Abstracts

RATIONALE: Considerable previous work has established that the network nuclei required for audiogenic seizures (AGS) reside exclusively in the brainstem. The forms of AGS that have led to this conclusion include the severe seizure strain of genetically epilepsy-prone rats (GEPR-9s) and the Wistar AGS-susceptible rats of Strasbourg, which both exhibit tonic seizures. Highly epileptogenic forebrain limbic structures, such as the amygdala (AMG) and perirhinal cortex (PRC), which are critical in producing the facial and forelimb (F&F) clonus characteristic of forebrain-driven seizures, are not requisite structures in the neuronal network in the well-studied forms of AGS. However, the AMG becomes a critical component of the expanded seizure network in the Wistar and GEPR-9 forms of AGS after repetitive induction of AGS (AGS kindling). The less well-studied moderate seizure strain of genetically epilepsy-prone rats (GEPR-3s) exhibits running and bouncing (R&B) clonic (but not tonic) behaviors during AGS. After AGS kindling in GEPR-3s, F&F clonus began to occur immediately following the R&B clonic AGS. Recent studies in GEPR-3s suggest that the neuronal network for AGS involves the same brainstem sites that have previously been implicated in other forms of AGS. However, the role of forebrain sites such as the AMG and PRC in the neuronal network for seizures has not been evaluated in GEPR-3s.
METHODS: Cannula guide tubes were stereotaxically implanted bilaterally over the lateral AMG or PRC in GEPR-3s in ketamine/xylazine anesthetized rats. At least 7 days later focal microinjections (0.2 for 5 min or 0.25 [mu]l/min/side for 2 min) of a NMDA receptor antagonist (2-amino-7-phosphonoheptanoate, AP7) or saline vehicle were carried out in behaving GEPR-3s through cannulae inserted into AMG or PRC. Histological verification of the microinjection sites were subsequently carried out.
RESULTS: Microinjection of AP7 (1 nmol/side) in AMG significantly decreased AGS severity at 30 min post-infusion in both kindled and non-kindled GEPR-3s with recovery by 24 hr. AP7 (7.5 nmol) in the AMG reversibly (by 24 hr) blocked AGS and F&F clonus at 30 min post-infusion in kindled GEPR-3s. The 0.2 nmol dose of AP7 in AMG significantly and reversibly (by 24 hr) reduced the incidence of F&F clonus 30 min post-infusion in AGS kindled GEPR-3s without affecting R&B clonic AGS. Microinjection into PRC of AP7 (1 nmol) significantly and reversibly (by 24 hr) reduced the incidence of F&F clonus 30 min post-infusion of AGS kindled GEPR-3s but did not affect R&B clonic AGS in kindled or non-kindled GEPR-3s.
CONCLUSIONS: The ability of AP7 in the AMG to block AGS completely indicates that the AMG plays a critical role in the network for AGS in GEPR-3s, unlike the GEPR-9 and Wistar forms of AGS. The finding that lower doses of AP7 in the AMG block F&F clonus with no effect on R&B clonic AGS suggests that the AMG plays a critical role in the neuronal network for both R&B clonic AGS and AGS kindling-induced F&F clonus. The effects of PRC microinjections in GEPR-3s suggest that this site is only a critical component in the expanded seizure network induced by AGS kindling.
[Supported by: NIH AA 11628]