Epilepsy is a potentially devastating neurologic condition that affects about 2 million Americans and is often resistant to medical treatment. Animal studies have demonstrated that epilepsy is associated with compensatory changes in the brain, which includes the aberrant growth and rewiring of neuronal circuits. In particular, epilepsy is associated with altered connectivity in te hippocampus, a region of the brain that is frequently the focal point for the initiation of seizure. The hippocampus is also one of few brain regions exhibiting constitutive adult neurogenesis, in which hippocampal granule cells are born in adulthood, and these new neurons play important roles in learning and memory. The generation of these adult-born neurons increases after certain types of injury, including seizures and traumatic brain injury, and might represent a homeostatic response to enhance recovery. One particular hippocampal circuit rearrangement associated with epilepsy involves the growth (sprouting) of granule cell axons (the mossy fibers) in a retrograde direction. These sprouted fibers could directly cause hippocampal hyperexcitability by forming recurrent excitatory circuits, or alternatively increase the activity f inhibitory circuits and thus prevent seizures. Although experimental evidence exists to support each of these possibilities, direct functional analysis of these fibers has been lacking, due primarily to an inability to selectively isolate these fibers for physiologic characterization. Thu, their role in epileptogenesis is still unclear. Animal studies have suggested that sprouted mossy fibers might selectively, or perhaps exclusively, derive from adult-born cells. If these fibers are involved in generating seizure activity, adult-born neurons might then directly contribute to the development of epileptic circuits. Thus, they would possess a detrimental, rather than salutary, role during epileptogenesis. Furthermore, as granule cells contribute a major excitatory input into hippocampal region CA3, and also drive potent feed-forward inhibition in that region, changes in the development of this projection by adult-born cells could cause an imbalance between excitation and inhibition. Again, the functional role of these adult-born granule cell projections in epilepsy has not been explored, as it has not been possible to selectively analyze these cells and their connections in an efficient manner. In this grant, we propose to study whether adult-born neurons contribute to the formation of hyper- excitable circuits in a mouse model of epilepsy, and whether they directly promote the occurrence of seizures. We have combined various lines of genetically modified mice, which allow us to specifically label and activate these cells in live tissue. We will induce experimental epilepsy using the well-established pilocarpine model of epilepsy, and use electrophysiologic recording techniques to study the functional connectivity of these adult- born cells in the hippocampal circuit. Furthermore, we will use additional genetic manipulations to modify the electrical activity of these cells in epileptic mice in vivo, to determine how this affects seizure frequency. Our work will answer long-standing questions regarding the pathogenesis of several forms of epilepsy, by directly defining the functional role of this aberrant fiber pathway. We will be able to selectivel study sprouted mossy fiber function, regardless of the source of these fibers, as our technique allows for the selective stimulation of granule cell axons from either postnatally derived or adult born granule cells. This will provide an insight into the function of this pathway regardless of it source, but also allow us to determine whether the sprouting is partially, or perhaps predominantly, derived from adult born cells. If adult-born neurons directly contribute to the development of epilepsy, this would provide a specific therapeutic target to potentially prevent the development of epilepsy after injury, by modulating the generation and synaptic integration of these adult- born cells.

Public Health Relevance

Veterans recovering from severe traumatic brain injury (TBI) often develop epilepsy, and post-traumatic epilepsy accounts for up to 20% of all symptomatic epilepsy nationwide. Mechanisms underlying the development of epilepsy (epileptogenesis) after injury are unclear, but human and animal studies suggest that it can involve neuronal circuits in the hippocampal region of the brain. Both TBI and epileptic seizures drive the birth of new neurons in the hippocampus, and these adult-born neurons become integrated into the hippocampal circuit. We have developed new methods to image and functionally examine the connections formed by these adult-born cells, and we will test the hypothesis that these neurons directly contribute to epileptogenesis. By understanding how these adult-born cells contribute to brain rewiring during the development of epilepsy, we hope to eventually design therapies to prevent several forms of epilepsy, including epilepsy after TBI.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX002949-02
Application #
9210540
Study Section
Neurobiology B (NURB)
Project Start
2016-01-01
Project End
2019-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Portland VA Medical Center
Department
Type
DUNS #
089461255
City
Portland
State
OR
Country
United States
Zip Code
97239
Hendricks, William D; Chen, Yang; Bensen, AeSoon L et al. (2017) Short-Term Depression of Sprouted Mossy Fiber Synapses from Adult-Born Granule Cells. J Neurosci 37:5722-5735