Epilepsy is a common severe neurological disorder with one-year prevalence ~7/1,000, whose circuit mechanisms are poorly understood. Its prevalence is high among veterans. Patients with post-traumatic brain injury carry a high risk of epilepsy for decades following injury, causing considerable morbidity. At 15 years following injury 51% of the subjects in the Vietnam Head Injury Study carried a diagnosis of seizure. Clearly epilepsy is an important problem for the VA population. Acquired trauma often leads to focal imbalance between excitation and inhibition, which drives otherwise normal neural circuits into self-perpetuating oscillatory activity states manifesting as seizures on cortical surface EEG. This phenomenon clearly warrants study as it is shared by multiple neurological disorders presenting with focal seizures, including chronic focal epilepsy, which is the most common form of post-traumatic epilepsy. Specifically, we need to understand how individual neurons get recruited into ictal events in vivo, what is the sequence of recruitment, how properties of recruitment change with time leading to the onset and offset of ictal activity, how recruitment depends on the interaction between excitatory neurons with specific classes of inhibitory interneurons, and whether recruitment proceeds more efficiently along certain circuit pathways more than others. We will combine large scale in vivo 2-photon microscopy techniques with specific optogenetic modulation of selected cell types and individual unit patch-clamp recordings to study the emergence and spread of focally initiated seizures in the 4-aminopyridine (4-AP) mouse model of focal ictogenesis. We propose to study and compare visual and motor cortex, two areas with different potential for ictogenicity. The 4-AP model is a reliable, well-established, model of focal neocortical seizures inducing electroencephalographic (EEG) events similar to the low-voltage fast-onset events observed in human patients with focal post-traumatic epilepsy. Compared to other chemo-convulsants, GABA-ergic transmission is relatively preserved, making 4-AP an ideal model for studying how normal inhibitory circuits fail to contain the spread of abnormal events driven by an excess of excitation as has been argued to occur in post-traumatic epilepsy. In Aim #1, we will measure the profile of recruitment of individual neurons to the phases of progression of focal neocortical seizure events observed by EEG after 4-AP injection, and will determine how recruitment depends on cell type and position along the cortical circuit. The 3 major classes of GABA-ergic interneurons (PV+, SOM+, VIP+) will...