title: Glutamate receptor subtypes mediating synaptic activation of prefrontal cortex neurons: relevance for schizophrenia.
abstract: Schizophrenia may involve hypofunction of NMDA receptor (NMDAR)-mediated signaling, and alterations 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 NMDAR activation and that, consequently, FS neuron dysfunction in schizophrenia is secondary to NMDAR hypofunction. However, NMDARs are abundant in synapses onto PFC pyramidal neurons; thus, a key question is whether FS neuron or pyramidal cell activation is more dependent on NMDARs. We examined the AMPAR and NMDAR 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 NMDAR contribution, whereas in pyramidal cells, EPSCs were significantly prolonged by NMDAR-mediated currents. Moreover, the AMPAR/NMDAR EPSC ratio was higher in FS cells. NMDAR antagonists decreased EPSPs and EPSP-spike coupling more strongly in pyramidal cells than in FS neurons, showing that FS neuron activation is less NMDAR dependent than pyramidal cell excitation. The precise 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 AMPAR-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 NMDAR hypofunction to alterations of FS neurons in schizophrenia.
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Diana C
authors.initials: DC
authors.lastname: Rotaru
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshino
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
authors.forename: G Bard
authors.initials: GB
authors.lastname: Ermentrout
authors.forename: Guillermo
authors.initials: G
authors.lastname: Gonzalez-Burgos
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001703:Biophysics / Q000379:methods; D003198:Computer Simulation; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009474:Neurons / Q000145:classification / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D017397:Prefrontal Cortex / Q000166:cytology*; D011336:Probability; D011724:Pyridazines / Q000494:pharmacology; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013569:Synapses / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D011724:Pyridazines; D017470:Receptors, Glutamate; C049853:gabazine; C013411:biocytin; D008239:Lysine