Doctor of Philosophy
Drug-resistant epilepsy (DRE) is a common clinical sequela of developmental cortical malformations such as polymicrogyria. Unfortunately, much remains unknown about the aberrant GABA-mediated circuit alterations that underlie DRE's onset and persistence in this context. To address this knowledge gap, we utilized the transcranial freeze lesion model in optogenetic mice lines (Somatostatin (SST)-Cre or Parvalbumin (PV)-Cre x floxed channelrhodopsin-2) to dissect features of the SST, PV, and pyramidal neuron microcircuit that are potentially associated with DRE. Investigations took place within developmental microgyria’s known pathological substrate, the adjoined and epileptogenic paramicrogyral region (PMR). As well, microcircuit relationships within the previously unexplored range of normal-appearing cortex beyond PMR’s terminus were also interrogated. We previously demonstrated SST interneuron output enhancement onto postsynaptic layer V pyramidal neurons of PMR. Dissertation studies elaborated on this SST-interneuron mediated effect through the utilization of ex vivo slice electrophysiology in conjunction with selective optical activation of either SST or PV interneurons.
An ostensible mechanism was identified in the form of a novel structural schematic for SST interneurons of PMR whereby they exhibit wider reaching, within-layer arborization of axons within this pathological substrate. Also, within PMR, SST interneuron output was not enhanced onto postsynaptic layer V PV interneurons, indicating targeting specificity of the SST to pyramidal neuron effect. Moving beyond PMR, past its terminus, SST interneuron output onto layer V pyramidal cells was found to be equivalent to controls, indicating effect focality. Finally, a novel disinhibitory relationship was demonstrated beyond PMR’s terminus, wherein PV interneurons exhibited output enhancement onto postsynaptic layer V SST interneurons. This indicates a putative in vivo mechanism for the PMR-focality of the SST to pyramidal neuron output enhancement scheme.
These novel discoveries will provide the field with more context as to the role SST and PV interneurons potentially play in the emergence and/or modulation of drug-resistant epilepsy in and outside the terminus of PMR.
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Available for download on Saturday, July 31, 2021
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