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

CAROLINA WEDEMEYER; JAVIER ZORRILLA DE SAN MARTÍN; JIMENA BALLESTERO; MARIA EUGENIA GÓMEZ CASATI; ANA VANESSA TORBIDONI; PAUL A FUCHS; BERNHARD BETTLER; ANA BELÉN ELGOYHEN; ELEONORA KATZ

JOURNAL OF NEUROSCIENCE

SOC NEUROSCIENCE

Lugar: Washington; Año: 2013 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 alpha9alpha10 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 γ-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) receptors (GABAB(1a,2)Rs) that down-regulate the amount of ACh released at the OC-hair cell synapse, by inhibiting P/Q-type VGCCs. We confirmed the expression of GABABRs at OC terminals contacting the hair cells by co-inmmunostaining for GFP and synaptophysin in transgenic mice expressing GABAB1-GFP fusion proteins. Moreover, co-immunostainings with antibodies against the GABA-synthetic enzyme GAD and synaptophysin support that GABA is directly synthesized at OC terminals contacting the hair cells during development. Thus, we demonstrate for the first time a physiological role for GABA in cochlear synaptic function. In addition, our data suggest that selectively the GABAB1a isoform inhibits release at efferent cholinergic synapses.