Presynaptic GABAB 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 GABAB receptor activation facilitates recovery. However, the presynaptic or postsynaptic sites of action of GABAB receptors in vestibular nuclei neurons after lesions have not been determined. Accordingly, here presynaptic and postsynaptic GABAB 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 GABAB receptor subunit-2 (GABABR2) in controls and operated chickens shortly after unilateral vestibular ganglionectomy (UVG). Baclofen, a GABAB agonist, generated no postsynaptic currents in principal cells in controls, which correlated with weak GABABR2 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 GABAB 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 GABABR2 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 GABABR2 pixel brightness and percentage overlap in synaptotagmin 1-labeled terminals. Altogether, these results revealed changes in presynaptic GABAB receptor function and expression which differed in compensating and uncompensated chickens shortly after UVG. This work supports an important role for GABAB autoreceptor-mediated inhibition in vestibular nuclei neurons on the intact side during early stages of vestibular compensation, and a role for GABAB heteroreceptor-mediated inhibition of glutamatergic terminals on the intact side in the failure to recover function.