Activation of presynaptic GABAB(1a,2) receptors inhibits synaptic transmission at mammalian inhibitory cholinergic olivocochlear-hair cell synapses

WEDEMEYER C; ZORRILA DE SAN MARTIN J; BALLESTERO J; GOMEZ CASATI ME; TORBIDONI AV; FUCHS PA; BETTLER B; ELGOYHEN AB; KATZ E

JOURNAL OF NEUROSCIENCE

SOC NEUROSCIENCE

Lugar: Washington; Año: 2013 vol. 33 p. 15477 - 15487

0270-6474

The synapse between olivocochlear (OC) neurons and cochlear mechanosensory hair cells is cholinergic, fast and inhibitory. The inhibitory sign of this cholinergic synapse is accounted for by the activation of Ca2+ permeable postsynaptic á9á10 nicotinic receptors coupled to the opening of hyperpolarizing Ca2+-activated SK2 K+ channels. Acetylcholine (ACh) release at this synapse is supported by both P/Q- and N-type voltage-gated calcium channels (VGCCs). Although the OC synapse is cholinergic, an abundant OC ã-aminobutyric acid (GABA) innervation is present along the mammalian cochlea. The role of this neurotransmitter at the OC efferent innervation, however, is for the most part unknown. We show that GABA fails to evoke fast postsynaptic inhibitory currents in apical developing inner and outer hair cells. However, electrical stimulation of OC efferent fibers activates presynaptic GABAB(1a,2)Rs which down-regulate the amount of ACh released at the OC-hair cell synapse by inhibiting P/Q-type VGCCs. The expression of GABABRs at OC terminals contacting the hair cells was confirmed by double inmmunostainings for GFP and synaptophys in transgenic mice expressing GABAB1-GFP fusion proteins. Moreover, double-immunostainings with antibodies against the GABA-synthetic enzyme GAD and synaptophysin confirm that GABA is synthesized at OC terminals contacting the hair cells during development. Thus, we demonstrate for the first time a clear role for GABA in cochlear synaptic function. In addition, we provide new evidence for the presynaptic localization of the GABAB1a isoform and its functional role in the regulation of transmitter release.