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

Memantine is a blocker of Ca 2+ -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 Ca 2+ -activated K + channels via a highly Ca 2+ -permeable nAChR containing the α9 subunit. We show that inhibitory postsynaptic currents recorded from OHCs were reversibly blocked by memantine with an IC 50 value of 16 μM. RT-PCR revealed that a newly cloned nAChR subunit, α10, is expressed in OHCs. In contrast to homomeric expression, coexpression of α9 and α10 subunits in Xenopus laevis oocytes resulted in robust acetylcholine-induced currents, indicating that the OHC nAChR may be an α9/α10 heteromer. Accordingly, nAChR currents evoked by application of the ligand to OHCs and currents through α9/α10 were blocked by memantine with a similar IC 50 value of about 1 μM. Memantine block of α9/α10 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 Ca 2+ influx through nAChRs. Importantly, prolonged receptor activation and consequently massive Ca 2+ 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.