Impaired Fear Extinction Due to a Deficit in Ca(2+) Influx Through L-Type Voltage-Gated Ca(2+) Channels in Mice Deficient for Tenascin-C

TY - JOUR

T1 - Impaired Fear Extinction Due to a Deficit in Ca(2+) Influx Through L-Type Voltage-Gated Ca(2+) Channels in Mice Deficient for Tenascin-C

AU - Morellini, Fabio

AU - Malyshev, Aleksey

AU - Volgushev, Maxim

AU - Chistiakova, Marina

AU - Papashvili, Giorgi

AU - Fellini, Laetitia

AU - Kleene, Ralf

AU - Schachner, Melitta

AU - Dityatev, Alexander

PY - 2017/8/2

Y1 - 2017/8/2

N2 - Mice deficient in the extracellular matrix glycoprotein tenascin-C (TNC(-/-)) express a deficit in specific forms of hippocampal synaptic plasticity, which involve the L-type voltage-gated Ca(2+) channels (L-VGCCs). The mechanisms underlying this deficit and its functional implications for learning and memory have not been investigated. In line with previous findings, we report on impairment in theta-burst stimulation (TBS)-induced long-term potentiation (LTP) in TNC(-/-) mice in the CA1 hippocampal region and its rescue by the L-VGCC activator Bay K-8644. We further found that the overall pattern of L-VGCC expression in the hippocampus in TNC(-/-) mice was normal, but Western blot analysis results uncovered upregulated expression of the Cav1.2 and Cav1.3 α-subunits of L-VGCCs. However, these L-VGCCs were not fully functional in TNC(-/-) mice, as demonstrated by Ca(2+) imaging, which revealed a reduction of nifedipine-sensitive Ca(2+) transients in CA1 pyramidal neurons. TNC(-/-) mice showed normal learning and memory in the contextual fear conditioning paradigm but impaired extinction of conditioned fear responses. Systemic injection of the L-VGCC blockers nifedipine and diltiazem into wild-type mice mimicked the impairment of fear extinction observed in TNC(-/-) mice. The deficiency in TNC(-/-) mice substantially occluded the effects of these drugs. Our results suggest that TNC-mediated modulation of L-VGCC activity is essential for fear extinction.

AB - Mice deficient in the extracellular matrix glycoprotein tenascin-C (TNC(-/-)) express a deficit in specific forms of hippocampal synaptic plasticity, which involve the L-type voltage-gated Ca(2+) channels (L-VGCCs). The mechanisms underlying this deficit and its functional implications for learning and memory have not been investigated. In line with previous findings, we report on impairment in theta-burst stimulation (TBS)-induced long-term potentiation (LTP) in TNC(-/-) mice in the CA1 hippocampal region and its rescue by the L-VGCC activator Bay K-8644. We further found that the overall pattern of L-VGCC expression in the hippocampus in TNC(-/-) mice was normal, but Western blot analysis results uncovered upregulated expression of the Cav1.2 and Cav1.3 α-subunits of L-VGCCs. However, these L-VGCCs were not fully functional in TNC(-/-) mice, as demonstrated by Ca(2+) imaging, which revealed a reduction of nifedipine-sensitive Ca(2+) transients in CA1 pyramidal neurons. TNC(-/-) mice showed normal learning and memory in the contextual fear conditioning paradigm but impaired extinction of conditioned fear responses. Systemic injection of the L-VGCC blockers nifedipine and diltiazem into wild-type mice mimicked the impairment of fear extinction observed in TNC(-/-) mice. The deficiency in TNC(-/-) mice substantially occluded the effects of these drugs. Our results suggest that TNC-mediated modulation of L-VGCC activity is essential for fear extinction.

KW - Journal Article

U2 - 10.3389/fnint.2017.00016

DO - 10.3389/fnint.2017.00016

M3 - SCORING: Journal article

C2 - 28824389

VL - 11

SP - 16

JO - FRONT INTEGR NEUROSC

JF - FRONT INTEGR NEUROSC

SN - 1662-5145

ER -