective GluN1 knockout leads to inappropriate attribution of salience for irrelevant stimuli as characterized by abnormalities in both behavior and brain circuitry functions.
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Funding for the current study was provided by 1-P50-MH-096891-01.
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Steven Siegel reports grant support from Astellas and Merck that is unrelated to the content of this paper. Alexandra Forrest, Jakyung Bang, Jonathan Bloom, Rebecca Zhang, Christopher Gajewski, and Matthew Luminais were undergraduate students supported on the Education Core of this P50. Mary McMullen, Yuling Liang, and Robert Featherstone have no disclosures.
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Forrest, A.D., Bang, J., Featherstone, R.E. et al. Pyramidal cell-selective GluN1 knockout causes impairments in salience attribution and related EEG activity. Exp Brain Res 236, 837–846 (2018). https://doi.org/10.1007/s00221-017-5152-8
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DOI: https://doi.org/10.1007/s00221-017-5152-8