GABA receptor mechanisms in the central nervous system

The hippocampus, in particular the neocortex-hippocampus-neocortex circuit, is widely believed to be crucial in memory. Information flow in this circuit is strongly influenced by relatively sparse afferents derived from subcortical centres, such as the septum, involved in arousal, emotions and autonomic control. A powerful mechanism, by which numerically small inputs can produce profound effects, is feed-forward inhibition, that is, the activation of local inhibitory interneurons, which, in turn, control the activity of large populations of principal cells in the hippocampus. An example is the cholinergic input to the hippocampus from the septum, which is likely to be involved in feed-forward operations. Here, we demonstrate the existence of a circuit underlying another powerful mechanism of subcortical control of hippocampal information processing. We show that GABA-containing afferents originating in the septum innervate most of the GABA-containing interneurons in the hippocampus, making many synaptic contacts with each of them. Activation of the GABA-containing neurons in the septum is likely to lead to disinhibition of the principal neurons in the hippocampal formation and so this pathway is probably crucial in the induction of hippocampal electrical activity patterns, and may be involved in NMDA (N-methyl-D-aspartate) receptor-mediated functions, such as memory, in a permissive manner.

1. The ion-selective and ion transport properties of glycine receptor (GlyR) and gamma-aminobutyric acid receptor (GABAR) channels in the soma membrane of mouse spinal cord neurones were investigated using the whole-cell, cell-attached and outside-out patch versions of the patch-clamp technique. 2. Current-voltage (I-V) relations of transmitter-activated currents obtained from whole-cell measurements with 145 mM-Cl- intracellularly and extracellularly, showed outward rectification. In voltage-jump experiments, the instantaneous I-V relations were linear, and the steady-state I-V relations were rectifying outwardly indicating that the gating of GlyR and GABAR channels is voltage sensitive. 3. The reversal potential of whole-cell currents shifted 56 mV per tenfold change in internal Cl- activity indicating activation of Cl(-)-selective channels. The permeability ratio of K+ to Cl- (PK/PCl) was smaller than 0.05 for both channels. 4. The permeability sequence for large polyatomic anions was formate greater than bicarbonate greater than acetate greater than phosphate greater than propionate for GABAR channels; phosphate and propionate were not measurably permeant in GlyR channels. This indicates that open GlyR and GABAR channels have effective pore diameters of 5.2 and 5.6 A, respectively. The sequence of relative permeabilities for small anions was SCN- greater than I- greater than Br- greater than Cl- greater than F- for both channels. 5. GlyR and GABAR channels are multi-conductance-state channels. In cell-attached patches the single-channel slope conductances close to 0 mV membrane potential were 29, 18 and 10 pS for glycine, and 28, 17 and 10 pS for GABA-activated channels. The most frequently observed (main) conductance states were 29 and 17 pS for the GlyR and GABAR channel, respectively. 6. In outside-out patches with equal extracellular and intracellular concentrations of 145 mM-Cl-, the conductance states were 46, 30, 20 and 12 pS for GlyR channels and 44, 30, 19 and 12 pS for GABAR channels. The most frequently occurring main state was 46 pS for the GlyR and 30 pS for the GABAR channel. 7. Single-channel conductances measured in equal 140 mM concentrations of small anions on both membrane faces revealed a conductance sequence of Cl- greater than Br- greater than I- greater than SCN- greater than F- for both channels. This is nearly the inverse sequence of that found for the permeability of these ions indicating the presence of binding sites for ions in the channel.(ABSTRACT TRUNCATED AT 400 WORDS)

Recent studies of the effects of stimulating the superior colliculus (SC) in rodents suggest that this structure mediates at least two classes of response to novel sensory stimuli. One class contains the familiar orienting response, together with movements resembling tracking or pursuit, and appears appropriate for undefined sensory 'events'. The second class contains defensive movements such as avoidance or flight, together with cardiovascular changes, that would be appropriate for a sudden emergency such as the appearance of a predator, or of an object on collision course. The two response systems appear to depend on separate output projections, and are probably subject to different sensory and forebrain influences. These findings (1) suggest an explanation for the complex anatomical organization of the SC, with multiple output pathways differentially accessed by a very wide variety of inputs, (2) emphasize the similarities between the SC and the optic tectum in non-mammalian species, and (3) suggest that the SC may be useful as a model for studying both the sensory control of defensive responses, and how intelligent decisions can be taken about relatively simple sensory inputs.