G Protein-Gated K+ Channel Ablation in Forebrain Pyramidal Neurons Selectively Impairs Fear Learning

Nicole C. Victoria, Ezequiel Marron Fernandez de Velasco, Olga Ostrovskaya, Stefania Metzger, Zhilian Xia, Lydia Kotecki, Michael A. Benneyworth, Anastasia N. Zink, Kirill A. Martemyanov, Kevin Wickman

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Background 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. Methods 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. Results 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/flox mice) 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/flox mice) exhibited diminished GIRK-dependent signaling in dorsal, but not ventral, hippocampal pyramidal neurons. CaMKII-Cre(+):Girk2flox/flox mice 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. Conclusions 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.

Original languageEnglish (US)
Pages (from-to)796-806
Number of pages11
JournalBiological psychiatry
Issue number10
StatePublished - Nov 15 2016

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grant Nos. MH106190 and DA007234 (NCV), DA007234 (ANZ), DA007097 (LLK), NS062158 (SM and MAB), DA036596 and DA026405 (KAM), and DA034696 and MH061933 (KW).

Publisher Copyright:
© 2015 Society of Biological Psychiatry


  • Anxiety
  • Hippocampus
  • Kir3
  • Learning
  • Memory
  • Synaptic plasticity


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