Abstracts

Rationale: Imbalances between excitatory and inhibitory signals due to altered GABA transmission causes neurological disorders, including epilepsy, autism, mental retardation. The urokinase plasminogen activator receptor (uPAR), as an activator of hepatocyte growth factor/scatter factor (HGF/SF), mediates multiple biological functions. The uPAR null mouse lacks the GABAergic interneurons in frontal cortical regions suggesting altered frontal lobe function. The uPAR-/- mouse has intact learning and memory function, but displays abnormal emotional and social behavior, indicating the uPAR-/- mouse is rodent model of frontal lobe epilepsy. Loss of uPAR decreases HGF/SF levels, and we hypothesized that genetic supplementation of HGF/SF will recover the deficits observed in the uPAR-/- mouse. Methods: The uPAR-/-:Gfap-HGF mouse, generated by crossing a mouse that expresses HGF/SF under the control of the glial fibrillary acidic protein promoter (Gfap) with the uPAR-/- mouse, showed anatomical recovery of cortical GABAergic interneurons, as compared to the uPAR-/- mouse. Previously the uPAR-/- mouse demonstrated dramatically increased susceptibility to pentylenetetrazole (PTZ) seizure induction, spontaneous seizures, and abnormal EEG activityResults: The seizure behavior was reversed in the uPAR-/-:Gfap-HGF mice that had increased levels of active HGF/SF in the postnatal brain. We tested mice with inhibitory GABAergic defects on behavior tests such as the resident-intruder assay, elevated plus maze, social interaction paradigm, and the mouse reversal/set-shifting test. The uPAR-/- mouse has a difficulty on these tests, suggesting that loss of uPAR alters social behavior, anxiety, and cognition. We are investigating whether overexpressing HGF/SF recovers the behavioral defects. We are also performing cortical EEG recordings in the awake mouse to probe whether exogenous HGF/SF changes the abnormal cortical neural circuitry in uPAR-/- mouse. Conclusions: This study demonstrates a successful genetic approach to remediate the adverse effects of frontal lobe epilepsy in a rodent model.