title: Mitogen-Activated Protein Kinase Phosphatase-2 Deletion Impairs Synaptic Plasticity and Hippocampal-Dependent Memory.
abstract: Mitogen-activated protein kinases (MAPKs) regulate brain function and their dysfunction is implicated in a number of brain disorders, including Alzheimer's disease. Thus, there is great interest in understanding the signaling systems that control MAPK function. One family of proteins that contribute to this process, the mitogen-activated protein kinase phosphatases (MKPs), directly inactivate MAPKs through dephosphorylation. Recent studies have identified novel functions of MKPs in development, the immune system, and cancer. However, a significant gap in our knowledge remains in relation to their role in brain functioning. Here, using transgenic mice where the Dusp4 gene encoding MKP-2 has been knocked out (MKP-2(-/-) mice), we show that long-term potentiation is impaired in MKP-2(-/-) mice compared with MKP-2(+/+) controls whereas neuronal excitability, evoked synaptic transmission, and paired-pulse facilitation remain unaltered. Furthermore, spontaneous EPSC (sEPSC) frequency was increased in acute slices and primary hippocampal cultures prepared from MKP-2(-/-) mice with no effect on EPSC amplitude observed. An increase in synapse number was evident in primary hippocampal cultures, which may account for the increase in sEPSC frequency. In addition, no change in ERK activity was detected in both brain tissue and primary hippocampal cultures, suggesting that the effects of MKP-2 deletion were MAPK independent. Consistent with these alterations in hippocampal function, MKP-2(-/-) mice show deficits in spatial reference and working memory when investigated using the Morris water maze. These data show that MKP-2 plays a role in regulating hippocampal function and that this effect may be independent of MAPK signaling.
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, United Kingdom, and.
authors.forename: Nor Zaihana
authors.initials: NZ
authors.lastname: Abdul Rahman
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, United Kingdom, and.
authors.forename: Sam M
authors.initials: SM
authors.lastname: Greenwood
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, United Kingdom, and.
authors.forename: Ros R
authors.initials: RR
authors.lastname: Brett
authors.affiliation: Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Tossell
authors.affiliation: Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.
authors.forename: Mark A
authors.identifier: http://orcid.org/0000-0002-1730-3353
authors.initials: MA
authors.lastname: Ungless
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, United Kingdom, and.
authors.forename: Robin
authors.initials: R
authors.lastname: Plevin
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, United Kingdom, and trevor.bushell@strath.ac.uk.
authors.forename: Trevor J
authors.identifier: http://orcid.org/0000-0003-4145-9670
authors.initials: TJ
authors.lastname: Bushell
mesh_terms: D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D017353:Gene Deletion; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology*; D009924:Organ Culture Techniques; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency* / Q000235:genetics
chemical_list: C522186:Dusp4 protein, mouse; D017027:Protein Tyrosine Phosphatases
keywords: MAPK; MKP-2; hippocampal-dependent memory; sEPSC; synaptic plasticity