Presynaptic serotonergic gating of the subthalamonigral glutamatergic projection.
1. Autonomous, pacemaker-like activity of serotonergic raphe neurones and its autoregulation by somatodendritic 5-HT1A receptors are well described, but little is known of synaptic inputs onto raphe neurones or their modulation. Therefore, we recorded unitary excitatory postsynaptic currents (EPSCs) in caudal raphe neurones (raphe obscurus and pallidus) following local electrical stimulation in a neonatal rat brainstem slice preparation; most neurones (79 %; n = 72/91) recovered following post hoc immunohistochemistry were tryptophan hydroxylase-immunoreactive, indicating that they were serotonergic. 2. Evoked EPSCs occurred at relatively constant latency with variable amplitude and apparent 'failures' at fixed suprathreshold stimulus intensity. At -60 mV, EPSCs were wholly due to CNQX-sensitive, non-NMDA glutamate receptors; at depolarized potentials, a small AP-5-sensitive NMDA component was often observed. 3. EPSCs were potently and reversibly inhibited by 5-HT with an EC50 of 0.1 microM. This effect was mimicked by 5-HT1B agonists (CP-93,129 and anpirtoline), but not by a 5-HT1A agonist (8-OH-DPAT), indicating that 5-HT1B receptors mediate the inhibition of EPSCs. 4. Multiple lines of evidence indicate that inhibition of EPSCs by 5-HT was mediated presynaptically. First, currents evoked by exogenous glutamate application were unaffected by 5-HT and/or 5-HT1B agonists. In addition, the frequency of spontaneous glutamatergic miniature EPSCs was diminished by CP-93,129 and paired-pulse facilitation of EPSCs was enhanced by 5-HT. Finally, the 5-HT1B receptor agonists that blocked synaptic transmission had no effect on resting membrane properties of raphe neurones. 5. These data indicate that serotonergic caudal raphe neurones receive glutamatergic inputs that are inhibited by presynaptic 5-HT1B receptors; inhibition of excitatory synapses onto raphe cells may represent a novel mechanism for autoregulation of serotonergic neuronal activity by 5-HT.