| First Author | Lau LA | Year | 2017 |
| Journal | eNeuro | Volume | 4 |
| Issue | 5 | PubMed ID | 29109971 |
| Mgi Jnum | J:255842 | Mgi Id | MGI:6114206 |
| Doi | 10.1523/ENEURO.0316-17.2017 | Citation | Lau LA, et al. (2017) alpha2delta-1 Signaling Drives Cell Death, Synaptogenesis, Circuit Reorganization, and Gabapentin-Mediated Neuroprotection in a Model of Insult-Induced Cortical Malformation. eNeuro 4(5):ENEURO.0316-17.2017 |
| abstractText | Developmental cortical malformations (DCMs) result from pre- and perinatal insults, as well as genetic mutations. Hypoxia, viral infection, and traumatic injury are the most common environmental causes of DCMs, and are associated with the subsyndromes focal polymicrogyria and focal cortical dysplasia (FCD) Type IIId, both of which have a high incidence of epilepsy. Understanding the molecular signals that lead to the formation of a hyperexcitable network in DCMs is critical to devising novel treatment strategies. In a previous study using the freeze-lesion (FL) murine model of DCM, we found that levels of thrombospondin (TSP) and the calcium channel auxiliary subunit alpha2delta-1 were elevated. TSP binds to alpha2delta-1 to drive the formation of excitatory synapses during development, suggesting that overactivation of this pathway may lead to exuberant excitatory synaptogenesis and network hyperexcitability seen in DCMs. In that study, antagonizing TSP/alpha2delta-1 signaling using the drug gabapentin (GBP) reduced many FL-induced pathologies. Here, we used mice with a genetic deletion of alpha2delta-1 to determine how alpha2delta-1 contributes to cell death, elevated excitatory synapse number, and in vitro network function after FL and to examine the molecular specificity of GBP's effects. We identified a critical role for alpha2delta-1 in FL-induced pathologies and in mediating the neuroprotective effects of GBP. Interestingly, genetic deletion of alpha2delta-1 did not eliminate GBP's effects on synaptogenesis, suggesting that GBP can have alpha2delta-1-independent effects. Taken together these studies suggests that inhibiting alpha2delta-1 signaling may have therapeutic promise to reduce cell death and network reorganization associated with insult-induced DCMs. |
