The effects of gabapentin and thrombospondins on enhanced excitatory connectivity, new synapse formation and epileptogenesis after neocortical injury sprouting of new excitatory wiring between neurons in cerebral cortex and hippocampus, changes in glial cells and formation of excitatory synapses are consequences of brain injury that are thought to contribute to epilepsy in animal models and human brain. There is no effective prophylactic treatment available to prevent epileptogenesis after brain injury. The planned experiments focus on a new approach for limiting the development of the increased excitatory connections and epilepsy after cortical trauma. Astrocyte-secreted thrombospondins (TSPs) are involved in new excitatory synapse formation during development and after cortical injury. Experiments will test the hypothesis that pregabalin (PGB) (Lyrica), an approved drug that interferes with the binding of TSPs to their alpha2delta-1 receptor, will decrease excitatory synapse formation and sprouting and limit development of epileptiform activity. The effects of PGB and TSPs will be explored in the partial cortical isolation ("undercut", UC) model of epileptogenic neocortical injury in nave mice, in TSP "knockout" mice and alpha2delta-1 overexpressing epileptic mice. The incidence of epileptiform activity recorded in in vitro cortical slices after injury, sprouting of axons, density of excitatory synapses and network connectivity will be measured using electrophysiological and anatomical techniques. Laser scanning photostimulation of caged glutamate will be used in conjunction with whole cell recordings to map excitatory connections in cortical slices. A possible link between excessive neuronal activity and increases in TSPs, the alpha2delta-1 receptor and new synapse formation will be studied in nave or injured cortex. The effects of PGB treatment after cortical injury in vivo on these measures will be assessed to test the hypothesis that the drug will decrease the structural and functional abnormalities that follow brain trauma and lead to the development of epilepsy. Relevance: Posttraumatic epilepsy is a prominent consequence of serious neocortical or hippocampal injury that alters neuronal and glial structure and function and induces hyperexcitability in cortical circuits. Unfortunately, treatment is often ineffective at relieving seizures once they occur and no drug is available that will prevent the epileptogenic processes that lead to posttraumatic epilepsy. Results of these experiments will contribute to understanding cellular and circuit effects of cortical injury, and provide new information about a potential role for gabapentin and pregabalin to prevent development of epilepsy after brain injury.

Public Health Relevance

Posttraumatic epilepsy is a prominent consequence of serious neocortical or hippocampal injury that alters neuronal and glial structure and function and induces hyperexcitability in cortical circuits. Unfortunately, treatment is often ineffective a relieving seizures once they occur and no drug is available that will prevent the epileptogenic processes that lead to posttraumatic epilepsy. Results of these experiments will contribute to understanding cellular and circuit effects of cortical injury, and provide new information about a potential role for gabapentin and pregabalin to prevent development of epilepsy after brain injury.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01NS090076-01
Application #
8802778
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304