5-HT1A receptor-mediated attenuation of synaptic transmission in rat medial vestibular nucleus impacts on vestibular-related motor function.

Chemogenetic activation of medial vestibular nucleus-projecting 5-HT neurons resulted in deficits in vestibular-mediated tasks, including negative geotaxis, balance beam and rota-rod tests. The 5-HT1A receptor mediates the vestibular-related behavioural effects of 5-HT in the vestibular nucleus. 5-HT1A receptor activation attenuated evoked excitatory postsynaptic currents and evoked inhibitory postsynaptic currents via a presynaptic mechanism in the vestibular nucleus. While the anxiolytic effects of serotonergic neuromodulation are well studied, its role in sensorimotor coordination and postural control is unclear. In this study, we show that an increase of serotonin (5-hydroxytryptamine, 5-HT) at the medial vestibular nucleus (MVN), a brainstem centre for vestibulospinal coordination, by either direct cannula administration or chemogenetic stimulation of MVN-projecting serotonergic neurons, adversely affected performance of rats in vestibular-mediated tasks, including negative geotaxis, balance beam and rota-rod tests. Application of the 5-HT1 and 5-HT7 receptor co-agonist 8-hydroxy-2-(di-n-propylamino) tetralin recapitulated the effect of 5-HT, while co-administration of the specific 5-HT1A receptor antagonist WAY 100135 effectively abolished all 5-HT-induced behavioural deficits. This indicated that 5-HT1A receptors mediated the effects of 5-HT in the rat MVN. Using whole-cell patch-clamp recording, we demonstrated that 5-HT1A receptor activation attenuated both evoked excitatory and evoked inhibitory postsynaptic currents through a presynaptic mechanism in the rat MVN. The results thus highlight the 5-HT1A receptor as the gain controller of vestibular-related brainstem circuits for posture and balance.