Regionally Selective Blockade Of Gabaergic Inhibition By Zinc In The Thalamocortical System: Functional Significance. John W. Gibbs III3, Yun-Fu Zhang1, Melissa D. Shumate2, and Douglas A. Coulter4,5. Departments of Neurology1, Physiology2, and Anatomy3 Medical College of Virginia of Virginia Commonwealth University, Richmond, VA 23298-0599 and Divisions of Neurology and Neuroscience, Department of Pediatrics, University of Pennsylvania School of Medicine4 and the Pediatric Regional Epilepsy Program of the Children's Hospital of Philadephia5, Philadelphia, PA 19104-4318.
APStracts 6:0469N, 1999.
The thalamocortical (TC) system is a tightly coupled synaptic circuit in which ?-aminobutyric acid (GABA)ergic 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 GABAA-mediated responses was examined in order to investigate possible presence or absence of specific GABAA receptor (GABAR) subunits. These properties of GABARs have been previously hypothesized 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, while cTBCs were completely blocked 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, NMDA receptor currents, and transient potassium (A) currents. D-2-amino-5-phosphonovaleric acid (APV) and 4-aminopyridine (4-AP) 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.
Received 18 November 1998; accepted in final form 15 September 1999.
APS Manuscript Number J885-8.
Article publication pending Journal of Neurophysiology.
ISSN 1080-4757 Copyright 1999 The American Physiological Society.
Published in APStracts on 21 December 1999