The idea that synaptically released copper affects the excitability of cells around the release site has been proposed based on several indirect evidences: a) uneven distribution of copper, generally co- stored with zinc, in synaptic vesicles in different zones of the central nervous system (CNS), b) neurological symptoms of patients of Menkes and Wilson diseases, whose copper levels in the CNS are decreased or increased respectively and c) reports that several neurotransmitter activated currents are blocked by nano to micro molar copper concentration in vitro(1). We started a direct characterization of the effect of Cu⁺⁺ upon neuronal excitability using olfactory neurons from the toad C. caudiververa as model cells. The olfactory epithelia was obtained from animals killed after ice immersion, a procedure authorized by the University of Chile Ethics Committee. These cells present a TTX sensitive Na⁺ current (I_Na|), a non inactivating Ca⁺⁺ current (I_Ca), a delayed rectifier K⁺ current (I_K) and a Ca⁺⁺ activated K⁺ current (I_Ca-K). The effect of [Cu⁺⁺] upon each current was determined under voltage clamp in the whole cell configuration. Micromolar Cu⁺⁺ (1 – 10) caused a dose dependent block of I_Na and also of I_Ca. As a consequence, I_Ca-K was reduced but I_K was basically not affected. The neuronal firing rate induced by depolarizing current pulses was decreased by copper in this concentration range. Copper in the nanomolar range (10 – 100) caused an increase in the amplitude of I_Na due to an increase in the activation and inactivation rates and it did not appreciably affect the other 3 currents. An increase of I_Na activation rate hints that in these conditions neurons could be more excitable. Indeed, the firing rate induced by depolarizing current pulses was increased by 10-50 nM Cu⁺⁺. The spontaneous firing rate of groups of cells in the whole undissociated epithelia recorded extracellularly increased and then decreased when exposed to nanomolar followed by micromolar copper (4.2 fold ± 2.3 SD increase by 50 nM Cu⁺⁺, 2.9 fold ± 1.3 SD decrease by 5 μM Cu⁺⁺; n=4). Since Cu⁺⁺ is generally co-liberated with Zn⁺⁺ we also tested its effect upon I_Na. Nanomolar Zn⁺⁺ also activates I_Na but the blockade of this current by micromolar Zn++ is less effective (100 μM blocked only 25% of I_Na). The activating effect of nanomolar copper was not reverted by washing it from the solution nor by adding chelators but 2mM of the reducing agent DTT reversibly modulated the basal firing rate. We propose that at least part of the effect of Cu⁺⁺ upon excitability is redox-mediated. These results directly support a role for copper as modulator of neuronal excitability .