Functional impacts of neurogenesis and axonal sprouting in epilepsy Public Deposited

Seizures are patterns of abnormal electrical activity in the brain that can result in altered sensory perception, loss of consciousness, and involuntary motor spasms. Epilepsy is the diagnosis of spontaneous and recurrent seizures. Of the many varieties of epilepsy, temporal lobe epilepsy is a common acquired epilepsy in adults and is in many cases medically intractable. Acquired temporal lobe epilepsy can result following brain trauma; however, the mechanism for the development of epilepsy from a precipitating neurological insult has remained elusive. Temporal lobe epilepsy is correlated with altered structure and function of neural circuits, changes that are hypothesized as a primary factor in epilepsy etiology, though it is unclear how individual circuit changes affect excitability in epileptic brains. One such example of circuit rearrangement in epilepsy is the pathologic retrograde sprouting of granule cell mossy fiber axons within the hippocampal dentate gyrus. Despite their proximal location, large presynaptic terminals, and excitation of target neurons, the ultimate impact of sprouted mossy fiber activity is unclear. Additionally, the dentate gyrus is a locus for adult neurogenesis and adult-born granule cells have been hypothesized to directly give rise to sprouted mossy fibers. If sprouted mossy fibers do primarily arise from adult-born dentate granule cells, then seizure-enhanced neurogenesis might play a role in establishing these aberrant connections. Using the pilocarpine model of epilepsy and transgenic labeling of age-defined cohorts of granule cells in mice, I demonstrate that adult-born neurons contribute to sprouting and are more likely to develop sprouted mossy fibers than their neonatally-born counterparts. Using super resolution confocal microscopy and whole-cell recordings from acute brain slices, I reveal sprouted mossy fiber axons form large synapses in the inner molecular layer that release glutamate and excite other dentate granule cells. Despite a prominent short-term depression of sprouted mossy fiber terminals, these cells had an increased probability of release during single stimulation episodes. Additionally, optogenetic activation of sprouted mossy fibers reliably triggered action potential firing in postsynaptic dentate granule cells and triggered polysynaptic bursts of EPSCs. A high probability of release and lack of tonic adenosine signaling at sprouted synapses contributed the generation of these bursts and activation of presynaptic adenosine 1 receptors decreased bursting of EPSCs. Taken together, my data suggest that sprouted mossy fibers from adult-born granule cells can quickly propagate recurrent excitation through the dentate gyrus and initiate bursts of recurrent excitation.

  • hendricks.william.2019.pdf
Publication Date
  • 2019
Document type