Chopping Out CHOP Chops the Fate of Neurons.

Commentary We all seem to know that " seizures beget seizures, " but do we really know why? Seizure-induced neuronal cell death may play a contributing role under certain circumstances (1, 2), and a variety of endogenous neuroprotective mechanisms are in place to limit neuronal injury (3–5). Neuronal cell loss in epilepsy is not straightforward and can depend upon spatial patterns, cell types, and timing of pathways that can either promote or reduce injury (3). Prolonged seizures are thought to induce excessive glutamate receptor activation, leading to the disruption of intracellular calcium homeostasis, oxidative stress, DNA damage, and dysfunction of intracellular organ-elles—among which, the unfolded protein response and associated endoplasmic reticulum stress might play a crucial role. This response can trigger apoptosis through the proto-oncogene CCAAT/enhancer-binding protein homologous protein (CHOP), which is a transcription factor induced by all three differing pathways triggered by the unfolded protein response (6). The precise role of CHOP in cell death pathways has been highly controversial. Based on findings that CHOP-enhances neuronal cell death in models of neurodegeneration and acute brain injury, the therapeutic inhibition of CHOP has been suggested as a neuroprotective strategy (7). That said, CHOP was shown to promote neuronal survival after endoplasmic reticulum stress, supporting a neuroprotective role of CHOP (8). Since CHOP expression in the hippocampus is induced by seizures (9), the question arises whether this increase promotes neuronal cell death in epilepsy or whether an increase in CHOP is an adaptive response to limit neuronal cell loss. The distinction between those possibilities is of obvious relevance for the development of neuroprotective strategies in epilepsy. The study by Engel and colleagues was designed to gain mechanistic and functional insight into the role of CHOP in seizure induced neuronal cell death. The authors used a mouse model of focal onset status epilepticus (SE), triggered by unilateral injection of the excitotoxin kainic acid (KA) into the basolateral amygdala. This treatment leads to acute neuronal cell loss in region CA3 of the ipsilateral hippocampus, followed by development of spontaneous seizures. Using quantitative analyses, they first showed that CHOP protein expression was increased in the whole hippocampus 8 hours after the SE, whereas CA3-selective neuronal cell loss was found 24 hours after the SE. Likewise, CHOP expression was found to be increased in all subfields of the hippocampus 8 hours following a seizure preconditioning stimulus—a well-established neu-roprotective strategy—or 8 hours after combining the SE …