Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice.
Excitotoxicity involves over activation of brain excitatory glutamate receptors and has been implicated in neurological, neurodegenerative and neuropsychiatric diseases. Metabolism of arachidonic acid (AA) through the phospholipase A(2) (PLA(2))/prostaglandin-endoperoxide synthase (PTGS) pathway is increased after excitotoxic stimulation. However, the individual roles of the PTGS isoforms in this process are not well established. We assessed the role of the PTGS isoforms in the process of excitotoxicity by exposing mice deficient in either PTGS-1 (PTGS-1(-/-)) or PTGS-2 (PTGS-2(-/-)) to the prototypic excitotoxin, kainic acid (KA). Seizure intensity and neuronal damage were significantly elevated in KA-exposed PTGS-2(-/-), but not in PTGS-1(-/-), mice. The increased susceptibility was not associated with an alteration in KA receptor binding activity or mediated through the CB1 endocannabinoid receptor. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was decreased in the CA1 pyramidal neurons of PTGS-2(-/-) mice, suggesting an alteration of GABAergic function. In wild-type mice, six weeks treatment with the PTGS-2 selective inhibitor celecoxib recapitulated the increased susceptibility to KA-induced excitotoxicity observed in PTGS-2(-/-) mice, further supporting the role of PTGS-2 in the excitotoxic process. The increased susceptibility to KA was also associated with decreased brain levels of PGE(2), a biomarker of PTGS-2 activity. Our results suggest that PTGS-2 activity and its specific products may modulate neuronal excitability by affecting GABAergic neurotransmission. Further, inhibition of PTGS-2, but not PTGS-1, may increase the susceptibility to seizures.
Toscano
Christopher D
CD
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, 9 Memorial Drive, Bethesda, MD 20892, USA.
Ueda
Yumi
Y
Tomita
York A
YA
Vicini
Stefano
S
Bosetti
Francesca
F
D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D000068579:Celecoxib; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D051545:Cyclooxygenase 1 / Q000172:deficiency; D051546:Cyclooxygenase 2 / Q000172:deficiency*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006624:Hippocampus / Q000473:pathology; D007608:Kainic Acid; D008297:Male; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D010880:Piperidines / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D012640:Seizures / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D018709:Statistics, Nonparametric; D013449:Sulfonamides / Q000097:blood / Q000494:pharmacology; D009435:Synaptic Transmission / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D008565:Membrane Proteins; D010880:Piperidines; D011720:Pyrazoles; D013449:Sulfonamides; C103505:AM 251; D005680:gamma-Aminobutyric Acid; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D000068579:Celecoxib; D007608:Kainic Acid