gms | German Medical Science

60th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN)

German Society for Neuropathology and Neuroanatomy

26. - 28.08.2015, Berlin

Deficiency in LIM-domain-binding proteins 1/2 and STE-20 like kinase leads to loss of distal dendrites and inhibitory synapse degeneration

Meeting Abstract

  • corresponding author presenting/speaker Barbara Robens - Bonn University Clinic, Neuropathology, Bonn, Germany
  • Robert Maresch - Bonn University Clinic, Epileptology, Bonn, Germany
  • Alexander Grote - bonn University Clinic, Neurosurgery, Bonn, Germany
  • Karen M. J. van Loo - Bonn University Clinic, Neuropathology, Bonn, Germany
  • Heinz Beck - Bonn University Clinic, Epileptology, Bonn, Germany
  • Susanne Schoch - Bonn University Clinic, Neuropathology, Bonn, Germany
  • Albert Becker - Bonn University Clinic, Neuropathology, Bonn, Germany

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. 60th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN). Berlin, 26.-28.08.2015. Düsseldorf: German Medical Science GMS Publishing House; 2015. Doc15dgnnP1

doi: 10.3205/15dgnn25, urn:nbn:de:0183-15dgnn258

Published: August 25, 2015

© 2015 Robens et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.


Outline

Text

Question: LIM-domain-binding (LDB) proteins 1 and 2 are multi adapter proteins, which have been reported to bind to the STE-20 like kinase (SLK). LDBs and SLK are abundantly expressed during brain development in the cerebral cortex, which may suggest a critical role during neurogenesis. How do LDB1 and LDB2 interact with SLK during brain development and what impact do these molecules have on neuronal migration and maturation?

Methods: We transfected primary cortical neuronal cultures in vitro and mouse embryos (E14) in utero with shRNAs targeting LDB1, LDB2 or SLK alone or in combination with resistant overexpression plasmids for LDB1, LDB2 or SLK. Afterwards, adult mice were PFA-perfusion fixed. For electrophysiological characterization, voltage clamp measurements were performed with acute brain slices from in utero electroporated (IUE) mice.

Results: In primary cortical neuronal cultures, shRNA mediated silencing of murine LDB1, LDB2 or SLK caused loss of distal dendrites and impaired axon outgrowth and branching. Rescue experiments with shRNA resistant LDB or SLK proteins restored the phenotype. Loss of either LDB1 or 2 could be rescued by overexpression of SLK but not vice versa, indicating a key role of the interaction between LDB1/2 and SLK for regular neurite growth in vitro and placing SLK downstream of LDB1/2 in the respective pathway. Intraventricular IUE of SLK shRNAs resulted in a migration defect of SLK-deficient neurons. In addition, properly positioned SLK-deficient layer III/IV neurons showed a dramatic loss of distal dendrites similar to the in vitro results. Surprisingly, the loss of tertiary dendrites caused a marked loss of inhibitory synapses at postnatal stages >P15, despite the fact that these synapses are normally found predominantly on proximal dendrites. This finding was corroborated by a markedly reduced frequency of miniature inhibitory postsynaptic currents in adult mice.

Conclusion: Our present findings indicate a critical role for LDB1, LDB2 and SLK for development of dendritic arbors, as well as the proper balance of dendritic inhibitory and excitatory synapses. Aberrant degeneration of inhibitory synaptic inputs has substantially new implications for the emergence of hyperexcitable neuronal networks and potentially subsequent neurodegeneration.