Pathology and pathophysiology of the amygdala in epileptogenesis and epilepsy

Abstract

Acute brain insults, such as traumatic brain injury, status epilepticus, or stroke are common etiologies for the development of epilepsy, including temporal lobe epilepsy (TLE), which is often refractory to drug therapy. The mechanisms by which a brain injury can lead to epilepsy are poorly understood. It is well recognized that excessive glutamatergic activity plays a major role in the initial pathological and pathophysiological damage. This initial damage is followed by a latent period, during which there is no seizure activity, yet a number of pathophysiological and structural alterations are taking place in key brain regions, that culminate in the expression of epilepsy. The process by which affected/injured neurons that have survived the acute insult, along with well-preserved neurons are progressively forming hyperexcitable, epileptic neuronal networks has been termed epileptogenesis. Understanding the mechanisms of epileptogenesis is crucial for the development of therapeutic interventions that will prevent the manifestation of epilepsy after a brain injury, or reduce its severity. The amygdala, a temporal lobe structure that is most well known for its central role in emotional behavior, also plays a key role in epileptogenesis and epilepsy. In this article, we review the current knowledge on the pathology of the amygdala associated with epileptogenesis and/or epilepsy in TLE patients, and in animal models of TLE. In addition, because a derangement in the balance between glutamatergic and GABAergic synaptic transmission is a salient feature of hyperexcitable, epileptic neuronal circuits, we also review the information available on the role of the glutamatergic and GABAergic systems in epileptogenesis and epilepsy in the amygdala.

Figure 1

Photomicrographs of cresyl violet-stained coronal sections (section thickness: (A) 35μm, (B) 16μm) from the rat piriform cortex-amygdala region, at different time points after kainic acid-induced SE (KA-SE), and from control animals. Sections are approximately -2.12mm from bregma (after Paxinos and Watson, 1998). Upper images (A) demonstrate the extensive edema present at 3 days after KA-SE in the piriform cortex and the amygdala (outlined with dotted line). (B) Edema is no longer present at 24 days after KA-SE, while dramatically severe neuronal loss is evident in the piriform cortex (small arrows). The cortical nucleus of the amygdala is also damaged but to a lower extent (*). The magnocellular division of the basal nucleus of the amygdala (large arrows) remains well preserved at both time points after KA-SE. Scale bar: 500 μm.

Figure 2

Field potentials evoked by stimulation of the external capsule in the BLA region of in vitro brain slices. In rats which had undergone status epilepticus (SE) by systemic injection of kainic acid, eliciting field potentials required higher stimulus intensities compared to control rats (this is due at least in part to amygdala damage; see text), and the field potentials in these rats - which are already epileptic by day 7- contained multiple, low-amplitude population spikes. Bath application of the GluR5 agonist ATPA, which excites principal cells in the BLA (Gryder and Rogawski, 2003) and reduces evoked GABA_A receptor-mediated inhibition (Braga et al., 2003), produced epileptiform activity in both the control rats and the SE-rats. Epileptiform activity was always stronger in the control rats compared to the SE-rats, probably due to the neuronal damage in the SE-rat. It is noteworthy however that the SE-damaged amygdala can still sustain strong epileptiform activity.