title: G Protein-Gated K+Channel Ablation in Forebrain Pyramidal Neurons Selectively Impairs Fear Learning.
abstract: Cognitive dysfunction occurs in many debilitating conditions including Alzheimer's disease, Down syndrome, schizophrenia, and mood disorders. The dorsal hippocampus is a critical locus of cognitive processes linked to spatial and contextual learning. G protein-gated inwardly rectifying potassium ion (GIRK/Kir3) channels, which mediate the postsynaptic inhibitory effect of many neurotransmitters, have been implicated in hippocampal-dependent cognition. Available evidence, however, derives primarily from constitutive gain-of-function models that lack cellular specificity.
  
  
  
  We used constitutive and neuron-specific gene ablation models targeting an integral subunit of neuronal GIRK channels (GIRK2) to probe the impact of GIRK channels on associative learning and memory.
  
  
  
  Constitutive Girk2-/-mice exhibited a striking deficit in hippocampal-dependent (contextual) and hippocampal-independent (cue) fear conditioning. Mice lacking GIRK2 in gamma-aminobutyric acid neurons (GAD-Cre:Girk2flox/floxmice) exhibited a clear deficit in GIRK-dependent signaling in dorsal hippocampal gamma-aminobutyric acid neurons but no evident behavioral phenotype. Mice lacking GIRK2 in forebrain pyramidal neurons (CaMKII-Cre(+):Girk2flox/floxmice) exhibited diminished GIRK-dependent signaling in dorsal, but not ventral, hippocampal pyramidal neurons. CaMKII-Cre(+):Girk2flox/floxmice also displayed a selective impairment in contextual fear conditioning, as both cue fear and spatial learning were intact in these mice. Finally, loss of GIRK2 in forebrain pyramidal neurons correlated with enhanced long-term depression and blunted depotentiation of long-term potentiation at the Schaffer collateral/cornu ammonis 1 synapse in the dorsal hippocampus.
  
  
  
  Our data suggest that GIRK channels in dorsal hippocampal pyramidal neurons are necessary for normal learning involving aversive stimuli and support the contention that dysregulation of GIRK-dependent signaling may underlie cognitive dysfunction in some disorders.
authors.affiliation: Departments of Pharmacologyand Neuroscience, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Victoria
authors.affiliation: Departments of Pharmacologyand Neuroscience, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Marron Fernandez de Velasco
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Olga
authors.initials: O
authors.lastname: Ostrovskaya
authors.affiliation: Departments of Pharmacologyand Neuroscience, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Stefania
authors.initials: S
authors.lastname: Metzger
authors.affiliation: Departments of Pharmacologyand Neuroscience, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Zhilian
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Departments of Pharmacologyand Neuroscience, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Lydia
authors.initials: L
authors.lastname: Kotecki
authors.affiliation: Departments of Pharmacologyand Neuroscience, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Benneyworth
authors.affiliation: Departments of Pharmacologyand Neuroscience, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Anastasia N
authors.initials: AN
authors.lastname: Zink
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Kirill A
authors.initials: KA
authors.lastname: Martemyanov
authors.affiliation: Departments of Pharmacologyand Neuroscience, University of Minnesota, Minneapolis, Minnesota. Electronic address: wickm002@umn.edu.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wickman
mesh_terms: D000818:Animals; D060825:Cognitive Dysfunction / Q000378:metabolism* / Q000503:physiopathology; D003213:Conditioning, Psychological; D005239:Fear / Q000502:physiology*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D007858:Learning / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology*; D017966:Pyramidal Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497069:Kcnj6 protein, mouse
keywords: Anxiety; Hippocampus; Kir3; Learning; Memory; Synaptic plasticity