Regionally selective blockade of GABAergic inhibition by zinc in the thalamocortical system: Functional significance

Regionally selective blockade of GABAergic inhibition by zinc in the thalam ocortical system: functional significance. J. Neurophysiol. 83: 1510-1521, 2000. The thalamocortical (TC) system is a tightly coupled synaptic circuit in which GABAergic inhibition originating from the nucleus reticularis tha lami (NRT) serves to synchronize oscillatory TC rhythmic behavior. Zinc is colocalized within nerve terminals throughout the TC system with dense stai ning for zinc observed in NRT, neocortex, and thalamus. Whole cell voltage- clamp recordings of GABA-evoked responses were conducted in neurons isolate d from ventrobasal thalamus, NRT, and somatosensory cortex to investigate m odulation of the GABA-mediated chloride conductance by zinc. Zinc blocked G ABA responses in a regionally specific, noncompetitive manner within the TC system. The regional levels of GABA blockade efficacy by zinc were: thalam us > NRT > cortex. The relationship between clonazepam and zinc sensitivity of GABA(A)-mediated responses was examined to investigate possible presenc e or absence of specific GABA(A) receptor (GABAR) subunits. These propertie s of GABARs have been hypothesized previously to be dependent on presence o r absence of the gamma 2 subunit and seem to display an inverse relationshi p. In cross-correlation plots, thalamic and NRT neurons did not show a stat istically significant relationship between clonazepam and zinc sensitivity; however, a statistically significant correlation was observed in cortical neurons. Spontaneous epileptic TC oscillations can be induced in vitro by p erfusion of TC slices with an extracellular medium containing no added Mg2. Multiple varieties of oscillations are generated, including simple TC bur st complexes (sTBCs), which resemble spike-wave discharge activity. A secon d variant was termed a complex TC burst complex (cTBC), which resembled gen eralized tonic cIonic seizure activity. sTBCs were exacerbated by zinc, whe reas cTBCs were blocked completely by zinc. This supported the concept that zinc release may modulate TC rhythms in vivo. Zinc interacts with a variet y of ionic conductances, including GABAR currents, N-methyl-D-aspartate (NM DA) receptor currents, and transient potassium (A) currents. D-2-amino-5-ph osphonovaleric acid and 4-aminopyridine blocked both s- and cTBCs in TC sli ces. Therefore NMDA and A current-blocking effects of zinc are insufficient to explain differential zinc sensitivity of these rhythms. This supports a significant role of zinc-induced GABAR modulation in differential TC rhyth m effects. Zinc is localized in high levels within the TC system and appear s to be released during TC activity. Furthermore application of exogenous z inc modulates TC rhythms and differentially blocks GABARs within the TC sys tem. These data are consistent with the hypothesis that endogenously releas ed zinc may have important neuromodulatory actions impacting generation of TC rhythms, mediated at least in part by effects on GABARs.