| First Author | Faria LC | Year | 2017 |
| Journal | Neurobiol Dis | Volume | 102 |
| Pages | 70-80 | PubMed ID | 28193459 |
| Mgi Jnum | J:258963 | Mgi Id | MGI:6140449 |
| Doi | 10.1016/j.nbd.2017.01.009 | Citation | Faria LC, et al. (2017) Epileptiform activity and behavioral arrests in mice overexpressing the calcium channel subunit alpha2delta-1. Neurobiol Dis 102:70-80 |
| abstractText | The alpha2delta-1 subunit (alpha2delta-1) of voltage-gated calcium channels is a receptor for astrocyte-secreted thrombospondins that promote developmental synaptogenesis. Alpha2delta-1 receptors are upregulated in models of injury-induced peripheral pain and epileptogenic neocortical trauma associated with an enhancement of excitatory synaptic connectivity. These results lead to the hypothesis that overexpression of alpha2delta-1 alone in neocortex of uninjured transgenic (TG) mice might result in increased excitatory connectivity and consequent cortical hyperexcitability and epileptiform activity. Whole cell recordings from layer V pyramidal neurons in somatosensory cortical slices of TG mice showed increased frequency and amplitude of miniature and spontaneous EPSCs and prolonged bursts of polysynaptic EPSCs. Epileptiform field potentials were evoked in layers II/III and V of brain slices from TG mice, but not controls. Dual immunoreactivity for Vglut-2 and PSD95 showed increased density of close appositions in TG mice compared to controls, suggesting an increased number of excitatory synapses. Video-EEG monitoring showed that 13/13 implanted TG mice aged >P21, but not controls, had frequent abnormal spontaneous epileptiform events, consisting of variable duration, high amplitude bi-hemispheric irregular bursts of delta activity, spikes and sharp waves lasting many seconds, with a variable peak frequency of ~1-3Hz, associated with behavioral arrest. The epileptiform EEG abnormalities and behavioral arrests were reversibly eliminated by treatment with i.p. ethosuximide. Behavioral seizures, consisting of ~15-30s duration episodes of rigid arched tail and head and body extension, followed by loss of balance and falling, frequently occurred in adult TG mice during recovery from isoflurane-induced anesthesia, but were rare in WT mice. Results show that over-expression of alpha2delta-1 subunits increases cortical excitatory connectivity and leads to neocortical hyperexcitability and epileptiform activity associated with behavioral arrests in adult TG mice. Similar increases in expression of alpha2delta-1 in models of cortical injury may play an important role in epileptogenesis. SIGNIFICANCE: Binding of astrocytic-secreted thrombospondins to their alpha2delta-1 receptor facilitates excitatory synapse formation and excitatory transmission during cortical development and after injury. Upregulation of alpha2delta-1 is present in models of injury-induced pain and epileptogenic cortical trauma, along with many other molecular alterations. Here we show that overexpression of alpha2delta-1 alone in TG mice can enhance excitatory connectivity in neocortex and lead to neural circuit hyperexcitability and episodes of electrographic epileptiform activity, associated with behavioral arrests in transgenic mice. alpha2delta-1 is the high-affinity receptor for gabapentinoids and a potential target for prophylactic treatment of posttraumatic epilepsy and other disorders in which excessive aberrant excitatory connectivity is a pathophysiological feature. |
