Pharmacological aspects of excitatory synaptic transmission to second‐order vestibular neurons in the frog

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Abstract
Synaptic excitation of second‐order vestibular neurons is mediated by two principal afferents: vestibular afferents projecting into the brain via the VIIIth cranial nerve and commissural afferents from the contralateral vestibular nuclear complex. The shape of the excitatory postsynaptic potentials (EPSPs) generated by selectively activating these two inputs differs qualitatively, such that ipsilateral VIIIth nerve afferents generate a faster‐rising EPSP than do the commissural afferents. We have investigated the synaptic pharmacology of these two inputs in the isolated, intact medulla of the frog in order to determine the nature of the transmitter substances released by the afferents and the nature of the subsynaptic receptors with which these transmitters interact. Electrical stimulation of the ipsilateral VIIIth cranial nerve evokes in the region of the vestibular nuclear complex a field potential that exhibits a presynaptic (afferent volley) and a postsynaptic (slow negativity) component. Bath application of glutamate receptor antagonists, such as kynurenic acid (KENYA), blocks the postsynaptic component of this field potential in a dose‐dependent manner, without affecting the presynaptic volley, suggesting that the VIIIth nerve afferent releases glutamate and/or similar substances as its neurotransmitter. A comparison of the actions of various glutamate receptor antagonists to block this postsynaptic negativity gives a rank order of effectiveness such that KENYA>γ‐D‐glutamylglycine (γDGG)=γ‐D‐glutamylaminomethylsulfonic acid (GAMS) >γ‐D‐glutamyltaurine (γDGT)>> γ‐D‐glutamylaminomethylphosphonic acid (GAMP)>D‐2‐amino‐5‐phosphonovaleric acid (D‐APV)>D, L‐APV>D‐2‐amino‐7‐phosphonoheptanoic acid (APH). This rank order of effectiveness suggests that the VIIIth nerve transmitter activates second‐order neurons through kainate (KA)/quisqualate (QUIS) synaptic receptors. Intracellular studies support these conclusions. Chemically mediated EPSPs evoked from ipsilateral VIIIth nerve stimulation are completely blocked by high concentrations of KENYA (γ1 mM). Occasionally an extremely short‐latency, probably electrically mediated, component to these EPSPs persists in the presence of KENYA. The slower‐rising EPSPs evoked from contralateral VIIIth nerve or contralateral vestibular nuclear complex stimulation are also completely blocked by KENYA, suggesting that the transmitter released by commissural afferents is also glutamate and/or related compounds. These EPSPs and those evoked from spinal stimulation (also slow‐rising) are selectively reduced by low concentrations of KENYA (<0.5 mM) and by D‐APV (γ0.05 mM), while the monosynaptic component of the ipsilaterally evoked EPSP is relatively unaffected. Such low concentrations of KENYA and D‐APV reduce depolarizations to the bath‐applied N‐methyl‐D‐aspartic acid (NMDA), while depolarizations due to KA and QUIS are resistant to these antagonists at these concentrations. These findings suggest that, while the fastrising, ipsilaterally evoked VIIIth nerve EPSP is mediated through apparent KA/QUIS synaptic receptors, the slowly rising EPSPs evoked from commissural and spinal stimulation are generated largely through NMDA synaptic receptors.