Feature Finding Title
Schizophrenia may involve hypofunction of NMDA receptor-mediated signaling, and dysfunction in parvalbumin-positive fast-spiking (FS) GABA neurons that may cause abnormal gamma oscillations. It was recently hypothesized that prefrontal cortex (PFC) FS neuron activity is highly dependent on NMDA receptor activation and that, consequently, FS neuron dysfunction in schizophrenia is secondary to NMDA receptor hypofunction. However, NMDA receptors are abundant in synapses onto PFC pyramidal neurons, thus a key question is whether FS neuron or pyramidal cell activation is more dependent on NMDA receptors. We examined the AMPA receptor and NMDA receptor contribution to synaptic activation of FS neurons and pyramidal cells in the PFC of adult mice. In FS neurons, EPSCs had fast decay and weak NMDA receptor contribution whereas in pyramidal cells EPSCs were significantly prolonged by NMDA receptor-mediated currents. Moreover, the AMPA receptor/NMDA receptor EPSC ratio was higher in FS cells (Figure). NMDA receptor antagonists decreased EPSPs and EPSP-spike coupling more strongly in pyramidal cells than in FS neurons, showing that FS neuron activation is less NMDA receptor-dependent than pyramidal cell excitation. The rapid EPSP-spike coupling produced by fast-decaying EPSCs in FS cells may be important for network mechanisms of gamma oscillations based on feedback inhibition. To test this possibility, we used simulations in a computational network of reciprocally-connected FS neurons and pyramidal cells and found that brief AMPA receptor-mediated FS neuron activation is crucial to synchronize, via feedback inhibition, pyramidal cells in the gamma frequency band. Our results raise interesting questions about the mechanisms that might link NMDA receptor hypofunction to alterations of FS neurons in schizophrenia.
Rotaru DC, Yoshino H, Lewis DA, Ermentrout GB, Gonzalez-Burgos G: Glutamate receptor subtypes mediating synaptic activation of prefrontal cortex neurons: relevance for schizophrenia. J Neurosci, 31:142-156, 2011.

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
3811 O'Hara Street, Biomedical Science Tower W1654
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