α2δ-1 Signaling Drives Cell Death, Synaptogenesis, Circuit Reorganization, and Gabapentin-Mediated Neuroprotection in a Model of Insult-Induced Cortical Malformation

eNeuro. 2017 Nov 6;4(5):ENEURO.0316-17.2017. doi: 10.1523/ENEURO.0316-17.2017. eCollection Sep-Oct 2017.

Abstract

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 α2δ-1 were elevated. TSP binds to α2δ-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/α2δ-1 signaling using the drug gabapentin (GBP) reduced many FL-induced pathologies. Here, we used mice with a genetic deletion of α2δ-1 to determine how α2δ-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 α2δ-1 in FL-induced pathologies and in mediating the neuroprotective effects of GBP. Interestingly, genetic deletion of α2δ-1 did not eliminate GBP's effects on synaptogenesis, suggesting that GBP can have α2δ-1-independent effects. Taken together these studies suggests that inhibiting α2δ-1 signaling may have therapeutic promise to reduce cell death and network reorganization associated with insult-induced DCMs.

Keywords: a2d-1; cell death; cortex; gabapentin; malformation; polymicrogyriax.

MeSH terms

  • Amines / pharmacology*
  • Animals
  • Calcium Channels / deficiency
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cyclohexanecarboxylic Acids / pharmacology*
  • Disease Models, Animal
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Female
  • Freezing
  • Gabapentin
  • Male
  • Malformations of Cortical Development / drug therapy
  • Malformations of Cortical Development / metabolism*
  • Malformations of Cortical Development / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Miniature Postsynaptic Potentials / drug effects
  • Miniature Postsynaptic Potentials / physiology
  • Neural Pathways / drug effects
  • Neural Pathways / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology
  • Neuroprotection / drug effects
  • Neuroprotection / physiology*
  • Neuroprotective Agents / pharmacology*
  • Somatosensory Cortex / abnormalities
  • Somatosensory Cortex / drug effects
  • Somatosensory Cortex / growth & development
  • Somatosensory Cortex / metabolism
  • Synapses / drug effects
  • Synapses / metabolism
  • Synapses / pathology
  • Tissue Culture Techniques
  • gamma-Aminobutyric Acid / pharmacology*

Substances

  • Amines
  • CACNA2D1 protein, mouse
  • Calcium Channels
  • Cyclohexanecarboxylic Acids
  • Neuroprotective Agents
  • gamma-Aminobutyric Acid
  • Gabapentin