postdoctoral fellow Boston Children's Hospital Boston, Massachusetts
Rationale: Cathodal direct current stimulation (cDCS) may suppress seizures, but its clinical efficacy is modest, and untested in genetic epilepsies. We tested, in vitro: a) whether cDCS can induce long-term depression (DCS-LTD) of cortical excitability in cortex derived from neuronal tuberous sclerosis complex 2 (TSC2) knockout mice (KOs) as it does in healthy mouse cortex; b) whether novel drug-DCS pairing can facilitate cortical DCS-LTD to improve its antiepileptic capacity. Methods: cDCS effects on modulating neocortical field excitatory postsynaptic potential (fEPSP) were recorded by microelectrode array (MEA), and were plotted as an interpolated two-dimensional map. Given that TSC is characterized by an impaired mGluR5-mTOR pathway, we also tested the effects of a positive mGluR5 allosteric modulator (CDPPB) and an mTOR inhibitor (rapamycin) on the microanatomy of the cDCS modulatory pattern. Results: Our preliminary results showed that in TSC2 KO cortex (but not in control) long-term potentiation (DCS-LTP) of the fEPSP slopes, instead of cortical DCS-LTD was induced in the cortical layers superficial to the test stimulus site. Under cathode, the fraction of MEA channels expressing DCS-LTD in superficial layers was reduced from 74.2 ± 8.5% in controls (n=10) to 44.7 ± 10.6% in TSC2 KOs (n=10; p< 0.05 as compared to controls). Interestingly, we also found that the fraction of MEA channels expressing DCS-LTD in superficial layers was increased to 72.9 ± 11.0% (n=4, p=0.09 as compared to TSC2 KO group) or 63.3 ± 12.8% (n=5, p=0.29 as compared to TSC2 KO group) by co-application of either CDPPB or rapamycin with cathodal DCS, respectively. Conclusions: cDCS induces a large proportion of DCS-LTP of cortical excitability in epileptic cortex in vitro, which may explain the weakness of cDCS clinical efficacy. Moreover, our pharmacological results indicate a therapeutic potential of drug-DCS coupling to facilitate DCS-LTD in epilepsy treatment. Funding: Please list any funding that was received in support of this abstract.: Boston Children's Hospital Translational Research Program
