Presynaptic α2δ-2 Calcium Channel Subunits Regulate Postsynaptic GABAA Receptor Abundance and Axonal Wiring

Stefanie Geisler, Clemens L Schöpf, Ruslan Stanika, Marcus Kalb, Marta Campiglio, Daniele Repetto, Larissa Traxler, Markus Missler, Gerald J Obermair

Research output: Journal article (peer-reviewed)Journal article

29 Citations (Scopus)

Abstract

Presynaptic α 2δ subunits of voltage-gated calcium channels regulate channel abundance and are involved in glutamatergic synapse formation. However, little is known about the specific functions of the individual α 2δ isoforms and their role in GABAergic synapses. Using primary neuronal cultures of embryonic mice of both sexes, we here report that presynaptic overexpression ofα 2δ-2 in GABAergic synapses strongly increases clustering of postsynaptic GABA ARs. Strikingly, presynaptic α 2δ-2 exerts the same effect in glutamatergic synapses, leading to a mismatched localization of GABA ARs. This mismatching is caused by an aberrant wiring of glutamatergic presynaptic boutons with GABAergic postsynaptic positions. The trans-synaptic effect ofα 2δ-2 is independent of the prototypical cell-adhesion molecules α-neurexins (α-Nrxns); however, α-Nrxns together with α 2δ-2 can modulate postsynaptic GABA AR abundance. Finally, exclusion of the alternatively spliced exon 23 of α 2δ-2 is essential for the trans-synaptic mechanism. The novel function of α 2δ-2 identified here may explain how abnormal α 2δ subunit expression can cause excitatory-inhibitory imbalance often associated with neuropsychiatric disorders.

Original languageEnglish
Pages (from-to)2581-2605
Number of pages25
JournalJournal of Neuroscience
Volume39
Issue number14
DOIs
Publication statusPublished - 03 Apr 2019
Externally publishedYes

Keywords

  • Animals
  • Axons/chemistry
  • Brain/cytology
  • Calcium Channels/analysis
  • Cells, Cultured
  • Coculture Techniques
  • Female
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Presynaptic Terminals/chemistry
  • Protein Subunits/analysis
  • Receptors, GABA-A/analysis
  • Synaptic Potentials/physiology
  • Cultured hippocampal neurons
  • Voltage-gated calcium channels
  • Cacna2d
  • Immunocytochemistry
  • Auxiliary subunits
  • Imaging

ASJC Scopus subject areas

  • General Neuroscience

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