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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.
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.
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