The Journal of Neurophysiology Vol. 83 No. 3 March 2000, pp. 1510-1521
Copyright ©2000 by the American Physiological Society

Regionally Selective Blockade of GABAergic Inhibition by Zinc in the Thalamocortical System: Functional Significance

 ¹Department of Neurology,  ²Department of Physiology, and  ³Department of Anatomy, Medical College of Virginia of Virginia Commonwealth University, Richmond, Virginia 23298-0599; and  ⁴Divisions of Neurology and Neuroscience, Department of Pediatrics, University of Pennsylvania School of Medicine and  ⁵Pediatric Regional Epilepsy Program of the Children's Hospital of Philadephia, Philadelphia, Pennsylvania 19104-4318

Gibbs III, John W., Yun-Fu Zhang, Melissa D. Shumate, and Douglas A. Coulter. Regionally Selective Blockade of GABAergic Inhibition by Zinc in the Thalamocortical 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 thalami (NRT) serves to synchronize oscillatory TC rhythmic behavior. Zinc is colocalized within nerve terminals throughout the TC system with dense staining for zinc observed in NRT, neocortex, and thalamus. Whole cell voltage-clamp recordings of GABA-evoked responses were conducted in neurons isolated from ventrobasal thalamus, NRT, and somatosensory cortex to investigate modulation of the GABA-mediated chloride conductance by zinc. Zinc blocked GABA responses in a regionally specific, noncompetitive manner within the TC system. The regional levels of GABA blockade efficacy by zinc were: thalamus > NRT > cortex. The relationship between clonazepam and zinc sensitivity of GABA_A-mediated responses was examined to investigate possible presence or absence of specific GABA_A receptor (GABAR) subunits. These properties of GABARs have been hypothesized previously to be dependent on presence or absence of the 2 subunit and seem to display an inverse relationship. In cross-correlation plots, thalamic and NRT neurons did not show a statistically 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 perfusion of TC slices with an extracellular medium containing no added Mg²⁺. Multiple varieties of oscillations are generated, including simple TC burst complexes (sTBCs), which resemble spike-wave discharge activity. A second variant was termed a complex TC burst complex (cTBC), which resembled generalized tonic clonic seizure activity. sTBCs were exacerbated by zinc, whereas cTBCs were blocked completely by zinc. This supported the concept that zinc release may modulate TC rhythms in vivo. Zinc interacts with a variety of ionic conductances, including GABAR currents, N-methyl-D-aspartate (NMDA) receptor currents, and transient potassium (A) currents. D2-amino-5-phosphonovaleric acid and 4-aminopyridine blocked both s- and cTBCs in TC slices. 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 rhythm effects. Zinc is localized in high levels within the TC system and appears to be released during TC activity. Furthermore application of exogenous zinc modulates TC rhythms and differentially blocks GABARs within the TC system. These data are consistent with the hypothesis that endogenously released zinc may have important neuromodulatory actions impacting generation of TC rhythms, mediated at least in part by effects on GABARs.