Effect of tacrolimus on the excitatory synaptic transmission between the parallel fibers and pyramidal cells in the rat dorsal cochlear nucleus.

Aim: The immunosuppressive drug tacrolimus has several effects on the central nervous system. Besides its protective effect in hearing deficiencies, it is also considered to be able to cause tinnitus. In the present work, we attempted to describe its effects on a characteristic synapse of the auditory system that may be involved in the pathogenesis of tinnitus.

Methods/materials: Slices of the dorsal cochlear nucleus (200 microm thick) were prepared from 9- to 14-day-old Wistar rats. In response to stimulation targeting the superficial layer of the nucleus, we recorded excitatory postsynaptic currents (EPSCs) developing in the cell bodies of the pyramidal neurons using whole-cell voltage clamps. Inhibitory synaptic activity was inhibited by the application of bicuculline and strychnine. Short-term plasticity was investigated using high-frequency stimulation (50 Hz). Unambiguous identification of the investigated neurons was ensured by employing biocytin in the pipette solution, which allowed the confocal reconstruction of the cells after the functional measurements. A concentration of 1 micromol/L tacrolimus was applied extracellularly.

Results: Tacrolimus effectively and reversibly inhibited glutamatergic neurotransmission in the investigated synapse from -145 +/- 26 pA to -55 +/- 15 pA (n = 7; P = .00928). In contrast, EPSC amplitudes without failures were not significantly reduced (from -153 +/- 26 pA to -131 +/- 23 pA) in the presence of tacrolimus, but there were increased failure numbers of synaptic transmission. These data suggested that application of tacrolimus produced a combined pre- and postsynaptic inhibition.

Conclusion: Tacrolimus affected short-term synaptic plasticity in the rat dorsal cochlear nucleus. It was also capable of inhibiting the glutamatergic neurotransmission. These effects suggested that tacrolimus may have neuroprotective effects in this structure.