Role of zincergic neurons in cortical function and plasticity

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Zinc ions are essential for life as they regulate the function of numerous structural, transcriptional and enzymatic proteins. In addition to its role in basic cellular functioning, zinc is contained within and released from the nerve terminals of a subset of glutamatergic neurons in the central nervous system. Physiological studies have shown that synaptically-released zinc can powerfully modulate synaptic transmission by regulating the activation of numerous voltage and ligand gated ion channels and intracellular signaling proteins. Consequently, the goal of this thesis was elucidate the anatomical organization and functional significance of zinc-releasing (ie. zincergic) neurons in the mammalian forebrain, particularly within the cerebral cortex. To do this, we first describe a novel procedure for staining the cell bodies of zincergic neurons that eliminates background staining of zinc within synaptic terminals, thereby enabling a clear and accurate description of these neurons. Using this method, we found that zincergic neurons were typically pyramidal in shape and densely populated telencephalic structures such as the cerebral cortex, hippocampus and amygdala. In addition, labeled neurons were found in the lateral ventricle, lateral septum, zona incerta, as well as select regions of the hypothalamus, a region previously thought to be devoid of neurons with a zincergic phenotype. In order to implicate zincergic neurons in cerebral cortical plasticity, we characterized zincergic innervation of the mouse barrel cortex, our model system. Utilizing a zinc-specific retrograde labeling method, we found that the majority of zincergic projections to the barrel cortex originated from ipsilateral and callosal neurons situated within layers 2/3 and 6 of the cerebral cortex. Given that zinc is potent modulator of synaptic transmission, and that intracortical circuits drive experience-dependent reorganizations in the adult cortex, we then examined the effect of tactile stimulation or deprivation on the homeostatic regulation of zinc within barrel cortex synapses. Our data indicate that levels of synaptic zinc in layer 4 were rapidly and bi-directionally regulated by tactile experience. Furthermore, we found that the experience-dependent regulation of synaptic zinc was highly dependent on age, with aged animals no longer showing this capability. In summary, these results suggest that zincergic circuits comprise a chemospecific associative network that reciprocally interconnects telencephalic structures. Furthermore, our data implicate zincergic circuits in rapid, experience-dependent plasticity in the adult cerebral cortex, as well decrements in this plasticity that accompany senescence.
Bibliography: p. 155-184
Brown, C. E. (2004). Role of zincergic neurons in cortical function and plasticity (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from doi:10.11575/PRISM/24443