Abstracts

Rationale: Evidence from in vitro hippocampal slice studies suggest that group I mGluR stimulation induces epileptogenesis. Furthermore, a group I mGluR-dependent mechanism appears to underlie epilepsy encountered in Fragile X patients (Chung et al., 2005). In this study DHPG, a group I mGluR agonist was infused into the lateral ventricle of the rat to determine whether this epileptogenic process can occur in normal wild-type animals. Methods: Adult male Sprague-Dawley rats (275-325g; n= 6) were anesthetized with isoflurane. Each rat was placed in a stereotaxic apparatus, the skull surface exposed and a hole was drilled to allow for drug infusion. A needle attached to a Hamilton syringe was lowered into the lateral ventricle at the following coordinates measured from bregma: A-P -0.8mm, M-L 1.5mm, D-V 4.2mm from skull surface. DHPG dissolved in saline (50mM, 2ul) was infused over 40min and the needle was left in place for an additional 10min. The wound was closed and the rat was allowed to recover. Behavior was monitored continuously for 5hr after infusion. Each animal was also observed for limited periods over the next 48hr. Control rats (n=3) were treated in a similar manner except they received a saline infusion. Results: All rats recovered from anesthesia within 20min. The experimental animals exhibited the following behaviors: face washing, backwards walking, prolonged episodes of wet dog shakes (WDS; n=6/6), prolonged staring episodes (SE; n=6/6) and limbic seizures (n=1/6). DHPG-treated rats exhibited a significant increase in the mean ( SEM) number of SE (10.33 2.12 vs 0.33 0.33, p<0.02). The maximum duration of the SE ranged from 9-25min. There was also a significant increase in the mean number of WDS episodes (23.5 5.56 vs 2.33 1.2; p<0.04) in the DHPG-treated rats. Twenty-four to 48hr after drug infusion multiple WDS and seizures were observed. Control animals exhibited a limited number of post surgery WDS but spent the majority of the observation period sleeping. Conclusions: These results provide evidence that activation of group I mGluR receptors induced recurrent seizure and sub-seizure epileptic activities long after receptor activation. The observation indicates that group I mGluR stimulation constitutes a broadly relevant epileptogenic process. Since DHPG was infused into the ventricle its direct site of action is unknown. However the observation of pronounced wet dog shake activity suggests a hippocampal origin and site of action. Supported by NINDS and FRAXA (Wong) and New York State OMRDD (Goodman).