Role of L-type Ca²⁺channel isoforms in the extinction of conditioned fear

Abstract

Dihydropyridine (DHP) L-type Ca2+ channel (LTCC) antagonists, such as nifedipine, have been reported to impair the extinction of conditioned fear without interfering with its acquisition. Identification of the LTCC isoforms mediating this DHP effect is an essential basis to reveal their role as potential drug targets for the treatment of specific anxiety disorders. Ca V 1.2 and Ca V 1.3 are the predominant LTCCs in the mammalian brain. However, since no isoform-selective DHP blockers are available, their individual contribution to fear memory extinction is unknown. We used a novel mouse model expressing DHP-insensitive Ca V 1.2 LTCCs (Ca V 1.2DHP −/− mice) to address this question. In line with previous studies, wild-type (WT) mice treated with systemic nifedipine displayed markedly impaired fear extinction. This DHP effect was completely abolished in Ca V 1.2DHP −/− mice, indicating that it is mediated by Ca V 1.2, but not by Ca V 1.3 LTCCs. Supporting this conclusion, Ca V 1.3-deficient mice (Ca V 1.3 −/− ) showed extinction identical to the respective WT mice. The inhibition of fear extinction was not observed after intracerebroventricular (i.c.v.) application of different doses of nifedipine, suggesting that this effect is secondary to inhibition of peripheral Ca V 1.2 channels. The LTCC activator BayK, which lacks neurotoxic effects in Ca V 1.2DHP −/− mice, did not influence the extinction time course. In summary, we demonstrate that LTCC signaling through the Ca V 1.2 isoform of LTCCs interferes with fear memory extinction, presumably via a peripherally mediated mechanism. Activation of other LTCC isoforms (predominantly Ca V 1.3) is not sufficient to accelerate extinction of conditioned fear in mice.

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.…”

“…Remarkably, however, Busquet et al (2008) fail to find an effect of multiple doses of nifedipine on fear extinction following intracerebroventricular infusion of the drug, suggesting that the effects of nifedipine on fear extinction are mediated via peripheral Ca v 1.2 channels. Further, in a test of activity in the open field, they show that mice given systemic injection of nifedipine exhibit marked reductions in exploratory behavior, possibly indicative of a hypotensive effect.…”

“…Further, given that deletion of Ca v 1.2 and Ca v 1.3 is confined to CaMKII-expressing excitatory neurons, are we missing a possible role for L-VGCCs in inhibitory networks during fear extinction? This is possible, but the pharmacological findings of Busquet et al (2008) now suggest that a central role for L-VGCCs is unlikely. Another outstanding question concerns the effects of L-VGCC manipulations on fear memory consolidation.…”

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…Ca V 1.3 is not required for acquisition and extinction of conditioned contextual fear memory (Moosmang et al, 2005a;Busquet et al, 2008) but is required for its consolidation (McKinney et al, 2009). Impaired consolidation in Ca V 1.3 2/2 mice was associated with significantly reduced LTP in the basolateral amygdala synapse receiving input from the entorhinal cortex and enhanced excitability of basolateral amygdala neurons (McKinney et al, 2009).…”

Homeostatic Switch in Hebbian Plasticity and Fear Learning after Sustained Loss of Cav1.2 Calcium Channels

“…On the other hand, extinction of contextual fear memory has been shown to be impaired by LTCC blockers (Cain et al, 2002;Suzuki et al, 2004). To complicate matters, recently it has been postulated that block of LTCC signaling through Ca v 1.2 after peripheral, not intracerebral, injection interferes with fear memory extinction, presumably via a peripherally mediated mechanism (Busquet et al, 2008;Waltereit et al, 2008). Here, we investigated the role of Ca v 1.2 LTCCs in synaptic plasticity in the LA and extended these in vitro findings to animal behavior in an auditory fear-conditioning paradigm.…”