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  • Neonatal NMDA receptor blockade disrupts spike timing and glutamatergic synapses in fast spiking interneurons in a NMDA receptor hypofunction model of schizophrenia.

Neonatal NMDA receptor blockade disrupts spike timing and glutamatergic synapses in fast spiking interneurons in a NMDA receptor hypofunction model of schizophrenia.

PloS one (2014-10-08)
Kevin S Jones, Joshua G Corbin, Molly M Huntsman
ABSTRACT

The dysfunction of parvalbumin-positive, fast-spiking interneurons (FSI) is considered a primary contributor to the pathophysiology of schizophrenia (SZ), but deficits in FSI physiology have not been explicitly characterized. We show for the first time, that a widely-employed model of schizophrenia minimizes first spike latency and increases GluN2B-mediated current in neocortical FSIs. The reduction in FSI first-spike latency coincides with reduced expression of the Kv1.1 potassium channel subunit which provides a biophysical explanation for the abnormal spiking behavior. Similarly, the increase in NMDA current coincides with enhanced expression of the GluN2B NMDA receptor subunit, specifically in FSIs. In this study mice were treated with the NMDA receptor antagonist, MK-801, during the first week of life. During adolescence, we detected reduced spike latency and increased GluN2B-mediated NMDA current in FSIs, which suggests transient disruption of NMDA signaling during neonatal development exerts lasting changes in the cellular and synaptic physiology of neocortical FSIs. Overall, we propose these physiological disturbances represent a general impairment to the physiological maturation of FSIs which may contribute to schizophrenia-like behaviors produced by this model.

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