L-type voltage-gated calcium channels in conditioned fear: A genetic and pharmacological analysis

Abstract

Using pharmacological approaches, others have suggested that L-type voltage-gated calcium channels (L-VGCCs) mediate both consolidation and extinction of conditioned fear. In the absence of L-VGCC isoform-specific antagonists, we have begun to investigate the subtype-specific role of LVGCCs in consolidation and extinction of conditioned fear using a molecular genetics approach. Previously, we used this approach to demonstrate that the Ca v 1.3 isoform mediates consolidation, but not extinction, of contextually conditioned fear. Here, we used mice in which the gene for the L-VGCC pore-forming subunit Ca v 1.2 was conditionally deleted in forebrain excitatory neurons (Ca v 1.2 cKO mice) to address the role of Ca v 1.2 in consolidation and extinction of conditioned fear. We demonstrate that Ca v 1.2 cKO mice consolidate and extinguish conditioned fear as well as control littermates. These data suggest that Ca v 1.2 is not critical for these processes and together with our previous data argue against a role for either of the brain-expressed L-VGCCs (Ca v 1.2 or Ca v 1.3) in extinction of conditioned fear. Additionally, we present data demonstrating that the L-VGCC antagonist nifedipine, which has been used in previous conditioned fear extinction studies, impairs locomotion, and induces an aversive state. We further demonstrate that this aversive state can enter into associations with conditioned stimuli that are present at the time that it is experienced, suggesting that previous studies using nifedipine were likely confounded by drug toxicity. Taken together, our genetic and pharmacological data argue against a role for Ca v 1.2 in consolidation of conditioned fear as well as a role for L-VGCCs in extinction of conditioned fear.Pavlovian fear conditioning is a popular paradigm for both the study of associative learning (Fanselow and Poulos 2005) and modeling anxiety disorders (Delgado et al. 2006;Hofmann 2007). In this paradigm, an association between a conditional stimulus (CS) and an aversive unconditional stimulus (US) is acquired through pairing the CS with the US. Learning of this association is identified by the emergence of new responses to the CS, termed conditioned fear responses. The process by which this learning is transformed into a stable long-term memory with the

Rethinking the role of L-type voltage-gated calcium channels in fear memory extinction

“…Next, Waltereit et al (2008) examine locomotor activity and rearing behavior in mice injected with nifedipine. In agreement with the findings of McKinney et al (2008) and Busquet et al (2008), they observe decreases in locomotor activity and a complete loss of rearing behavior that lasts up to 4 h after s.c. administration of nifedipine. Further, both i.p.…”

“…However, in that study, deletion of Ca v 1.3 had no effect on fear extinction; Ca v 1.3 knockout mice show normal within-session extinction and intact long-term recall of extinction 24 h later (McKinney and Murphy 2006). In the present article, McKinney et al (2008) examine the role of Ca v 1.2 in fear memory extinction. A recent study found that deletion of Ca v 1.2 impairs spatial learning and the L-VGCC-dependent form of LTP in the hippocampus (Moosmang et al 2005).…”

“…Surprisingly, however, McKinney et al (2008) find that mice lacking Ca v 1.2 in the forebrain have intact acquisition, consolidation, and extinction of fear memory. Thus, using a genetic approach, forebrainexpressed Ca v 1.3 appears necessary for fear memory consolidation, but neither Ca v 1.3 nor Ca v 1.2 appears to be necessary, at least in isolation, for fear memory extinction.Turning to a pharmacological analysis, McKinney et al (2008) next revisit the question of whether L-VGCC antagonists impair fear extinction, and, if so, why this method of manipulating L-VGCCs is so much more effective than using a molecular genetic approach. They first verify that systemic administration of a dose of nifedipine that has been used in previous experiments (Cain et al 2002(Cain et al , 2005 impairs fear extinction.…”

“…A recent study found that deletion of Ca v 1.2 impairs spatial learning and the L-VGCC-dependent form of LTP in the hippocampus (Moosmang et al 2005). Surprisingly, however, McKinney et al (2008) find that mice lacking Ca v 1.2 in the forebrain have intact acquisition, consolidation, and extinction of fear memory. Thus, using a genetic approach, forebrainexpressed Ca v 1.3 appears necessary for fear memory consolidation, but neither Ca v 1.3 nor Ca v 1.2 appears to be necessary, at least in isolation, for fear memory extinction.…”

“…Turning to a pharmacological analysis, McKinney et al (2008) next revisit the question of whether L-VGCC antagonists impair fear extinction, and, if so, why this method of manipulating L-VGCCs is so much more effective than using a molecular genetic approach. They first verify that systemic administration of a dose of nifedipine that has been used in previous experiments (Cain et al 2002(Cain et al , 2005 impairs fear extinction.…”