Impaired Fear Extinction Due to a Deficit in Ca2+ Influx Through L-Type Voltage-Gated Ca2+ Channels in Mice Deficient for Tenascin-C.

Fabio Morellini,Alexander Dityatev,Maxim Volgushev,Aleksey Malyshev,Giorgi Papashvili,Marina Chistiakova,Ralf Kleene,Melitta Schachner,Laetitia Fellini

doi:10.3389/fnint.2017.00016

Abstract

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 Ca2+ 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 Ca2+ imaging, which revealed a reduction of nifedipine-sensitive Ca2+ 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.

Highlights

Tenascin-C (TNC) is prominently expressed in various tissues during development
Since our prior work showed that this reduction in long-term potentiation (LTP) magnitude in TNC−/− mice was mimicked by treating slices from TNC+/+ mice with the L-type voltage-gated Ca2+ channels (L-VGCCs) blocker nifedipine and that the effects of TNC deficiency and nifedipine showed full occlusion, we hypothesized that the function of L-VGCCs was impaired in TNC−/− mice (Evers et al, 2002)
We have shown that impaired L-VGCCdependent LTP in TNC−/− hippocampi is not caused by reduced expression of L-VGCC α1 subunits, but it is most likely due to a reduced influx of Ca2+ via L-type channels

Summary

Introduction

Tenascin-C (TNC) is prominently expressed in various tissues during development. In the developing central nervous system, TNC is involved in regulating the proliferation of oligodendrocyte precursor cells and astrocytes. Only specific forms of synaptic plasticity induced by protocols that involve activation of L-type voltage-gated Ca2+ channels (L-VGCCs), such as repeated theta-burst stimulation (TBS) of Schaffer collaterals, application of the K+ channel blocker tetraethylammonium, or low-frequency stimulation-induced long-term depression, were impaired in constitutively TNC deficient (TNC−/−) mice (Evers et al, 2002). Reduction in the magnitude of TBS-induced long-term potentiation (LTP) in TNC−/− mice was occluded by a decrease in LTP in the presence of nifedipine, a blocker of L-VGCCs. Nifedipine did not affect LTP in TNC−/− mice but reduced LTP in wild-type mice to the levels seen in the mutants, supporting the view of a link between TNC and L-VGCCs (Evers et al, 2002). The observed changes in synaptic transmission and LTP of TNC−/− mice were specific for CA3-CA1 connections and not found in the dentate gyrus at perforant path synapses. TNC−/− mice showed increased exploratory activity in a novel environment, decreased anxiety and delayed adaptation to daylight reversal (Morellini and Schachner, 2006)

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Results

Conclusion