Complex receptor mediation of acute ketamine application on in vitro gamma oscillations in mouse prefrontal cortex: modeling gamma band oscillation abnormalities in schizophrenia.
Schizophrenia (Sz), along with other neuropsychiatric disorders, is associated clinically with abnormalities in neocortical gamma frequency (30-80 Hz) oscillations. In Sz patients, these abnormalities include both increased and decreased gamma activity, and show a strong association with Sz symptoms. For several decades, administration of sub-anesthetic levels of ketamine has provided the most comprehensive experimental model of Sz-symptoms. While acute application of ketamine precipitates a psychotic-like state in a number of animal models, as well as humans, the underlying mechanisms behind this effect, including alteration of neuronal network properties, are incompletely understood, making an in vitro level analysis particularly important. Previous in vitro studies have had difficulty inducing gamma oscillations in neocortical slices maintained in submerged-type recording chambers necessary for visually guided whole-cell recordings from identified neurons. Consequently, here, we validated a modified method to evoke gamma oscillations using brief, focal application of the glutamate receptor agonist kainate (KA), in slices prepared from mice expressing green fluorescent protein in GABAergic interneurons (GAD67-GFP knock-in mice). Using this method, gamma oscillations dependent on activation of AMPA and GABA(A) receptors were reliably elicited in slices containing mouse prelimbic cortex, the rodent analogue of the human dorsolateral prefrontal cortex. Examining the effects of ketamine on this model, we found that bath application of ketamine significantly potentiated KA-elicited gamma power, an effect mimicked by selective NMDAR antagonists including a selective antagonist of NMDARs containing the NR2B subunit. Importantly, ketamine, unlike more specific NMDAR antagonists, also reduced the peak frequency of KA-elicited oscillatory activity. Our findings indicate that this effect is mediated not through NMDAR, but through slowing the decay kinetics of GABA(A) receptor-mediated inhibitory postsynaptic currents in identified GABAergic interneurons. These in vitro findings may help explain the complexities of gamma findings in clinical studies of Sz and prove useful in developing new therapeutic strategies.
Laboratory of Neuroscience, VA Boston Healthcare System and Department of Psychiatry, Harvard Medical School, 940 Belmont Street, Research 151C, Brockton, MA 02301, USA.
J M
JM
McNally
R W
RW
McCarley
J T
JT
McKenna
Y
Y
Yanagawa
R E
RE
Brown
D000818:Animals; D004195:Disease Models, Animal; D004569:Electroencephalography; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D059330:GABAergic Neurons / Q000187:drug effects*; D055879:Gene Knock-In Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D007150:Immunohistochemistry; D007395:Interneurons / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology*; D051379:Mice; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology; D011963:Receptors, GABA-A / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D012559:Schizophrenia / Q000503:physiopathology*
D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D049452:Green Fluorescent Proteins; D007649:Ketamine