GABA Transporter-1 (GAT1)-Deficient Mice: Differential Tonic Activation of GABA_A Versus GABA_B Receptors in the Hippocampus

Abstract

. GABA transporter-1 (GAT1)-deficient mice: differential tonic activation of GABA A versus GABA B receptors in the hippocampus. J Neurophysiol 90: 2690 -2701. First published June 18, 2003 10.1152/jn.00240.2003. After its release from interneurons in the CNS, the major inhibitory neurotransmitter GABA is taken up by GABA transporters (GATs). The predominant neuronal GABA transporter GAT1 is localized in GABAergic axons and nerve terminals, where it is thought to influence GABAergic synaptic transmission, but the details of this regulation are unclear. To address this issue, we have generated a strain of GAT1-deficient mice. We observed a large increase in a tonic postsynaptic hippocampal GABA A receptor-mediated conductance. There was little or no change in the waveform or amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) or miniature IPSCs. In contrast, the frequency of quantal GABA release was one-third of wild type (WT), although the densities of GABA A receptors, GABA B receptors, glutamic acid decarboxylase 65 kDa, and vesicular GAT were unaltered. The GAT1-deficient mice lacked a presynaptic GABA B receptor tone, present in WT mice, which reduces the frequency of spontaneous IPSCs. We conclude that GAT1 deficiency leads to enhanced extracellular GABA levels resulting in an overactivation of GABA A receptors responsible for a postsynaptic tonic conductance. Chronically elevated GABA levels also downregulate phasic GABA release and reduce presynaptic signaling via GABA B receptors thus causing an enhanced tonic and a diminished phasic inhibition.

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

“…Tonic GABA inhibition was determined as the steady-state inward current that was sensitive to the GABA A R antagonist bicuculline (50 mM). Consistent with previous reports, 22,23 we observed only a small tonic GABA current in CA1 pyramidal cells from wt mice (11.3 ± 1.1 pA, n = 10). In striking contrast, CA1 pyramidal cells from two independent lines of dnActRIB mice (L1 and L3), 7 displayed significantly stronger tonic GABA inhibition (L1 25.5±3.3 pA, n = 6, P = 0.006; L3 27.4±2.3 pA, n = 5, P = 0.001; Figures 3a and b; left columns).…”

“…23 However, the higher efficacy of the GABA B R agonist baclofen to activate GIRK current in tg neurons, as compared to wt neurons, clearly demonstrated that the GABA B R-dependent pathway is another postsynaptic target of activin. By downregulating GABA B R-activated GIRK currents, activin signaling would be expected to raise the excitability of CA1 pyramidal cells, enhance their firing probability and, by decreasing the shunting inhibition of incoming excitatory input, modify information processing and gain control.…”

“…GAT1 is the main GABA transporter in the hippocampus and is predominantly, but not exclusively expressed in neurons. 23 In addition to rapidly clearing released GABA from the synaptic cleft, GAT1 plays also an essential role in the extent of tonic inhibition in the CA1 region, since it removes diffusely distributed GABA with high efficacy from the extracellular space. 24 In fact, blockade of GAT1 with NO-711 (5 mM) in the presence of GABA B R antagonist CGP 55845 (1 mM) raised the tonic current of wt pyramidal cells into the range typically observed in cells from dnActRIB hippocampi (25.7 ± 6.9 pA, n = 7, P = 0.03).…”

Molecular Targets for Antiepileptic Drug Development

“…324 However, in GAT-1 knockout mice, IPSCs are not potentiated, phasic GABA release is downregulated, and GABA-mediated tonic conductance is potentiated. 329 Thus, the long-term antiepileptic action of tiagabine may be mediated by potentiation of the tonic inhibitory effect of GABA in the forebrain rather than enhancement of phasic inhibition. 330 Studies with a novel GABA-transporter inhibitor, EF1502, that potently inhibits GAT-1 and GAT-2 (BGT-1)-but not GAT-3 and GAT-4 -indicate that inhibition of GAT-2 potentiates the anticonvulsant activity of GAT-1.…”

Reduced Anxiety and Depression-Like Behaviors in Mice Lacking GABA Transporter Subtype 1

“…Our previous work had demonstrated that the GAT1 gene knockout mice have decreased ethanol aversion and ethanol reward, and insensitivity to both the sedative/ hypnotic and the motor stimulant effects of ethanol (Cai et al, 2006). It was also reported that GAT1 deficiency leads to enhanced extracellular GABA levels and results in an overactivation of GABA A receptors (Jensen et al, 2003).…”