TY - JOUR T1 - Optogenetically-Induced Population Discharge Threshold as a Sensitive Measure of Network Excitability JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0229-18.2019 SP - ENEURO.0229-18.2019 AU - D.C. Klorig AU - G.E. Alberto AU - T. Smith AU - D.W. Godwin Y1 - 2019/10/16 UR - http://www.eneuro.org/content/early/2019/10/16/ENEURO.0229-18.2019.abstract N2 - Network excitability is governed by synaptic efficacy, intrinsic excitability, and the circuitry in which these factors are expressed. The complex interplay between these factors determines how circuits function and, at the extreme, their susceptibility to seizure. We have developed a sensitive, quantitative estimate of network excitability in freely behaving mice using a novel optogenetic intensity-response procedure. Synchronous activation of deep sublayer CA1 pyramidal cells produces abnormal network-wide epileptiform population discharges (PD) that are nearly indistinguishable from spontaneously-occurring interictal spikes. By systematically varying light intensity, and therefore the magnitude of the optogenetically-mediated current, we generated intensity-response curves using the probability of PD as the dependent variable. Manipulations known to increase excitability, such as sub-convulsive doses (20 mg/kg) of the chemoconvulsant pentylenetetrazol (PTZ), produced a leftward shift in the curve compared to baseline. The anti-epileptic drug levetiracetam (40 mk/kg), in combination with PTZ, produced a rightward shift. Optogenetically-induced population discharge threshold (oPDT) baselines were stable over time, suggesting the metric is appropriate for within-subject experimental designs with multiple pharmacological manipulations.Significance Statement Abnormal excitability is associated with a number of neurological disorders, including epilepsy. Excitability can be measured in single cells in vitro, but it is difficult to extrapolate from these values to the functional impact on the associated network. Epileptiform population discharges are network-wide events that represent a distinct transition from normal to abnormal functional modes. We developed a new method that uses light intensity-response curves to precisely determine the threshold for this transition as a surrogate measure of network excitability. ER -