Microcircuits of the Subiculum and Epilepsy

Project Summary / Abstract The subiculum is a critical output network of the hippocampal formation and participates in a variety of important physiological functions. However, in pathological conditions such as temporal lobe epilepsy, its own intrinsic circuits may initiate hyper-synchronous discharges leading to generalized seizures. In fact, a prominent theory of TLE proposes a key role for the subicular-specific down-regulation of the KCC2 potassium chloride co- transporter in the alteration of GABAergic inhibition that leads to the generation of pathological activity. During the previous cycle, we have studied the isolated subicular circuitry in vitro. We have shown with direct and sophisticated techniques that subicular pyramidal cells are highly reciprocally interconnected and require physiological GABAergic inhibition to prevent the emergence of epileptiform self-synchronization. Furthermore, we have shown that the subicular circuitry is sufficient to initiate epileptiform activity when KCC2 function is pharmacologically blocked. Here, we propose to study the critical role of specific populations of local GABAergic interneurons, (parvalbumin- somatostatin- and neuron derived neurotrophic factor-expressing cells) as well as pyramidal cell functional diversity under conditions of reduced KCC2 activity. We have found that the exposure of subicular tissue to brain derived neurotrophic factor (BDNF, which is abundantly released in the epileptic brain and is known to downregulated KCC2 in neural membranes) produces a surprising (and yet unreported) change in GABAergic network signaling. The experiments proposed in the application will study the biophysical, pharmacological, anatomical and network mechanisms involved in this (previously unreported) GABA-dependent recruitment of excitatory polysynaptic pathways. Given the lack of seizure control in ~30% of TLE cases, a new mechanistic understanding of the chain of events leading to the initiation and/or propagation of epileptiform activity in central networks is of critical importance for the development of novel therapeutic strategies.