title: Suppression of PKR promotes network excitability and enhanced cognition by interferon-γ-mediated disinhibition.
abstract: The double-stranded RNA-activated protein kinase (PKR) was originally identified as a sensor of virus infection, but its function in the brain remains unknown. Here, we report that the lack of PKR enhances learning and memory in several behavioral tasks while increasing network excitability. In addition, loss of PKR increases the late phase of long-lasting synaptic potentiation (L-LTP) in hippocampal slices. These effects are caused by an interferon-γ (IFN-γ)-mediated selective reduction in GABAergic synaptic action. Together, our results reveal that PKR finely tunes the network activity that must be maintained while storing a given episode during learning. Because PKR activity is altered in several neurological disorders, this kinase presents a promising new target for the treatment of cognitive dysfunction. As a first step in this direction, we show that a selective PKR inhibitor replicates the Pkr(-/-) phenotype in WT mice, enhancing long-term memory storage and L-LTP.
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ping Jun
authors.initials: PJ
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Djanenkhodja
authors.initials: D
authors.lastname: Kalikulov
authors.forename: Jong W
authors.initials: JW
authors.lastname: Yoo
authors.forename: Andon N
authors.initials: AN
authors.lastname: Placzek
authors.forename: Loredana
authors.initials: L
authors.lastname: Stoica
authors.forename: Hongyi
authors.initials: H
authors.lastname: Zhou
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Friedlander
authors.forename: Krešimir
authors.initials: K
authors.lastname: Krnjević
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Noebels
authors.forename: Mauro
authors.initials: M
authors.lastname: Costa-Mattioli
mesh_terms: D000818:Animals; D004594:Electrophysiology; D006624:Hippocampus / Q000502:physiology*; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D017774:Long-Term Potentiation; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D013569:Synapses; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D007371:Interferon-gamma; D019892:eIF-2 Kinase