Grauert, A; (2013) Modulation of GABAA receptor-mediated synaptic transmission by Zn2+ at a dentate gyrus circuit. Doctoral thesis , UCL (University College London).

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Abstract

Zinc (ionic form Zn2+) is a common trace element in the forebrain, and is especially enriched in the hippocampus, a brain structure important for learning and memory. A large amount of vesicular Zn2+ which is thought to be released upon presynaptic depolarisation is found at synapses formed by the axons of dentate granule cells (GCs), known as mossy fibres (MFs). Zn2+ inhibits NMDA and GABAA receptors (NMDAR and GABAAR) at mono-synaptic inputs between MFs and CA3 pyramidal neurons but its role in synaptic integration in the dentate gyrus remains elusive. Whole-cell recordings were obtained from GCs held in voltage-clamp in acute rat hippocampal slices. One tungsten electrode was positioned in stratum lucidum (SL) of CA3b to activate MFs and another in stratum granulosum (SG) to directly stimulate dentate interneurons. Evoked synaptic currents were blocked by superfusion of the GABAAR antagonist bicuculline implying that they were mediated by GABAARs. In contrast, the AMPA/kainate receptor antagonist NBQX abolished SL evoked inhibitory postsynaptic currents (IPSCs) but had little effect on IPSCs evoked by SG stimulation. Similarly, the group 2 metabotropic receptor agonist DCG-IV depressed SL but not SG evoked IPSCs. These results imply a poly-synaptic inhibitory feedback projection from CA3 to the dentate gyrus via recurrent MFs, and a mono-synaptic input from dentate interneurons to GCs. Zn2+ reversibly depressed evoked IPSCs whereas superfusion of different Zn2+ chelators had the opposite enhancing effect. Blocking T-type Ca2+ channels abolished the effect of Zn2+ chelators. When recording from dentate basket cells, Zn2+ chelation increased spike width, decreased spike threshold, enhanced NMDAR-mediated excitatory postsynaptic currents (EPSCs) and facilitated T–type Ca2+ currents. Finally, chelation of Zn2+ narrowed the time window for integration of perforant path inputs and facilitated GC spiking. Together, the results demonstrate that Zn2+ modulates MF–interneuron–GC communication and thus regulates information transfer to dentate and hippocampal networks.

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