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 language | English |
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Pages (from-to) | 2581-2605 |
Number of pages | 25 |
Journal | Journal of Neuroscience |
Volume | 39 |
Issue number | 14 |
DOIs | |
Publication status | Published - 03 Apr 2019 |
Externally published | Yes |
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