Vol. 60, Issue 1, 183-189, July 2001

Memantine Inhibits Efferent Cholinergic Transmission in the Cochlea by Blocking Nicotinic Acetylcholine Receptors of Outer Hair Cells

Dominik Oliver, Jost Ludwig, Ellen Reisinger, Werner Zoellner, J. Peter Ruppersberg, and Bernd Fakler

Department of Physiology II, University of Tübingen, Tübingen, Germany (D.O., J.L., E.R., J.P.R., B.F.); and SEED GmbH, Tübingen, Germany (W.Z.)

Memantine is a blocker of Ca²⁺-permeable glutamate and nicotinic acetylcholine receptors (nAChR). We investigated the action of memantine on cholinergic synaptic transmission at cochlear outer hair cells (OHCs). At this inhibitory synapse, hyperpolarization of the postsynaptic cell results from opening of SK-type Ca²⁺-activated K⁺ channels via a highly Ca²⁺-permeable nAChR containing the 9 subunit. We show that inhibitory postsynaptic currents recorded from OHCs were reversibly blocked by memantine with an IC₅₀ value of 16 µM. RT-PCR revealed that a newly cloned nAChR subunit, 10, is expressed in OHCs. In contrast to homomeric expression, coexpression of 9 and 10 subunits in Xenopus laevis oocytes resulted in robust acetylcholine-induced currents, indicating that the OHC nAChR may be an 9/10 heteromer. Accordingly, nAChR currents evoked by application of the ligand to OHCs and currents through 9/10 were blocked by memantine with a similar IC₅₀ value of about 1 µM. Memantine block of 9/10 was moderately voltage dependent. The lower efficacy of memantine for inhibition of inhibitory postsynaptic currents (IPSCs) most probably results from a blocking rate that is slow with respect to the short open time of the receptor channels during an IPSC. Thus, synaptic transmission in OHCs is inhibited by memantine block of Ca²⁺ influx through nAChRs. Importantly, prolonged receptor activation and consequently massive Ca²⁺ influx, as might occur under pathological conditions, is blocked at low micromolar concentrations, whereas the fast IPSCs initiated by short receptor activation are only blocked at concentrations above 10 µM.