Xie, Xinmin; (1992) Physiological and pharmacological effects of zinc on rat hippocampal pyramidal neurones in vitro. Doctoral thesis (Ph.D.), University College London.

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Abstract

The mammalian brain contains an abundance of zinc and stimulation of the mossy fibres in the hippocampus can induce Zn2+ release. However, a physiological role for endogenous zinc in synaptic transmission has not been shown. The present study was undertaken to address this fundamental issue by using electrophysiological techniques, including intracellular and simultaneous extracellular recordings from rat hippocampal brain slices in vitro. Pyramidal neurones were identified by histological methods using intracellular labelling based on the avidin-biotin system. Exogenous zinc (50-300?M) induced the appearance of rhythmically occurring giant depolarizing synaptic potentials (GDPs) in adult hippocampal neurons (n=245). These zinc-induced GDPs were mediated by GABAA receptors and appeared similar to spontaneous large depolarizing potentials which occur naturally in immature CAS neurones (n=160) from young rats (postnatal days 2-12). Selective zinc-chelating agents (CP94 and CP40) based on heterocyclic pyridinones reversibly inhibited these innate GDPs in young neurones in a concentration (1-400μM) dependent manner. The mechanism underlying GDP generation was investigated by examining the effect of zinc on membrane properties and synaptic neurotransmission in adult neurones. Zinc had a wide variety of actions on voltage-operated and/or ligand-gated channels, including i) increasing the membrane input resistance and enhancing cell excitability; ii) augmenting postsynaptic GABAA responses; ill) inhibiting postsynaptic GABAB receptors; iv) increasing the release of GABA; v) inhibiting N-methyl-D-aspartate (NMDA) receptors; vi) potentiating non-NMDA receptor mediated responses; and vii) depressing stimulus-evoked excitatory postsynaptic potentials and population spikes. The long-term potentiation in CA1 and CA3 regions induced by high frequency stimulation was also blocked by zinc. Zinc-induced GDPs occurred in the apparent absence of any functional excitatory synaptic transmission but could be reversibly inhibited by the specific adrenergic β1-receptor antagonist, atenolol. The action of zinc in inducing GDPs was not reproduced by other cations, such as Ba2+, Cd2+, Co2+, Cu2+, Fe2+, Mn2+, Al3+ and a K+ channel blocker 4-aminopyridine. These results provide the first evidence of a physiological role for endogenous zinc in immature hippocampal synaptic neurotransmission and suggest that exogenous zinc can differentially modulate inhibitory and excitatory synaptic transmission in the adult hippocampus.

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