Impaired cognition, sensorimotor gating, and hippocampal long-term depression in mice lacking the prostaglandin E2 EP2 receptor.
Cyclooxygenase-2 (COX-2) is a neuronal immediate early gene that is regulated by N-methyl d aspartate (NMDA) receptor activity. COX-2 enzymatic activity catalyzes the first committed step in prostaglandin synthesis. Recent studies demonstrate an emerging role for the downstream PGE(2) EP2 receptor in diverse models of activity-dependent synaptic plasticity and a significant function in models of neurological disease including cerebral ischemia, Familial Alzheimer's disease, and Familial amyotrophic lateral sclerosis. Little is known, however, about the normal function of the EP2 receptor in behavior and cognition. Here we report that deletion of the EP2 receptor leads to significant cognitive deficits in standard tests of fear and social memory. EP2-/- mice also demonstrated impaired prepulse inhibition (PPI) and heightened anxiety, but normal startle reactivity, exploratory behavior, and spatial reference memory. This complex behavioral phenotype of EP2-/- mice was associated with a deficit in long-term depression (LTD) in hippocampus. Our findings suggest that PGE(2) signaling via the EP2 receptors plays an important role in cognitive and emotional behaviors that recapitulate some aspects of human psychopathology related to schizophrenia.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. asavone1@jhmi.edu
A
A
Savonenko
P
P
Munoz
T
T
Melnikova
Q
Q
Wang
X
X
Liang
R M
RM
Breyer
T J
TJ
Montine
A
A
Kirkwood
K
K
Andreasson
D000704:Analysis of Variance; D000818:Animals; D001288:Attention / Q000502:physiology; D001362:Avoidance Learning / Q000502:physiology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003072:Cognition Disorders / Q000235:genetics*; D003712:Dendrites / Q000473:pathology; D004192:Discrimination, Psychological; D000076122:Disks Large Homolog 4 Protein; D004597:Electroshock / Q000379:methods; D005106:Exploratory Behavior / Q000502:physiology; D051528:Guanylate Kinases; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D066298:In Vitro Techniques; D007266:Inhibition, Psychological; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000235:genetics*; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009483:Neuropsychological Tests; D009812:Odorants; D018078:Receptors, Prostaglandin E / Q000172:deficiency*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D055139:Sensory Gating / Q000235:genetics*; D012919:Social Behavior; D013037:Spatial Behavior / Q000502:physiology
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C545644:PTGER2 protein, human; C545645:Ptger2 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D002795:Choline O-Acetyltransferase; D051528:Guanylate Kinases