Neuroplasticity in specific limbic system circuits may mediate specific kindling induced changes in animal affect - implications for understanding anxiety associated with epilepsy

In two complementary experiments, we studied the effects of low frequency s timulation (LFS) of the amygdala on behavioral effects of kindling in rats and cats. These studies tested the hypothesis that kindling induced long te rm potentiation (KLTP) in amygdala circuits underlies interictal behavioral change. Since LFS can depotentiate LTP, it was predicted that LFS should b oth depotentiate KLTP and reverse behavioral effects of kindling. In cats, the effects of LFS on KLTP of amygdala efferents was studied, and related t o behavioral effects. Partial ventral hippocampal kindling in cats and righ t amygdala kindling in rodents lastingly increased defensive response to ra ts in cats, and anxiety-like behavior (ALB) in the elevated plus-maze in ra ts. In addition, partial kindling reduced predatory attack behavior in cats independent of its effects on defensive response. Partial kindling also in duced KLTP of amygdala efferent transmission to ventromedial hypothalamus ( VMH) and periaqueductal gray (PAG) in left and right hemispheres. Depotenti ation of amygdala efferent KLTP by bilateral amygdala LFS selectively reduc ed KLTP in right amygdala efferents. At the same time, defensive behavior, but not attack behavior, was returned to levels seen prior to partial kindl ing. Defensiveness returned to post kindling levels between 44 and 76 days after LFS. At the same time, LTP was restored in the right Amygdalo-PAG pat hway only. These findings suggest that lasting change in affect produced by kindling depends on LTP of right amygdala efferent transmission to PEG, re plicating studies of the effects of FG-7142 on brain and behavior in the ca t. The findings suggest further that the spectrum of behavioral changes pro duced by partial kindling are dependent on changes in a variety of neural c ircuits, and that amygdala efferent transmission changes are responsible fo r changes in defensive behavior, but not attack behavior. Effects of LFS we re not due to damage, as thresholds to evoke amygdala efferent response wer e unchanged. Other data suggest KLTP and depotentiation in right Amygdalo-P AG may reflect changes in glutamate receptor density/synapse number. Kindli ng effects on rat ALE persisted for at least 1 month. Bilateral but not uni lateral amygdala LFS reversed the effects of kindling on risk assessment in the plus maze for at least 3 weeks. Bilateral LFS also reversed the effect s of kindling on open arm exploration, but effects were shorter lived, appe aring at 1 day but not 3 weeks after kindling and LFS. These findings are c onsistent with other studies which suggest that amygdala neuroplasticity in separable amygdala circuits mediates lasting changes in open arm avoidance and risk assessment. Taken together, the findings of both studies support the hypothesis that a form of LTP of specific amygdala circuits underlies l asting changes in affect produced by limbic kindling. Clinical implications of these findings are discussed. Crown Copyright (C) 2000 Published by Els evier Science Ltd. All rights reserved.