Abstract
Glycogen synthase kinase-3 (GSK-3) is ubiquitously expressed throughout the brain and involved in vital molecular pathways such as cell survival and synaptic reorganization and has emerged as a potential drug target for brain diseases. A causal role for GSK-3, in particular the brain-enriched GSK-3β isoform, has been demonstrated in neurodegenerative diseases such as Alzheimer’s and Huntington’s, and in psychiatric diseases. Recent studies have also linked GSK-3 dysregulation to neuropathological outcomes in epilepsy. To date, however, there has been no genetic evidence for the involvement of GSK-3 in seizure-induced pathology. Status epilepticus (prolonged, damaging seizure) was induced via a microinjection of kainic acid into the amygdala of mice. Studies were conducted using two transgenic mouse lines: a neuron-specific GSK-3β overexpression and a neuron-specific dominant-negative GSK-3β (GSK-3β-DN) expression in order to determine the effects of increased or decreased GSK-3β activity, respectively, on seizures and attendant pathological changes in the hippocampus. GSK-3 inhibitors were also employed to support the genetic approach. Status epilepticus resulted in a spatiotemporal regulation of GSK-3 expression and activity in the hippocampus, with decreased GSK-3 activity evident in non-damaged hippocampal areas. Consistent with this, overexpression of GSK-3β exacerbated status epilepticus-induced neurodegeneration in mice. Surprisingly, decreasing GSK-3 activity, either via overexpression of GSK-3β-DN or through the use of specific GSK-3 inhibitors, also exacerbated hippocampal damage and increased seizure severity during status epilepticus. In conclusion, our results demonstrate that the brain has limited tolerance for modulation of GSK-3 activity in the setting of epileptic brain injury. These findings caution against targeting GSK-3 as a treatment strategy for epilepsy or other neurologic disorders where neuronal hyperexcitability is an underlying pathomechanism.
Highlights
Epilepsy is one of the most common chronic neurological brain disorders[1]
Spatiotemporal changes in GSK-3β expression and phosphorylation following Status epilepticus (SE) To explore the response of GSK-3β to prolonged seizures, we used a well-characterized model of intraamygdala kainic acid (KA)-induced SE in mice[59]
We focused our analysis on the PI3K/Akt, Wnt, insulin, and the mammalian target of rapamycin (mTOR) pathways that are linked to both epilepsy and Glycogen synthase kinase-3 (GSK-3) function[8,60,61,62,63]
Summary
Epilepsy is one of the most common chronic neurological brain disorders[1]. Despite the development of several new anti-epileptic drugs (AEDs), approximately 30% of patients remain drug refractory[1]. Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and is prone to pharmacoresistance and is Official journal of the Cell Death Differentiation Association. Engel et al Cell Death and Disease (2018)9:969 associated with pathological changes in the hippocampus including neurodegeneration[2]. Status epilepticus (SE) is a prolonged seizure and clinical emergency associated with a high mortality rate and wide-spread brain damage[3]. Pharmacoresistance in SE remains a serious clinical challenge with ~30% of patients not responding to currently available drugs[1,3]. There is an urgent need to identify new drug targets, preferably with novel mechanisms of action
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