Abstracts

Rationale: Neuronal hyperexcitability plays a central role in the generation of epileptiform activity; however, cellular mechanisms underlying hyperexcitability in dysplastic cortical neurons are not clear. Low [Ca2+]o or [Mg2+]o conditions/models can induce hyperexcitability. Transient receptor potential canonical type 3 (TRPC3) channels are developmentally expressed. They play a pivotal role in neuronal excitability and they are activated in low Ca and/or Mg to depolarize neurons. We determined whether 0.4 mM Ca and 0.4 mM Mg (0.4 Ca-Mg) can induce differential depolarization in an animal model cortical dysplasia (compared to controls) and examined the role of TRPC3 channels in this process. Methods: Pregnant rats on E17 were sham-exposed or exposed to 2.25 Gy of external irradiation. Male offspring from pregnant rats were subjected to slice electrophysiology (at P29-P31) and histology (at P30). For comparisons of electrophysiological data, significance was set at P < 0.05. Results: TRPC3 staining was heavy in dysplastic cortex but weak in controls. Perfusion of 0.4 Ca-Mg induced a larger depolarization in pyramidal neurons from rat dysplastic cortex than in controls (Tab. 1, P< 0.01). Intracellular application of anti-TRPC3 antibody (to block TRPC3 channels) and bath application of Pyr3 (a selective TRPC3 inhibitor) almost completely abolished 0.4 Ca-Mg-induced depolarization in dysplastic cortex (Tab. 1, P< 0.01). The residual depolarization was not different between the two groups after blocking TRPC3 channels (Tab. 1, P> 0.05). 0.4 Ca-Mg induced epileptiform activity only in dysplastic cortex and it was completely suppressed 10 - 15 min after the addition of 10 μM Pyr3. Conclusions: TRPC3 channels primarily mediate 0.4 Ca-Mg-induced depolarization and epileptiform activity in dysplastic cortex. In 0.4 Ca-Mg, the dysplastic cortex is more hyperexcitable and more susceptible to epileptiform activity due to higher TRPC3 channel function.