Abstracts

In response to acoustic stimulation genetically epilepsy-prone rats (GEPR-9s) exhibit tonic extension audiogenic seizures (AGS). However, with frequent repetitive AGS (audiogenic kindling) seizures increase in duration and an additional behavior, post-tonic clonus (PTC) is induced, which increases in incidence and duration as kindling proceeds. This AGS kindling-induced convulsive behavior change is long-lasting and is considered to be a model of epileptogenesis. Previous studies indicate that plastic changes in the synaptic projection to the lateral nucleus of amygdala (LAMG) are critical in the processes involved in production of PTC. Activation of NMDA receptors in LAMG can transiently cause the emergence of PTC in non-kindled GEPR-9s (NK-GEPR-9s) and conversely, inhibition of NMDA receptors by a NMDA receptor antagonist reversibly blocks PTC in kindled GEPR-9s (K-GEPR-9s). Previous studies of AGS kindling also observed increased expression of an immediate early gene, as indicated by c-fos changes in LAMG. A number of steps in the molecular cascade occur between NMDA receptor activation and c-fos expression, and cAMP is implicated in this cascade. The present study examined whether PTC incidence was altered by focal microinjection into LAMG of agents that alter adenylyl cyclase (AC) activity, which is the enzyme responsible for cAMP production., GEPR-9s (200-400 g) used in the present study all exhibited tonic hindlimb extension. Audiogenic kindling involved once daily presentation of an electric bell (122 dB SPL re: 0.0002 dyne/cm) for a maximum of 60 sec given on 14 consecutive days. Microinjection cannula guides (21G) were implanted stereotaxically above LAMG bilaterally under ketamine/xylazine (100/3 mg/kg) anesthesia, and all rats continued to exhibit tonic AGS one week after implantation. An AC activator forskolin (50-200 [mu]Mol/side) or an AC inhibitor (SQ22536, 0.5-1.0 nMol/side), was focally microinjected (at 0.5 [mu]l/min for 2 min) into LAMG bilaterally via an infusion cannulae (26G). The animals were then tested for AGS at 1, 12, 24 and subsequently every 24 hrs and then once a week., Bilateral microinjection of forskolin caused the appearance of PTC in NK-GEPR-9s in response to presentation of the acoustic stimulus with an onset of 12 hr. However, AGS with PTC continued to be observed thereafter for a minimum of 5 weeks after the single microinjection. The AC inhibitor, SQ22536, transiently blocked PTC in K-GEPR-9s with an onset of 1 hr post microinjection. A complete blockade of seizures was observed at 12 hrs subsequent to which the animals gradually recovered to display a tonic hindlimb extension seizure followed by PTC at 120 hr post microinjection., These data indicate a potentially important role of AC activation in the LAMG in the molecular cascade subserving AGS kindling in GEPR-9s, a model of epileptogenesis., (Supported by SIUSM EAM grant.)