Abstracts

Rationale: Altered GABA transmission is implicated in various neurological disorders, including epilepsy, autism and mental retardation. These disorders may be due to imbalances between excitatory and inhibitory signals in neural circuitry. The urokinase plasminogen activator receptor (uPAR, gene: Plaur) mediates the activation of hepatocyte growth factor/scatter factor (HGF/SF). Loss of uPAR causes GABAergic interneuron defects in the cerebral cortex, leading to dramatically increased susceptibility to pentylenetetrazole (PTZ) seizure induction, spontaneous seizures, and abnormal EEG activity. Altered frontal lobe GABAergic interneurons also suggest that the Plaur-/- mouse may have neuropsychiatric comorbidities similar to those seen in human epilepsy patients. Lack of uPAR decreases HGF/SF levels and we hypothesized that genetic supplementation of HGF/SF will recover the seizure behaviors and neuropsychiatric comorbidities observed in the Plaur-/- mouse. Methods: To recover HGF/SF levels in the Plaur-/- mice, the Plaur-/-:GfapHGF mouse was generated by crossing a mouse that expresses human HGF/SF under the control of the mouse glial fibrillary acidic protein promoter (Gfap) with the Plaur-/- mouse. The seizure and neuropsychiatric comorbidities of Plaur-/- mice and their recovery in Plaur-/-:GfapHGF mouse were tested with the seizure behavior, resident-intruder assay, anxiety tests, the mouse reversal/set-shifting test, and EEG recording. Results: The Plaur-/- mouse showed intact learning and memory function, but alterations in social behavior, anxiety, and cognition, indicating the Plaur-/- mouse is a rodent model of frontal lobe epilepsy. The Plaur-/-:GfapHGF mice had increased levels of active HGF/SF in the postnatal brain, compared to Plaur-/- and anatomical recovery of GABAergic interneurons in cerebral cortex. The increase of GABAergic interneurons in the cerebral cortex of Plaur-/-:GfapHGF mice recovered much of the seizure phenotype and the cognitive defects of the Plaur-/- mouse. We are currently correlating EEG activity with behavioral responses with the presence of abnormal EEG activity to determine how disruptions in overall neural circuitry affect frontal lobe mediated cognition. Conclusions: GABAergic interneuron defects in the frontal cortex of the Plaur-/- mouse brought on a seizure phenotype along with mouse versions of human neuropsychiatric comorbidities. Alterations to exogenous HGF/SF levels can be a successful approach to remediate the adverse effects of frontal lobe epilepsy in a rodent model.