Functional Implications of Homer 1a Overexpression in Transgenic Mice for Seizure Susceptibility
Abstract number :
1.093
Submission category :
Year :
2000
Submission ID :
2395
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
Eckart Krupp, Heidrun Potschka, Wolfgang Loscher, Holger Hiemisch, Bo Xiao, Paul F Worley, BASF-LYNX Bioscience AG, Heidelberg, Germany; Sch of Veterinary Medicine, Hannover, Germany; Johns Hopkins Univ Sch of Medicine, Baltimore, MD.
RATIONALE: Constitutively expressed Homer proteins were shown to couple group I metabotropic glutamate receptors (mGluRs) with inositol triphosphate receptors (IP3Rs). Synaptic activity induces the expression of the immediate early gene form of Homer 1, Homer 1a, which disrupts the mGluR-IP3R-coupling in a competitive manner. Transfection of Purkinje cells with plasmids expressing Homer 1a reduced the peak amplitude of mGluR-evoked Ca2+ transients indicating a modulatory role for the Homer cascade in synaptic metabotropic receptor function. The aim of the present study was to determine the functional implications of constitutive neuronal overexpression of Homer 1a in transgenic (TG) mice with respect to neuronal hyperexcitability. METHODS: TG mice with neuronal overexpression of myc-tagged rat Homer 1a were generated. In two independent lines, expression of the transgene was examined by RT-PCR and PCR-transcripts were quantified using LightCycler analysis. TG mice were analyzed in different paradigms for behavioral or motor impairments, i.e., the open field test, holeboard test and rotarod test. In addition, an i.v.-pentylenetetrazol(PTZ)-threshold test was conducted to determine the seizure susceptibility of Homer 1a TG mice. RESULTS: TG line 95 showed a higher expression level of Homer 1a in the hippocampus as compared with TG line 93 as indicated by RT-PCR LightCycler analysis. In the rotarod test, impairment of motor coordination was observed in line 95. Furthermore, line 95 showed a significant increase in the PTZ seizure threshold in female mice as compared with the TG line 93 and littermate control mice. CONCLUSIONS: Homer 1a overexpression in TG mice has been shown to disrupt the mGluR-IP3R-complex. Our data indicate that increased expression levels of Homer 1a alter seizure susceptibility (in vivo) suggesting that the Homer pathway might be an attractive target for therapeutic intervention in neurological disorders including epileptic seizures. In order to confirm the functional implications of Homer 1a in seizure disorders further analysis in additional seizure models and in more TG lines are underway.