The L-type Voltage-gated Calcium Channel Ca1.2 Mediates Fear Extinction and Modulates Synaptic Tone in the Lateral Amygdala

Overview

Journal Learn Mem

Specialty Neurology

Date 2017 Oct 18

PMID 29038219

Citations 9

Authors

Stephanie J Temme

Geoffrey G Murphy

Affiliations

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Abstract

L-type voltage-gated calcium channels (LVGCCs) have been implicated in both the formation and the reduction of fear through Pavlovian fear conditioning and extinction. Despite the implication of LVGCCs in fear learning and extinction, studies of the individual LVGCC subtypes, Ca1.2 and Ca1.3, using transgenic mice have failed to find a role of either subtype in fear extinction. This discontinuity between the pharmacological studies of LVGCCs and the studies investigating individual subtype contributions could be due to the limited neuronal deletion pattern of the Ca1.2 conditional knockout mice previously studied to excitatory neurons in the forebrain. To investigate the effects of deletion of Ca1.2 in all neuronal populations, we generated Ca1.2 conditional knockout mice using the synapsin1 promoter to drive Cre recombinase expression. Pan-neuronal deletion of Ca1.2 did not alter basal anxiety or fear learning. However, pan-neuronal deletion of Ca1.2 resulted in a significant deficit in extinction of contextual fear, implicating LVGCCs, specifically Ca1.2, in extinction learning. Further exploration on the effects of deletion of Ca1.2 on inhibitory and excitatory input onto the principle neurons of the lateral amygdala revealed a significant shift in inhibitory/excitatory balance. Together these data illustrate an important role of Ca1.2 in fear extinction and the synaptic regulation of activity within the amygdala.

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References

Hofmann S . Cognitive processes during fear acquisition and extinction in animals and humans: implications for exposure therapy of anxiety disorders. Clin Psychol Rev. 2007; 28(2):199-210. PMC: 2268629. DOI: 10.1016/j.cpr.2007.04.009. View

Cain C, Blouin A, Barad M . L-type voltage-gated calcium channels are required for extinction, but not for acquisition or expression, of conditional fear in mice. J Neurosci. 2002; 22(20):9113-21. PMC: 6757698. View

Herry C, Ciocchi S, Senn V, Demmou L, Muller C, Luthi A . Switching on and off fear by distinct neuronal circuits. Nature. 2008; 454(7204):600-6. DOI: 10.1038/nature07166. View

Xu W, Lipscombe D . Neuronal Ca(V)1.3alpha(1) L-type channels activate at relatively hyperpolarized membrane potentials and are incompletely inhibited by dihydropyridines. J Neurosci. 2001; 21(16):5944-51. PMC: 6763157. View

El Ganouni S, Tazi A, Hakkou F . Potential serotonergic interactions with the anxiolytic-like effects of calcium channel antagonists. Pharmacol Biochem Behav. 1998; 60(2):365-9. DOI: 10.1016/s0091-3057(98)00014-8. View

Maren S . Neurobiology of Pavlovian fear conditioning. Annu Rev Neurosci. 2001; 24:897-931. DOI: 10.1146/annurev.neuro.24.1.897. View

Gordon D, Heimberg R, Tellez M, Ismail A . A critical review of approaches to the treatment of dental anxiety in adults. J Anxiety Disord. 2013; 27(4):365-78. DOI: 10.1016/j.janxdis.2013.04.002. View

Thompson A, Duke R, Lummis S . Binding sites for bilobalide, diltiazem, ginkgolide, and picrotoxinin at the 5-HT3 receptor. Mol Pharmacol. 2011; 80(1):183-90. PMC: 3127528. DOI: 10.1124/mol.111.071415. View

Crawley J, Belknap J, Collins A, Crabbe J, Frankel W, Henderson N . Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology (Berl). 1997; 132(2):107-24. DOI: 10.1007/s002130050327. View

10.

Shaban H, Humeau Y, Herry C, Cassasus G, Shigemoto R, Ciocchi S . Generalization of amygdala LTP and conditioned fear in the absence of presynaptic inhibition. Nat Neurosci. 2006; 9(8):1028-35. DOI: 10.1038/nn1732. View

11.

Haji Abdolvahab M, Brinks V, Schellekens H . A modified immune tolerant mouse model to study the immunogenicity of recombinant human interferon beta. J Immunol Methods. 2014; 415:17-23. DOI: 10.1016/j.jim.2014.10.004. View

12.

Maren S . Auditory fear conditioning increases CS-elicited spike firing in lateral amygdala neurons even after extensive overtraining. Eur J Neurosci. 2000; 12(11):4047-54. DOI: 10.1046/j.1460-9568.2000.00281.x. View

13.

Furini C, Myskiw J, Izquierdo I . The learning of fear extinction. Neurosci Biobehav Rev. 2014; 47:670-83. DOI: 10.1016/j.neubiorev.2014.10.016. View

14.

Maren S, Fanselow M . The amygdala and fear conditioning: has the nut been cracked?. Neuron. 1996; 16(2):237-40. DOI: 10.1016/s0896-6273(00)80041-0. View

15.

Bauer E, Schafe G, LeDoux J . NMDA receptors and L-type voltage-gated calcium channels contribute to long-term potentiation and different components of fear memory formation in the lateral amygdala. J Neurosci. 2002; 22(12):5239-49. PMC: 6757716. View

16.

Barad M, Gean P, Lutz B . The role of the amygdala in the extinction of conditioned fear. Biol Psychiatry. 2006; 60(4):322-8. DOI: 10.1016/j.biopsych.2006.05.029. View

17.

McKinney B, Murphy G . The L-Type voltage-gated calcium channel Cav1.3 mediates consolidation, but not extinction, of contextually conditioned fear in mice. Learn Mem. 2006; 13(5):584-9. PMC: 1783612. DOI: 10.1101/lm.279006. View

18.

Blair H, Schafe G, Bauer E, Rodrigues S, LeDoux J . Synaptic plasticity in the lateral amygdala: a cellular hypothesis of fear conditioning. Learn Mem. 2001; 8(5):229-42. DOI: 10.1101/lm.30901. View

19.

Garakani A, Mathew S, Charney D . Neurobiology of anxiety disorders and implications for treatment. Mt Sinai J Med. 2007; 73(7):941-9. View

20.

Clapham D . Calcium signaling. Cell. 2007; 131(6):1047-58. DOI: 10.1016/j.cell.2007.11.028. View