| First Author | Bikbaev A | Year | 2020 |
| Journal | J Neurosci | Volume | 40 |
| Issue | 25 | Pages | 4824-4841 |
| PubMed ID | 32414783 | Mgi Jnum | J:290668 |
| Mgi Id | MGI:6436735 | Doi | 10.1523/JNEUROSCI.1707-19.2020 |
| Citation | Bikbaev A, et al. (2020) Auxiliary alpha2delta1 and alpha2delta3 Subunits of Calcium Channels Drive Excitatory and Inhibitory Neuronal Network Development. J Neurosci 40(25):4824-4841 |
| abstractText | VGCCs are multisubunit complexes that play a crucial role in neuronal signaling. Auxiliary alpha2delta subunits of VGCCs modulate trafficking and biophysical properties of the pore-forming alpha1 subunit and trigger excitatory synaptogenesis. Alterations in the expression level of alpha2delta subunits were implicated in several syndromes and diseases, including chronic neuropathic pain, autism, and epilepsy. However, the contribution of distinct alpha2delta subunits to excitatory/inhibitory imbalance and aberrant network connectivity characteristic for these pathologic conditions remains unclear. Here, we show that alpha2delta1 overexpression enhances spontaneous neuronal network activity in developing and mature cultures of hippocampal neurons. In contrast, overexpression, but not downregulation, of alpha2delta3 enhances neuronal firing in immature cultures, whereas later in development it suppresses neuronal activity. We found that alpha2delta1 overexpression increases excitatory synaptic density and selectively enhances presynaptic glutamate release, which is impaired on alpha2delta1 knockdown. Overexpression of alpha2delta3 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 alpha2delta1 and alpha2delta3 subunits play distinct but complementary roles in driving formation of structural and functional network connectivity during early development. An alteration in alpha2delta 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 alpha2delta3 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, alpha2delta1 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 alpha2delta1 and alpha2delta3 subunits of calcium channels. |
