impaired fear extinction due to a deficit in ca2+ influx through l-type voltage-gated ca2+ channels in mice deficient for tenascin-c

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ID: 139568
2017
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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.
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morellini2017frontiersimpaired Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Fabio Morellini;Fabio Morellini;Aleksey Malyshev;Aleksey Malyshev;Maxim Volgushev;Maxim Volgushev;Maxim Volgushev;Marina Chistiakova;Marina Chistiakova;Giorgi Papashvili;Laetitia Fellini;Ralf Kleene;Melitta Schachner;Melitta Schachner;Alexander Dityatev;Alexander Dityatev;Alexander Dityatev;Alexander Dityatev
Journal drug research
Year 2017
DOI
10.3389/fnint.2017.00016
URL
http://journal.frontiersin.org/article/10.3389/fnint.2017.00016/full
Keywords
learning fear conditioning synaptic plasticity extracellular matrix l-type ca2+ channels diseases of the nervous system neuropsychiatryneurology biological psychiatry

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