Depression of glutamate and GABA release by presynaptic GABAB receptors in the entorhinal cortex in normal and chronically epileptic rats

Presynaptic GABAB receptors (GABABR) control glutamate and GABA release at many synapses in the nervous system. In the present study we used whole-cell patch-clamp recordings of spontaneous excitatory and inhibitory synaptic currents in the presence of TTX to monitor glutamate and GABA release from synapses in layer II and V of the rat entorhinal cortex (EC)in vitro. In both layers the release of both transmitters was reduced by application of GABABR agonists. Quantitatively, the depression of GABA release in layer II and layer V, and of glutamate release in layer V was similar, but glutamate release in layer II was depressed to a greater extent. The data suggest that the same GABABR may be present on both GABA and glutamate terminals in the EC, but that the heteroreceptor may show a greater level of expression in layer II. Studies with GABABR antagonists suggested that neither the auto- nor the heteroreceptor was consistently tonically activated by ambient GABA in the presence of TTX. Studies in EC slices from rats made chronically epileptic using a pilocarpine model of temporal lobe epilepsy revealed a reduced effectiveness of both auto- and heteroreceptor function in both layers. This could suggest that enhanced glutamate and GABA release in the EC may be associated with the development of the epileptic condition. Copyright © 2006 S. Karger AG

Distribution and localization of the GABAB receptor

The functional GABAB receptors (GABABRs) are formed by obligate heteromers composed of two principal subunits named GABAB1 and GABAB2. In Drosophila melanogaster three GABAB subunits have been identified: GB1, GB2 and GB3. The GB1 and GB2 subunits need to be co-expressed in Xenopus oocytes or in mammalian cell lines to produce functional GABABRs. A subfamily of potassium channel tetramerization domain-containing (KCTD8, 12, 12b, and 16) proteins that are constituents of native GABABRs were recently identified. KCTDs show a temporal and spatial distribution pattern that may contribute to the heterogeneity of native GABABRs and their pharmacological properties. Of several isoforms of the GABAB1 subunit identified to date, the most abundant in the brain are the isoforms 1a and 1b; they are co-expressed with the subunit GABAB2 and their expression differs across brain and neuronal populations. GABAB1a localizes to glutamatergic terminals and is necessary for hetero-receptor function. Both isoforms 1a and 1b are detected in dendrites, but only GABAB1b in spine heads. Electron microscopy studies show that in the central nervous system (CNS), GABAB1 and GABAB2 are both pre and postsynaptic, but mostly localize to postsynaptic sites. The GABAB1(a/b) and GABAB2 subunits show an overlapping pattern of distribution throughout the CNS with certain exceptions (i.e. caudate-putamen and cerebellum). GABABRs are also detected in Schwann cells, in several peripheral tissues, and in non-neuronal cells (cardiomyocytes and airway smooth muscle). The widespread distribution of GABABRs in the CNS and the periphery reflects their physiological, pathophysiological, and pharmacological relevance