Gating of long-term potentiation (LTP) in the thalamocortical auditory system of rats by serotonergic (5-HT) receptors

The neuromodulator serotonin (5-hydroxytryptamine, 5-HT) plays an important role in controlling the induction threshold and maintenance of long-term potentiation (LTP) in the visual cortex and hippocampus of rodents. Serotonergic fibers also innervate the rodent primary auditory cortex (A1), but the regulation of A1 plasticity by 5-HT receptors (5-HTRs) is largely uncharted. Thus, we examined the role of several, predominant 5-HT receptor classes (5-HT1ARs, 5-HT2Rs, and 5-HT3Rs) in gating in vivo LTP induction at A1 synapses of adult, urethane-anesthetized rats. Theta-burst stimulation (TBS) applied to the medial geniculate nucleus resulted in successful LTP induction of field postsynaptic potentials (fPSPs) generated by excitation of thalamocortical and intracortical A1 synapses. Local application (by reverse microdialysis in A1) of the broad-acting 5-HTR antagonist methiothepin suppressed LTP at both thalamocortical and intracortical synapses. In fact, rather than LTP, TBS elicited long-term depression during methiothepin application, an effect that was mimicked by the selective 5-HT2R antagonist ketanserin, but not the 5-HT1AR blocker WAY 100635. Interestingly, antagonism of 5-HT3Rs by granisetron selectively blocked LTP at thalamocortical, but not intracortical A1 synapses. Further, in the absence of TBS, granisetron application resulted in a pronounced increase in fPSP amplitude, suggesting that 5-HT3Rs play an important role in regulating baseline (non-potentiated) transmission at A1 synapses. Together, these results indicate that activation of 5-HT2Rs and 5-HT3Rs, but not 5-HT1ARs, exerts a clear, facilitating effect on LTP induction at A1 synapses, allowing 5-HT to act as a powerful regulator of long-term plasticity induction in the fully matured A1 of mammalian species.