Abstracts

Inhibitory neurotransmission functions in neural circuits by repressing of excitatory output. Local GABAergic interneurons are the main source of inhibition in the cerebral cortex. Loss of these neurons leads to epilepsy along with other neurological disorders. Interneuron development is tightly regulated by molecular cues including hepatocyte growth factor/scatter factor (HGF/SF). HGF/SF signals via its receptor MET to promote cellular survival, differentiation, mitogenesis and migration dependent upon cellular context. HGF/SF, which is secreted as a single chain precursor form, must be cleaved for biological function by serine proteases such as urokinase plasminogen activator (uPA). uPAR[italic],[/italic] the receptor of uPA, efficiently increases the protease cleavage by uPA. Adult [italic]uPAR^-/[/italic]^- mice have decreased numbers of neocortical GABAergic interneurons and severe behavioral dysfunction such as spontaneously generated seizure and increased susceptibility to PTZ(pentylenetretrazol)-induced seizures. These defects of GABAergic interneurons have been attributed to a reduction of HGF/SF., The [italic]uPAR^-/-[/italic] mouse was bred with transgenic mouse overexpressing HGF/SF under the astrocytic glial fibrillary acidic protein promoter (GFAP). Immunohistochemistry and seizure behaviors to PTZ (pentylenetetrazol) were used to evaluate anatomical and functional recovery of GABAergic interneuron in wildtype, [italic]GFAP-Hgf[/italic], [italic]uPAR^-/[/italic]^-, and [italic]uPAR^-/[/italic]^-:[italic]GFAP-Hgf[/italic] mice., The loss of interneurons in the [italic]uPAR^-/[/italic]^- mouse is restored in [italic]uPAR^-/[/italic]^-x[italic]GFAP-Hgf[/italic] mouse, in which the [italic]uPAR^-/-[/italic] mouse was bred with an HGF-overexpressing mouse line ([italic]GFAP-HGF[/italic]). Reduction of PV(parvalbumin), a marker of GABAergic neuron, in the [italic]uPAR^-/[/italic]^- mouse is rescued in [italic]uPAR^-/[/italic]^-x[italic]GFAP-Hgf[/italic] mouse (Figure 1). The seizure susceptibility to PTZ of [italic]uPAR^-/[/italic]^- mice is decreased in the [italic]uPAR^-/[/italic]^-x[italic]GFAP-Hgf[/italic] mouse, to frequencies and severity observed in wildtype animals. The latency to seizure activity after PTZ treatment is also increased in the [italic]uPAR^-/[/italic]^-x[italic]GFAP-Hgf[/italic] mouse as compared to [italic]uPAR^-/[/italic]^- mouse., These data suggest that restoring HGF/SF levels can recover the anatomical interneuron defects and neocortical circuitry, leading to prevention of the seizure activity of [italic]uPAR^-/[/italic]^- mice. This study will help uncover molecular mechanisms critical for seizure onset and their possible therapeutic targets for epilepsy.[figure1], (Supported by Epilepsy Foundation (EMP and MB) and by the Women[apos]s Health Research Group (EMP).)