Elsevier

Brain Research

Volume 1701, 15 December 2018, Pages 126-136
Brain Research

Review
Double-edged GABAergic synaptic transmission in seizures: The importance of chloride plasticity

https://doi.org/10.1016/j.brainres.2018.09.008Get rights and content

Highlights

  • Fast GABAergic transmission exerts seizure suppressing or promoting action.

  • Chloride plasticity contributes to the double-edged role of GABAergic synapse.

  • Chloride homeostasis is perturbed in activity and pathology-dependent seizure.

Abstract

GABAergic synaptic inhibition, which is a critical regulator of neuronal excitability, is closely involved in epilepsy. Interestingly, fast GABAergic transmission mediated by Cl permeable GABAA receptors can bi-directionally exert both seizure-suppressing and seizure-promoting actions. Accumulating evidence suggests that chloride plasticity, the driving force of GABAA receptor-mediated synaptic transmission, contributes to the double-edged role of GABAergic synapses in seizures. Large amounts of Cl influx can overwhelm Cl extrusion during seizures not only in healthy tissue in a short-term “activity-dependent” manner, but also in chronic epilepsy in a long-term, irreversible “pathology-dependent” manner related to the dysfunction of two chloride transporters: the chloride importer NKCC1 and the chloride exporter KCC2. In this review, we address the importance of chloride plasticity for the “activity-dependent” and “pathology-dependent” mechanisms underlying epileptic events and provide possible directions for further research, which may be clinically important for the design of GABAergic synapse-targeted precise therapeutic interventions for epilepsy.

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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