The schematic diagram of the antagonistic interactions of

The schematic diagram of the antagonistic interactions of Zn2+ and neurosteroids (NSs) at GABA-A receptors is summarized in Fig. 7. Neurosteroids exhibit powerful seizure protective effects against experimental seizures probably through the potentiation of synaptic and extrasynaptic GABA-A receptor-mediated inhibitory currents. However, Zn2+ selectively hinders neurosteroid-augmented tonic inhibition but not phasic inhibition, which may partially contribute to the Zn2+ antagonism of neurosteroid-induced antiseizure activity. Previous studies show that Zn2+ blocks the frequency of mIPSCs in DGGCs from kindled but not controls (Buhl et al., 1996). Reduced Zn2+ sensitivity in GABA currents is evident in DGGCs from rats with status epilepticus (Kapur and Macdonald, 1997). Zn2+ inhibition of GABA-A receptor function is also decreased in pilocarpine-induced status epilepticus (Banerjee et al., 1999). Overall, Zn2+ greatly contributes to the balance of neuronal excitation and inhibition in both physiological and pathophysiological conditions. There are many questions that remain unclear, including whether posttranslational modifications affect Zn2+ sensitivity of GABA-A receptors. In conclusion, the present study demonstrates selective antagonistic interactions of Zn2+ and GX at extrasynaptic δGABA-A receptors in the hippocampus. Zn2+ chelation sustains the potentiation of tonic inhibition by GX. Furthermore, intrahippocampal infusion of Zn2+ significantly blocks the antiseizure activity of GX in the mouse kindling model of epilepsy, indicating that Zn2+ reduces the antiseizure effects of neurosteroids by selective blockade of extrasynaptic δGABA-A receptors. These pharmacodynamic interactions may have clinical implications in neurosteroid therapy of JZL184 sale disorders susceptible to zinc fluctuations.
Conflicts of interest
Acknowledgements The author's research was supported by the CounterACT Program, National Institutes of Health, Office of the Director and the National Institute of Neurological Disorders and Stroke [Grant U01 NS083460].
We now know that GABA (or to give it its full name γ-amino--butyric acid or its strict chemical name 4-aminobutanoic acid) is a neurotransmitter of major significance in the brain, being released by up to 40% of neurones to activate chloride channels resulting generally in inhibition of firing . Research carried out in Australia has made highly significant contributions to our understanding of the function of GABA receptors over the last 50 years . GABA was first identified in the brain in 1950 by Eugene Roberts, Sidney Undenfriend, Jorge Awapara and their colleagues in the USA . It had been described earlier in potatoes. This led to Eugene Roberts giving lectures on “why the brain is like a potato”! A flurry of activity investigating the biological properties of this deceptively simple molecule then ensued. Its neuroactive effects were of particular interest. By 1958, Stephen Kuffler, Dominick Purpura, Ed Kravitz and their colleagues in the USA had published seminal papers relating to the likely effects of GABA as an inhibitory neurotransmitter. In that same year, David Curtis and John Phillis at the Australian National University in Canberra published a brief note, less than one page, to Nature entitled “Gamma-Amino--Butyric Acid and Spinal Synaptic Transmission” in which they described the depressant action of GABA on neuronal firing in the cat spinal cord . They stated “These results make it extremely unlikely that γ-amino--butyric acid is a transmitter substance in the mammalian spinal cord.” Further, they stated “Accordingly, it is probable that γ-amino--butyric acid has a depressant action on the whole soma-dendritic membrane of centrally located neurones”. Thus started the history of GABA research in Australia in an atmosphere of denial regarding its transmitter status and a mystery as to what its functions really were in the CNS.