Epilepsy affects 50 million people worldwide. In 40% of patients with temporal lobe epilepsy (TLE), antiepileptic drugs fail to prevent seizures, increasing the risk of injury, cognitive decline, and death. The impairment of inhibition by GABAergic interneurons (IN) is a key pathomechanism of epilepsy, however, our incomplete understanding of the network function of the diverse types of IN limits the development of treatment strategies. Perisomatic inhibition by basket cells controls the rate and synchrony of the firing of excitatory neurons. The two types of basket cells, expressing either cholecystokinin (CCK) or parvalbumin (PV), are equally abundant and are both preserved in chronic epilepsy. However, why there are two distinct classes of perisomatic IN, and how their function is altered in epilepsy, is not known. The candidate?s long-term goal is to develop a career as an independent neuroscientist to understand the role of interneuron diversity in neuronal microcircuit function, and how dysfunction in various interneuron subtypes is involved in and leads to epilepsy. Using recently developed tools to record the activity of CCK and PV IN selectively in awake, behaving animals, preliminary results show that in the hippocampus, the brain area most affected by TLE, CCK and PV IN are recruited in distinct brain states. Moreover, the activity of PV IN is correlated positively, while the activity of CCK IN is correlated negatively to the activity of excitatory neurons on the time scale of seconds, suggesting that CCK IN are suited to control average firing rates and associativity across the network. Therefore, the hypothesis of the current proposal is that the two classes of perisomatic IN are recruited in separate brain states in epilepsy, and this may lead to distinct outcome of antiepileptic interventions that selectively target CCK or PV IN. This proposal presents a plan to test this hypothesis in a chronic animal model of TLE (intrahippocampal kainate), using in vitro electrophysiology and in vivo 2-photon calcium imaging with correlated hippocampal field potential recording, to: 1) Test the hypothesis that CCK and PV IN are recruited in different brain states in epilepsy; 2) Test the hypothesis that excitatory inputs and reciprocal inhibition contribute to the differential recruitment of PV and CCK IN; and 3) Test the hypothesis that CCK IN are effective in dampening network activity in TLE without disrupting the representation of spatial information. Completion of the proposed study may advance the field by: 1) establishing a previously unknown temporal segregation of the activity of interneurons; 2) determining the underlying circuit mechanism; and 3) determining the efficacy of CCK IN for antiepileptic intervention. In addition, the candidate proposes a personalized plan to obtain training in scientific background (particularly in the epilepsy field), research methods (chronic epilepsy models and in vitro electrophysiology), and career development (grant writing, teaching and scientific management). The mentoring of Prof Ivan Soltesz at Stanford University will provide an ideal environment for the candidate to carry out the research and training plan successfully and thus will enable the candidate to establish an independent research program.
Inhibitory neurotransmission controls the activity and synchrony of excitatory neurons, and impaired inhibition contributes to the pathomechanism of neurological disorders such as epilepsy. The current experiments will determine whether specific types of inhibitory neurons are more effective at suppressing epileptic activity in the neuronal circuit without disrupting information encoding and may identify strategies to prevent seizures without adverse effects on cognitive function.
