Glial GABA Transporters as Modulators of Inhibitory Signalling in Epilepsy and Stroke

Abstract

Imbalances in GABA-mediated tonic inhibition are involved in several pathophysiological conditions. A classical way of controlling tonic inhibition is through pharmacological intervention with extrasynaptic GABA receptors that sense ambient GABA and mediate a persistent GABAergic conductance. An increase in tonic inhibition may, however, also be obtained indirectly by inhibiting glial GABA transporters (GATs). These are sodium-coupled membrane transport proteins that normally act to terminate GABA neurotransmitter action by taking up GABA into surrounding astrocytes. The aim of the review is to provide an overview of glial GATs in regulating tonic inhibition, especially in epilepsy and stroke. This entails a comprehensive summary of changes known to occur in GAT expression levels and signalling following epileptic and ischemic insults. Further, we discuss the accumulating pharmacological evidence for targeting GATs in these diseases.

Lack of evidence for synaptic high‐affinity γ‐hydroxybutyric acid (GHB) transport in rat brain synaptosomes and 11 Na+‐dependent SLC neurotransmitter transporters

“…[ 3 H]GHB uptake in intact synaptosomes First, to validate the quality of the isolated and purified rat brain cortical synaptosomes, we probed the GAT1 transporter, which is highly expressed in presynaptic nerve terminals (Lie et al 2017). We observed a clear GAT1mediated uptake of [ 3 H]GABA as the total uptake was significantly inhibited with the known GAT1 inhibitor tiagabine.…”

Shrm4 contributes to autophagy inhibition and neuroprotection following ischemic stroke by mediating GABA B receptor activation

“…26 The activation not just of GABA B , receptors, but also GABA A receptors are protective against ischemic neuronal damage. 11,12,27,28 In addition, activation of GABA A and GABA B receptors provided neuroprotection in the context of ischemia in vitro and in vivo through the PI3K/Akt signaling pathway. 29 More importantly, GABA B receptor activators/agonists such as baclofen are readily available for further research.…”

Pharmacological Characterization of a Betaine/GABA Transporter 1 (BGT1) Inhibitor Displaying an Unusual Biphasic Inhibition Profile and Anti-seizure Effects

“…Of particular relevance, BGT1 has been proposed to induce an extrasynaptic protecting mechanism following excitotoxic brain injury [24,25]. Additionally, reported increases in BGT1 expression levels after epileptic insults in patients and animal models [8] support a potential role for BGT1 during certain pathological conditions. The role of BGT1 in seizure management, however, is questioned by the unchanged seizure threshold in BGT1 knock out (KO) mice [26], although compensatory mechanisms from the remaining GATs could have masked the effect of deleting BGT1 [27][28][29].…”

“…An imbalance between excitatory and inhibitory signalling is reported in several neurological disorders including epilepsy, Alzheimer's disease, and ischemia [1][2][3][4][5][6][7]. Accordingly, enhanced GABAergic signalling may counterbalance the excessive excitatory neurotransmission and alleviate seizures in patients [8]. Fast inhibitory neurotransmission by GABA is mediated through ligand-gated ionotropic GABA A receptors [9,10], which are favoured therapeutic targets.…”