title: Presynaptic GABA(B) receptors decrease neurotransmitter release in vestibular nuclei neurons during vestibular compensation.
abstract: Unilateral damage to the peripheral vestibular receptors precipitates a debilitating syndrome of oculomotor and balance deficits at rest, which extensively normalize during the first week after the lesion due to vestibular compensation. In vivo studies suggest that GABA(B) receptor activation facilitates recovery. However, the presynaptic or postsynaptic sites of action of GABA(B) receptors in vestibular nuclei neurons after lesions have not been determined. Accordingly, here presynaptic and postsynaptic GABA(B) receptor activity in principal cells of the tangential nucleus, a major avian vestibular nucleus, was investigated using patch-clamp recordings correlated with immunolabeling and confocal imaging of the GABA(B) receptor subunit-2 (GABA(B)R2) in controls and operated chickens shortly after unilateral vestibular ganglionectomy (UVG). Baclofen, a GABA(B) agonist, generated no postsynaptic currents in principal cells in controls, which correlated with weak GABA(B)R2 immunolabeling on principal cell surfaces. However, baclofen decreased miniature excitatory postsynaptic current (mEPSC) and GABAergic miniature inhibitory postsynaptic current (mIPSC) events in principal cells in controls, compensating and uncompensated chickens three days after UVG, indicating the presence of functional GABA(B) receptors on presynaptic terminals. Baclofen decreased GABAergic mIPSC frequency to the greatest extent in principal cells on the intact side of compensating chickens, with concurrent increases in GABA(B)R2 pixel brightness and percentage overlap in synaptotagmin 2-labeled terminals. In uncompensated chickens, baclofen decreased mEPSC frequency to the greatest extent in principal cells on the intact side, with concurrent increases in GABA(B)R2 pixel brightness and percentage overlap in synaptotagmin 1-labeled terminals. Altogether, these results revealed changes in presynaptic GABA(B) receptor function and expression which differed in compensating and uncompensated chickens shortly after UVG. This work supports an important role for GABA(B) autoreceptor-mediated inhibition in vestibular nuclei neurons on the intact side during early stages of vestibular compensation, and a role for GABA(B) heteroreceptor-mediated inhibition of glutamatergic terminals on the intact side in the failure to recover function.
authors.affiliation: Department of Anatomy and Regenerative Biology, George Washington University School of Medicine, Washington, DC 20037, United States.
authors.forename: M
authors.initials: M
authors.lastname: Shao
authors.forename: R
authors.initials: R
authors.lastname: Reddaway
authors.forename: J C
authors.initials: JC
authors.lastname: Hirsch
authors.forename: K D
authors.initials: KD
authors.lastname: Peusner
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001418:Baclofen / Q000494:pharmacology; D002642:Chick Embryo; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D008239:Lysine / Q000031:analogs & derivatives; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D018709:Statistics, Nonparametric; D055366:Synaptic Potentials / Q000187:drug effects; D050863:Synaptotagmin I / Q000378:metabolism; D050861:Synaptotagmin II / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D015837:Vestibular Diseases / Q000473:pathology*; D014726:Vestibular Nuclei / Q000473:pathology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018682:GABA Agents; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D018377:Neurotransmitter Agents; D018080:Receptors, GABA-B; D026941:Sodium Channel Blockers; D050863:Synaptotagmin I; D050861:Synaptotagmin II; D013779:Tetrodotoxin; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; C013411:biocytin; D001418:Baclofen; D014633:Valine; D008239:Lysine