Characterization of the Neuronal Networks of the Subiculum and Their Contribution to Epileptiform Activity In Vitro.

다국어 초록 (Multilingual Abstract)

The exchange of information in the brain is accomplished through sequences of action potentials that result from the integration of local microcircuits. Unraveling the connectivity of the neurons that constitute these microcircuits and how they contribute to network activity is vital for understanding how information is relayed through the brain and how certain diseases arise when these circuits are disrupted. Despite its prominent role as the main output region of the hippocampus, the local microcircuits of the subiculum remain understudied. Much of the work on the subiculum has focused on the excitable properties of the constituent pyramidal neurons, which are typically classified as either burst-spiking or regular firing. However, the regional synaptic connectivity of the region has not been studied in an objective, quantitative way. Additionally, recent evidence from human epileptic tissue has emerged demonstrating that the subiculum can generate certain types of network activity that are closely associated with temporal lobe epilepsy. Closer analysis of subicular pyramidal neurons found changes in expression of the KCC2 transporter in a subset of neurons, a potentially epileptogenic change that might explain the ability of the subiculum to generate epileptiform activity.In this thesis, I have first evaluated the connectivity between pyramidal neurons using an objective classification method. I have found that the pyramidal neurons in this region are connected in a non-random fashion, and the putative synapses mediating these synaptic connections favor the basal dendrites of the post-synaptic neuron. Additionally, this excitatory network is capable of generating epileptiform-like activity when inhibitory signaling is impaired, a potential property that highlights the ictogenic potential of the region. The second half of this thesis is focused on modeling the changes in KCC2 transporter expression in a manner that restricts the changes to the subiculum. When KCC2 activity is inhibited, synchronous bursting events begin that are reminiscent of interictal activity observed in patients and animal models of TLE. These events are pharmacologically similar to interictal events and are originated by parvalbumin interneurons. In summary, my thesis work has enhanced our knowledge of how pyramidal neurons in the subiculum are connected at the level of individual neurons and has corroborated the idea that impaired KCC2 function might be a key epileptogenic step towards the progression of TLE.