Role of short-term dynamics of synpses between dentate gyrus interneurons in shaping excitability in normal and epileptic circuits
Creators: name: Crane, Alexander Burkam
Publisher: name: No Publisher Supplied
Year: 2016

description: Temporal lobe epilepsy (TLE) is a relatively common form of epilepsy that is difficult to manage and is characterized by recurrent unprovoked seizures originating in the temporal lobe of the brain. Seizures in TLE often start in the hippocampus, and are associated with structural and functional changes in the dentate gyrus (DG), a region within the hippocampus. Seizure activity can lead to physiologic changes that can underlie or worsen the severity of epilepsy. In order to elucidate the mechanisms underlying TLE, it is important to develop a detailed understanding of the specific physiological changes and their effects on network activity patterns.The main projection neuron in the DG is the granule cell (GC), an excitatory neuron. However, most of the other cell types in the DG are inhibitory interneurons. Two of these inhibitory interneurons are parvalbumin-expressing, fast-spiking basket cells (fsBCs), and accommodating cells (ACs). Recent research has shown that the synapses between ACs and fsBCs show a functional reduction in reliability of synaptic transmission after experimental seizure induction. Previous studies identified that this change affects oscillatory coupling in simulated networks including fsBCS and ACs. Similar network oscillation disruptions in the DG have been linked to complications of epilepsy. In addition to baseline characteristics of synaptic release, synapses show activity-dependent changes in synaptic properties. Of particular relevance, synapses from fsBCs undergo short-term depression and synapses from ACs undergo short-term facilitation. However, the impact of such short-term synaptic dynamics on large-scale circuit activity patterns is not commonly modeled.This study used computational modeling to examine how the short term dynamics of synapses between ACs and fsBCs modify network excitability and oscillations in networks with normal and epileptic synaptic characteristics. A model of the facilitation-depression synapse was successfully implemented in the NEURON programming environment and applied to a network of DG excitatory and inhibitory neurons. Cell-type specific short term synaptic dynamics were constrained based on published experimental data in specific cell types. Excitability was compared between models of a control network of DG neurons and a post-seizure network of DG neurons. The post-seizure network was modeled to mimic the functional reduction in reliability between ACs and fsBCs seen in experimental seizure induction by decreasing the probability of synaptic release in response to firing. Implementation of the seizure-induced decrease in AC to fsBC synaptic release probability failed to alter average granule cell firing frequency and duration in response to synchronous afferent activation. Excitability was also compared between networks incorporating synapse specific short term synaptic dynamics and networks that did not. Inclusion of short term synaptic dynamics led to modest increases in excitability which were not statistically significant. In contrast to the limited change in excitability, comparison of oscillatory behavior between control and post-seizure networks revealed an increase in coherence and a change in frequency power spectra. Addition of short term synaptic dynamics resulted in decreased coherence and a change in frequency power spectra. Overall, it was shown that a decrease in functional reliability in AC to fsBC synapses, when modeled with biologically realistic facilitation-depression synapses, has little effect on network excitability, but significant effects on network oscillatory behavior.