ReviewDouble-edged GABAergic synaptic transmission in seizures: The importance of chloride plasticity
Introduction
Epilepsy is a common neurological disorder characterized by recurrent, unprovoked seizures. Although the pathophysiologic mechanism underlying epilepsy is multifactorial, it is commonly recognized that seizures are caused by generalized hyperexcitability and excessive or hypersynchronous activity with enhanced neuronal excitability (Devinsky et al., 2018, Xu et al., 2016). GABAergic synapses can modulate the properties of principal cell firing and exert selective filtering of synaptic excitation in the brain (Fishell and Rudy, 2011). GABAergic synaptic transmission is involved in various phases of epilepsy, including seizure initiation (Dragunow, 1989, Uva et al., 2015), seizure propagation (Trevelyan and Schevon, 2013), and seizure termination (Stringer and Lothman, 1990, Wen et al., 2015), as well as epileptogenesis (Scharfman and Brooks-Kayal, 2014) and the formation of secondary epileptogenic mirror focuses (Khalilov et al., 2003). Interestingly, GABAergic synaptic transmission, particularly GABAA receptor-mediated fast synaptic transmission mainly permeable for chloride (Cl−), bi-directionally modulates seizures and exerts both seizure-suppressing and seizure-promoting actions (Cossart et al., 2005). Publications on the topic of “(depolarizing GABA OR depolarized GABA) AND epilepsy” indexed on PubMed between 1981 and 2018 demonstrate the growing interest in pro-epileptic GABAergic transmission research (Fig. 1). The seizure-promoting actions of GABAergic synaptic transmission can occur in acute seizure or chronic epilepsy with “activity-dependent” or “pathology-dependent” changes in Cl− plasticity that switch GABAergic signaling from hyperpolarizing to depolarizing. The double-edged role of GABAergic synaptic transmission in epilepsy may explain why pro-GABAergic drugs are frequently ineffective for controlling seizures in certain conditions (Löscher et al., 2013a). Therefore, we mainly address the importance of determining how chloride plasticity is dynamically regulated and how underlying activity-dependent and pathology-dependent mechanisms affect seizures in the brain. Understanding these mechanisms may be important for designing GABAergic synapse-targeted therapeutic interventions in a clinical perspective.
Section snippets
GABA neurotransmitter
In the mid-twentieth century, gamma-aminobutyric acid (GABA) was discovered as the chief inhibitory neurotransmitter in the mammalian central nervous system (Awapara et al., 1950). GABA is synthesized from glutamate (the principal excitatory neurotransmitter), which is converted to GABA via the enzyme glutamate decarboxylase (GAD) with pyridoxal phosphate (the active form of vitamin B6) as a cofactor (Roberts and Frankel, 1950). The principal role of GABA is to reduce neuronal excitability by
GABAA receptor-mediated synaptic transmission in the epileptic brain
There are two main aspects of the alterations of GABAA receptor-mediated synaptic transmission in epilepsy: structure-based change of GABAA receptor expression and function-based change of GABAA receptor-mediated inhibition.
“Activity-dependent” chloride plasticity in seizures
Short-term intense activation of GABAA receptors can convert initial hyperpolarizing GABA responses to depolarizing and even excitatory in a healthy brain (Isomura et al., 2003, Kaila et al., 2014b). During the period of intensive GABAA receptor activation, although there is no structure-based change of the chloride cotransporters, function-based Cl− influx can overwhelm Cl− extrusion, resulting in a high level of [Cl−]i and in a depolarizing shift in the reversal potential of the GABAA
“Pathology-dependent” chloride plasticity in epilepsy
Mechanisms underlying seizure generation in chronically epileptic tissues differ dramatically from those in healthy experimental animals. Cation-chloride cotransporter expression patterns, membrane trafficking, and protein degradation are sensitive to neuronal activity, and thus neuronal Cl− regulation is affected in multiple pathophysiological conditions (Kaila et al., 2014a, Moore et al., 2017). Following epileptogenic damage, including pathophysiological activity and various kinds of
Concluding remarks and further directions
As GABAergic neurons control circuit excitability, enhancing the activity of GABAergic neurons is believed to disrupt the onset or propagation of seizure activity. However, these manipulations have led to contradictory results, causing not only antiepileptic but also ictogenic effects, due to the perturbed Cl− homeostasis in different phases of seizure activity. [Cl−]i is partially controlled by NKCC1 and KCC2, and the alteration of their expression and function accounts for defective Cl−
Acknowledgements
This project was supported by grants from the National Natural Science Foundation of China (grant number 81630098 and 81603084).
Competing financial interests
The authors declare no competing financial interests.
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These authors contributed equally to the article.