Precipitous induction of audiogenic kindling by activation of adenylyl cyclase in the amygdala

Purpose: Kindling of audiogenic seizure (AGS) involves ≥14 AGS over 1–2 weeks in genetically epilepsy‐prone rats (GEPR‐9s) and induces gradual seizure duration increases, epileptiform electroencephalography (EEG), and emergence of post tonic clonus (PTC), which are long‐lasting. N‐methyl‐d ‐aspartate (NMDA)–receptor activation in lateral amygdala (LA) is implicated in AGS kindling initiation. However, the persistence of AGS kindling appears to be dependent on molecular mechanisms initiated by NMDA‐receptor activation, which may involve adenylyl cyclase (AC). This study attempted to mimic AGS kindling persistently in nonkindled GEPR‐9s by one‐time activation of AC in LA. Methods: The effects of a single focal bilateral microinjection into LA of an AC activator, MPB forskolin {7‐Deacetyl‐7‐[O‐(N‐methylpiperazino)‐γ‐butyryl]‐forskolin dihydrochloride} (25–100 pmol/side), on seizure behavior in GEPR‐9s were evaluated. Results: One‐time bilateral microinjection of MPB forskolin in GEPR‐9s precipitously induced an AGS kindling–like effect, which involved significant increases in seizure duration and long‐lasting susceptibility to AGS that culminates in PTC. This effect occurred at 24 h after MPB forskolin microinjection and lasted ≥5 weeks. The effect was seen when AGS was initiated at 1 and 12 h after microinjection, but not if AGS was induced only at 24 h, indicating the importance of the temporal proximity of AGS induction to the MPB forskolin microinjection. Discussion: These findings indicate that one‐time activation of AC within the NMDA receptor–mediated molecular cascade results in precipitous induction of AGS kindling. These data further suggest that AC activation in the LA may be an important epileptogenic mechanism that subserves the long‐lasting persistence of AGS kindling.