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Neuroanatomy of pain-deficiency and cross-modal activation in calcium channel subunit (CACN) α2δ3 knockout mice

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Abstract

The phenotype of calcium channel subunit (CACN) α2δ3 knockout (KO) mice includes sensory cross-activation and deficient pain perception. Sensory cross-activation defines the activation of a sensory cortical region by input from another modality due to reorganization in the brain such as after sensory loss. To obtain mechanistic insight into both phenomena, we employed a comprehensive battery of neuroanatomical techniques. While CACNα2δ3 was ubiquitously expressed in wild-type mice, it was absent in α2δ3 KO animals. Immunostaining of α1A, α1B, and α1E revealed upregulation of N-type and R-type, but not P/Q-type Cav2 channels in cortical neurons of CACNα2δ3 KO mice. Compared to wild-type mice, axonal processes in somatosensory cortex were enhanced, and dendritic processes reduced, in CACNα2δ3 KO mice. Immunohistochemical and MRI analyses, investigating morphology, thalamocortical and intra-/intercortical trajectories, revealed a disparity between projection and commissural fibers with reduction of the number of spatial specificity of thalamocortical projections. L1cam staining revealed wide-ranging projections of thalamocortical fibers reaching both somatosensory/motor and visual cortical areas. Activation (c-fos+) of excitatory and inhibitory neurons suggested that deficient pain perception in α2δ3 KO mice is unlikely to result from cortical disinhibition. Collectively, our data demonstrate that knock out of CACN α2δ3 results in some structural abnormalities whose functional implications converge to dedifferentiation of sensory activation.

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Acknowledgements

This work was supported by InterNeuro (GRK 1097), the graduate school funded by DFG and the “Promotion Program” for Young Researchers of the Helmholtz Alliance ICEMED. Furthermore, we received funding from the Research Academy Leipzig (RAL). We thank Prof. Dr. Fritz Rathjen for providing the rabbit anti-L1 antibody. Furthermore, we thank Claudia Merkwitz, Constance Hobusch, and Jana Brendler for their excellent technical assistance.

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Authors and Affiliations

  1. Institute of Anatomy, University of Leipzig, Oststrasse 25, 04317, Leipzig, Germany

    Julia Landmann & Ingo Bechmann

  2. Department of Veterinary Medicine, Institute of Pharmacology, Pharmacy and Toxicology, University of Leipzig, An den Tierkliniken 15, 04103, Leipzig, Germany

    Franziska Richter & Angelika Richter

  3. Institute of Neuroscience and Medicine (INM-4), Research Centre Jülich, Forschungszentrum Jülich, 52425, Jülich, Germany

    Ana-Maria Oros-Peusquens & N. Jon Shah

  4. Department of Neurology, University of Leipzig, Liebigstrasse 20, 04103, Leipzig, Germany

    Joseph Classen

  5. Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre and School of Life & Environmental Sciences, The University of Sydney, 2006, Camperdown, NSW, Australia

    G. Gregory Neely

  6. IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr-Gasse 3, 1030, Vienna, Austria

    Josef M. Penninger

  7. Department of Neurology, Faculty of Medicine, JARA, RWTH Aachen University, Aachen, Germany

    N. Jon Shah

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Landmann, J., Richter, F., Oros-Peusquens, AM. et al. Neuroanatomy of pain-deficiency and cross-modal activation in calcium channel subunit (CACN) α2δ3 knockout mice. Brain Struct Funct 223, 111–130 (2018). https://doi.org/10.1007/s00429-017-1473-4

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