GABA Metabolism and Transport: Effects on Synaptic Efficacy

Abstract

GABAergic inhibition is an important regulator of excitability in neuronal networks. In addition, inhibitory synaptic signals contribute crucially to the organization of spatiotemporal patterns of network activity, especially during coherent oscillations. In order to maintain stable network states, the release of GABA by interneurons must be plastic in timing and amount. This homeostatic regulation is achieved by several pre- and postsynaptic mechanisms and is triggered by various activity-dependent local signals such as excitatory input or ambient levels of neurotransmitters. Here, we review findings on the availability of GABA for release at presynaptic terminals of interneurons. Presynaptic GABA content seems to be an important determinant of inhibitory efficacy and can be differentially regulated by changing synthesis, transport, and degradation of GABA or related molecules. We will discuss the functional impact of such regulations on neuronal network patterns and, finally, point towards pharmacological approaches targeting these processes.

Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks

“…85,103,104 Together with the dendritictargeting interneurons, the pattern of convergence and divergence in hippocampal network connectivity thus reflects the intense feed-forward and feedback control of principal cells by GABAergic inhibition. 17,37,101,105,106 Importantly, PV þ basket cells and axo-axonic cells strongly increase their spiking rate during specific oscillating network states of the hippocampus, especially during theta-, gamma-, and ripple oscillations. 22,35,47,91,107 These interneurons are able to generate fast series of action potentials up to several hundred Hertz (hence: 'fast-spiking'), and they are active in almost every cycle of gamma oscillations (B30 to 100 Hz) in vitro and in vivo.…”

“…While GAD67 is expressed throughout the cytosol, GAD65 is the dominant presynaptic isoform, which is directly associated to presynaptic vesicles and therefore seems to be important for their filling. 106,155,156 This filling process, however, requires activity of a vacuolar H þ -ATPase that provides the electrical (DC) and chemical (DpH) components of the driving force for the vesicular inhibitory amino-acid transporter. 147,157 After release to the synaptic cleft, re-uptake of GABA occurs via Na þ -/Cl À -dependent GABA transporter 1 in the presynaptic terminal or via GAT-3 in processes of astrocytes that enwrap the synapse.…”

Irritable bowel syndrome, the microbiota and the gut-brain axis

“…They are able to modulate responses of vagal afferents innervating the GI tract but also posesses undesirable CNS effects, including sedation, respiratory depression and motor deficiency making potential therapeutic use difficult. 141 GABA analogs such as gabapentin and pregabalin have shown efficacy in preclinical models of visceral hypersensitivity 142,143 The mostly widely used GABA B receptor agonist, baclofen, is used for spasticity resulting from multiple sclerosis and concomitant pain, clonus, and muscular rigidity.…”

Long-distance mechanism of neurotransmitter recycling mediated by glial network facilitates visual function in Drosophila

“…A variety of transporters for glutamate, dopamine, GABA, glycine, histamine, and their metabolites have been found in both glial and neuronal membranes (6)(7)(8). Metabolic enzymes in the recycling process of transmitters, such as glutamate, GABA, and histamine, are also identified (3,8,9).…”

“…Metabolic enzymes in the recycling process of transmitters, such as glutamate, GABA, and histamine, are also identified (3,8,9). However, our knowledge of the trafficking route of inactive transmitter metabolites to neuronal terminals is still lacking.…”