Research ArticleNeuroscience

A switch in G protein coupling for type 1 corticotropin-releasing factor receptors promotes excitability in epileptic brains

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Sci. Signal.  14 Jun 2016:
Vol. 9, Issue 432, pp. ra60
DOI: 10.1126/scisignal.aad8676

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Why stress makes epilepsy worse

Seizures caused by uncontrolled neuronal activity easily starts in a part of the brain called the piriform cortex. Normally, the activity of the piriform cortex is suppressed by CRF, a neuropeptide that is released in response to stress. Narla et al. found that in rats with experimentally induced epilepsy, CRF enhanced, rather than suppressed, neuronal activity in this part of the brain. In the brains of epileptic rodents, the receptor for CRF signaled through a different Gα protein, and G protein switching contributed to the CRF-induced enhancement in neuronal activity. These results may explain why stress and anxiety tend to increase the frequency of seizures in epileptics.

Abstract

Anxiety and stress increase the frequency of epileptic seizures. These behavioral states induce the secretion of corticotropin-releasing factor (CRF), a 40–amino acid neuropeptide neurotransmitter that coordinates many behavioral responses to stress in the central nervous system. In the piriform cortex, which is one of the most seizurogenic regions of the brain, CRF normally dampens excitability. By contrast, CRF increased the excitability of the piriform cortex in rats subjected to kindling, a model of temporal lobe epilepsy. In nonkindled rats, CRF activates its receptor, a G protein (heterotrimeric guanosine triphosphate–binding protein)–coupled receptor, and signals through a Gαq/11-mediated pathway. After seizure induction, CRF signaling occurred through a pathway involving Gαs. This change in signaling was associated with reduced abundance of regulator of G protein signaling protein type 2 (RGS2), which has been reported to inhibit Gαs-dependent signaling. RGS2 knockout mice responded to CRF in a similar manner as epileptic rats. These observations indicate that seizures produce changes in neuronal signaling that can increase seizure occurrence by converting a beneficial stress response into an epileptic trigger.

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