Archival ReportG Protein-Gated K+ Channel Ablation in Forebrain Pyramidal Neurons Selectively Impairs Fear Learning
Section snippets
Animals
All animal experimentation was approved by the Institutional Animal Care and Use Committee at the University of Minnesota. Constitutive Girk2–/– and Girk2flox/flox mice were generated as described (38, 39). Girk2flox/flox mice were bred with B6.Cg-Tg(Camk2a-cre)T29-1Stl/J (calcium/calmodulin-dependent protein kinase II [CaMKII]-Cre) and B6N.Cg-Gad2tm2(cre)Zjh/J (glutamic acid decarboxylase [GAD]-Cre) (The Jackson Laboratory, Bar Harbor, Maine) to generate CaMKII-Cre:Girk2flox/flox and GAD-Cre:
Delay Fear Conditioning in Constitutive Girk2–/– Mice
We began by testing constitutive Girk2–/– mice in a delay fear conditioning paradigm that permits evaluation of both dorsal hippocampal-dependent (context) and independent (cue) associative learning and memory (6, 45, 46). Freezing triggered by the second and third conditioning tones was significantly reduced in Girk2–/– mice relative to wild-type control mice (Figure 1A), as was total freezing measured during conditioning (Figure 1B). On memory test day (24 hours later), Girk2–/– mice
Discussion
Mouse models exhibiting enhanced GIRK-dependent signaling show altered learning and memory (19, 32, 33, 34). Neither the behavioral impact of GIRK channel ablation nor the cell-specific contribution of GIRK channels to hippocampal-dependent cognition, however, has been examined. Here, we evaluated the impact of cell-specific ablation of GIRK channels on associative learning using a recently developed conditional Girk2 knockout mouse. We found that the loss of GIRK channels in forebrain
Acknowledgments and Disclosures
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).
We thank Matt Novitch for assistance with the mouse behavioral testing and Jennifer Kutzke and Alex Shnaydruk for exceptional care of the mouse colony.
The authors report no biomedical financial interests or potential conflicts of interest.
References (82)
- et al.
An fMRI investigation of memory encoding in PTSD: Influence of symptom severity
Neuropsychologia
(2008) - et al.
Stress, PTSD, and dementia
Alzheimers Dement
(2014) - et al.
Pyramidal cell selective ablation of N-methyl-d-aspartate receptor 1 causes increase in cellular and network excitability
Biol Psychiatry
(2015) - et al.
Are the dorsal and ventral hippocampus functionally distinct structures?
Neuron
(2010) - et al.
The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory
Cell
(1996) - et al.
Hippocampal long-term depression: Master or minion in declarative memory processes?
Trends Neurosci
(2007) - et al.
5-HT1A receptor agonist affects fear conditioning through stimulations of the postsynaptic 5-HT1A receptors in the hippocampus and amygdala
Eur J Pharmacol
(2006) - et al.
A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory
Trends Pharmacol Sci
(2008) - et al.
G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons
Neuron
(1997) - et al.
New insights into the therapeutic potential of GIRK channels
Trends Neurosci
(2014)
Epistatic interaction of CREB1 and KCNJ6 on rumination and negative emotionality
Eur Neuropsychopharmacol
Deletion of chromosome 21 disturbs human brain morphogenesis
Genet Med
Molecular cytogenetic characterization of an interstitial deletion of chromosome 21 (21q22.13q22.3) in a patient with dysmorphic features, intellectual disability and severe generalized epilepsy
Eur J Med Genet
GABAB-GIRK2- mediated signaling in Down syndrome
Adv Pharmacol
Abnormal synaptic plasticity in the Ts1Cje segmental trisomy 16 mouse model of Down syndrome
Neuropharmacology
Repeated cocaine weakens GABA(B)-GIRK signaling in layer 5/6 pyramidal neurons in the prelimbic cortex
Neuron
Sex differences in GABABR-GIRK signaling in layer 5/6 pyramidal neurons of the mouse prelimbic cortex
Neuropharmacology
GIRK2 deficient mice. Evidence for hyperactivity and reduced anxiety
Physiol Behav
A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex
Neuron
CaMKII regulation in information processing and storage
Trends Neurosci
DCC expression by neurons regulates synaptic plasticity in the adult brain
Cell Rep
Corticosteroids and cognition
J Psychiatr Res
Glucocorticoids are necessary for enhancing the acquisition of associative memories after acute stressful experience
Horm Behav
Effects of corticosterone on contextual fear consolidation in intact and ovariectomized female rats
Neurobiol Learn Mem
Chronic stress shifts the GABA reversal potential in the hippocampus and increases seizure susceptibility
Epilepsy Res
5-HT1A and 5-HT4 receptor colocalization on hippocampal pyramidal cells
Neuropharmacology
Major depressive disorder is associated with broad impairments on neuropsychological measures of executive function: A meta-analysis and review
Psychol Bull
Role of metal ions in the cognitive decline of Down syndrome
Front Aging Neurosci
Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning
Science
Requirement for hippocampal CA3 NMDA receptors in associative memory recall
Science
Regulation of hippocampus-dependent memory by the zinc finger protein Zbtb20 in mature CA1 neurons
J Physiol
Learning induces long-term potentiation in the hippocampus
Science
Baclofen infused in rat hippocampal formation impairs spatial learning
Hippocampus
Effects of intrahippocampal injection of GABAergic drugs on memory retention of passive avoidance learning in rats
J Psychopharmacol
Involvement of the 5-HT1A receptors in classical fear conditioning in C57BL/6J mice
J Neurosci
GABA(B(1)) receptor isoforms differentially mediate the acquisition and extinction of aversive taste memories
J Neurosci
Deficits in cognition and synaptic plasticity in a mouse model of Down syndrome ameliorated by GABAB receptor antagonists
J Neurosci
Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease
Nat Rev Neurosci
IRK(1-3) and GIRK(1-4) inwardly rectifying K+ channel mRNAs are differentially expressed in the adult rat brain
J Neurosci
Molecular and cellular diversity of neuronal G-protein-gated potassium channels
J Neurosci
Genome-wide association study of schizophrenia in Japanese population
PLoS One
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