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_V1.2 and Ca_V1.3 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_V1.2 LTCCs (Ca_V1.2DHP^−/− 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_V1.2DHP^−/− mice, indicating that it is mediated by Ca_V1.2, but not by Ca_V1.3 LTCCs. Supporting this conclusion, Ca_V1.3-deficient mice (Ca_V1.3^−/−) 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_V1.2 channels. The LTCC activator BayK, which lacks neurotoxic effects in Ca_V1.2DHP^−/− mice, did not influence the extinction time course. In summary, we demonstrate that LTCC signaling through the Ca_V1.2 isoform of LTCCs interferes with fear memory extinction, presumably via a peripherally mediated mechanism. Activation of other LTCC isoforms (predominantly Ca_V1.3) is not sufficient to accelerate extinction of conditioned fear in mice.