Auxiliary α2δ1 and α2δ3 Subunits of Calcium Channels Drive Excitatory and Inhibitory Neuronal Network Development
| Autor: | Miao Sun, Astrid Rohlmann, Anna Ciuraszkiewicz-Wojciech, Renato Frischknecht, Romy Freund, Sara Enrile Lacalle, Markus Missler, Arthur Bikbaev, Jessica Mitlöhner, Valentina Di Biase, Jennifer Heck, Gerald J. Obermair, Oliver Klatt, Daniele Repetto, Martin Heine, Cornelia Ablinger |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Neurogenesis Synaptogenesis Neurotransmission Inhibitory postsynaptic potential Hippocampus Synaptic Transmission 03 medical and health sciences Glutamatergic Mice 0302 clinical medicine VGCCs excitation to inhibition balance Biological neural network Premovement neuronal activity Animals Humans Calcium Signaling Research Articles Neurons synaptogenesis Chemistry General Neuroscience Glutamate receptor network connectivity Rats 030104 developmental biology HEK293 Cells Excitatory postsynaptic potential alpha2delta subunits Calcium Channels Nerve Net Neuroscience 030217 neurology & neurosurgery Cellular/Molecular |
| Zdroj: | The Journal of Neuroscience |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | VGCCs are multisubunit complexes that play a crucial role in neuronal signaling. Auxiliary α2δ subunits of VGCCs modulate trafficking and biophysical properties of the pore-forming α1 subunit and trigger excitatory synaptogenesis. Alterations in the expression level of α2δ subunits were implicated in several syndromes and diseases, including chronic neuropathic pain, autism, and epilepsy. However, the contribution of distinct α2δ subunits to excitatory/inhibitory imbalance and aberrant network connectivity characteristic for these pathologic conditions remains unclear. Here, we show that α2δ1 overexpression enhances spontaneous neuronal network activity in developing and mature cultures of hippocampal neurons. In contrast, overexpression, but not downregulation, of α2δ3 enhances neuronal firing in immature cultures, whereas later in development it suppresses neuronal activity. We found that α2δ1 overexpression increases excitatory synaptic density and selectively enhances presynaptic glutamate release, which is impaired on α2δ1 knockdown. Overexpression of α2δ3 increases the excitatory synaptic density as well but also facilitates spontaneous GABA release and triggers an increase in the density of inhibitory synapses, which is accompanied by enhanced axonaloutgrowth in immature interneurons. Together, our findings demonstrate that α2δ1 and α2δ3 subunits play distinct but complementary roles in driving formation of structural and functional network connectivity during early development. An alteration in α2δ surface expression during critical developmental windows can therefore play a causal role and have a profound impact on the excitatory-to-inhibitory balance and network connectivity. SIGNIFICANCE STATEMENT The computational capacity of neuronal networks is determined by their connectivity. Chemical synapses are the main interface for transfer of information between individual neurons. The initial formation of network connectivity requires spontaneous electrical activity and the calcium channel-mediated signaling. We found that, in early development, auxiliary α2δ3 subunits of calcium channels foster presynaptic release of GABA, trigger formation of inhibitory synapses, and promote axonal outgrowth in inhibitory interneurons. In contrast, later in development, α2δ1 subunits promote the glutamatergic neurotransmission and synaptogenesis, as well as strongly enhance neuronal network activity. We propose that formation of connectivity in neuronal networks is associated with a concerted interplay of α2δ1 and α2δ3 subunits of calcium channels. |
| Databáze: | OpenAIRE |
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