title: Rhythmic theta and delta activity of cortical and hippocampal neuronal networks in genetically or pharmacologically induced N-methyl-D-aspartate receptor hypofunction under urethane anesthesia.
abstract: N-Methyl-d-aspartate receptor (NMDAR) antagonists mimic several symptoms of schizophrenia in healthy subjects, and are used in preclinical disease models. In the present study, the impact of pharmacologically and genetically induced NMDAR hypofunction was assessed in rats and mice, including the NMDAR hypomorphic (Grin1) mice, with respect to neuronal network oscillations. Field potentials were recorded from the ventro-medial prefrontal cortex (mPFC) and hippocampus (CA1) in rats, as well as spontaneous and elicited hippocampal theta oscillations in response to brainstem stimulation in Grin1 and wild-type (WT) mice under anesthesia. Effects of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor positive allosteric modulator LY451395 were tested in Grin1 mice and in WT mice following an MK-801 challenge. Recordings from the mPFC and CA1 in rats revealed regular delta and theta oscillations, respectively, which were disrupted by MK-801. In WT mice, MK-801 reduced both spontaneous and elicited hippocampal theta power. Age-matched Grin1 mice showed abnormal hippocampal field potentials, resembling activity seen after administration of MK-801 in WT mice, but also epileptiform discharges. Administration of MK-801 achieved high levels of NMDAR occupancy (84-98%) in both rats and mice, which is comparable to the approximately 90-95% reduction of NMDAR expression in the Grin1 mouse. Impaired elicited CA1 theta oscillation in WT mice following MK-801, or Grin1 mice was significantly improved by LY451395. These findings demonstrate similar, although not identical, changes in network activity following reduction in functioning NMDARs induced by acute pharmacological or genetic manipulations, indicating that these novel neurophysiological models could be used in evaluating drug candidates targeting glutamate neurotransmission.
authors: Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. tamas.kiss@pfizer.com
authors: T
authors: T
authors: Kiss
authors: J
authors: J
authors: Feng
authors: W E
authors: WE
authors: Hoffmann
authors: C L
authors: CL
authors: Shaffer
authors: M
authors: M
authors: Hajós
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics*; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D003700:Delta Rhythm / Q000187:drug effects* / Q000235:genetics; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004558:Electric Stimulation; D004569:Electroencephalography; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate; D013449:Sulfonamides / Q000494:pharmacology; D013826:Theta Rhythm / Q000187:drug effects* / Q000235:genetics; D014520:Urethane / Q000494:pharmacology*
chemical_list: D001713:Biphenyl Compounds; D002352:Carrier Proteins; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C121673:Gprin1 protein, mouse; C512030:N-((2-(4'-(2-(methylsulfonyl)amino)ethyl)(1,1'-biphenyl)-4-yl)propyl)-2-propanesulfonamide; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D013449:Sulfonamides; D014520:Urethane; D016291:Dizocilpine Maleate