Activation of presynaptic GABA(B(1a,2)) receptors inhibits synaptic transmission at mammalian inhibitory cholinergic olivocochlear-hair cell synapses.
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 Ca(2+)-permeable postsynaptic α9α10 nicotinic receptors coupled to the opening of hyperpolarizing Ca(2+)-activated small-conductance type 2 (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 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 GABA(B(1a,2)) receptors [GABA(B(1a,2))Rs] that downregulate the amount of ACh released at the OC-hair cell synapse, by inhibiting P/Q-type VGCCs. We confirmed the expression of GABA(B)Rs at OC terminals contacting the hair cells by coimmunostaining for GFP and synaptophysin in transgenic mice expressing GABA(B1)-GFP fusion proteins. Moreover, coimmunostaining with antibodies against the GABA synthetic enzyme glutamic acid decarboxylase and synaptophysin support the idea 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 the GABA(B1a) isoform selectively inhibits release at efferent cholinergic synapses.
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres," 1428 Buenos Aires, Argentina, Tercera Cátedra de Farmacología, Facultad de Medicina, 1121 Buenos Aires, Argentina, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, Department of Biomedicine, Institute of Physiology, University of Basel, CH-4056 Basel, Switzerland, and Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina.
Carolina
C
Wedemeyer
Javier
J
Zorrilla de San Martín
Jimena
J
Ballestero
María Eugenia
ME
Gómez-Casati
Ana Vanesa
AV
Torbidoni
Paul A
PA
Fuchs
Bernhard
B
Bettler
Ana Belén
AB
Elgoyhen
Eleonora
E
Katz
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D020865:Calcium Channels, P-Type / Q000378:metabolism; D020907:Calcium Channels, Q-Type / Q000378:metabolism; D059329:Cholinergic Neurons / Q000378:metabolism / Q000502:physiology; D004558:Electric Stimulation; D006198:Hair Cells, Auditory / Q000378:metabolism / Q000502:physiology*; D053444:Inhibitory Postsynaptic Potentials; D051379:Mice; D008807:Mice, Inbred BALB C; D009476:Neurons, Efferent / Q000502:physiology; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D018080:Receptors, GABA-B; D016708:Synaptophysin; D005680:gamma-Aminobutyric Acid; D000109:Acetylcholine