5-HT1A and 5-HT7 receptors differently modulate AMPA receptor-mediated hippocampal synaptic transmission

We have studied the effects of 5-HT1A and 5-HT7 serotonin receptor activation in hippocampal CA3-CA1 synaptic transmission using patch clamp on mouse brain slices. Application of either 5-HT or 8-OH DPAT, a mixed 5-HT1A/5-HT7 receptor agonist, inhibited AMPA receptor-mediated excitatory post synaptic currents (EPSCs); this effect was mimicked by the 5-HT1A receptor agonist 8-OH PIPAT and blocked by the 5-HT1A antagonist NAN-190. 8-OH DPAT increased paired-pulse facilitation and reduced the frequency of mEPSCs, indicating a pre-synaptic reduction of glutamate release probability. In another group of neurons, 8-OH DPAT enhanced EPSC amplitude but did not alter paired-pulse facilitation, suggesting a post-synaptic action; this effect persisted in the presence of NAN-190 and was blocked by the 5-HT7 receptor antagonist SB-269970. To confirm that EPSC enhancement was mediated by 5-HT7 receptors, we used the compound LP-44, which is considered a selective 5-HT7 agonist. However, LP-44 reduced EPSC amplitude in most cells and instead increased EPSC amplitude in a subset of neurons, similarly to 8-OH DPAT. These effects were respectively antagonized by NAN-190 and by SB-269970, indicating that under our experimental condition LP-44 behaved as a mixed agonist. 8-OH DPAT also modulated the current evoked by exogenously applied AMPA, inducing either a reduction or an increase of amplitude in distinct neurons; these effects were respectively blocked by 5-HT1A and 5-HT7 receptor antagonists, indicating that both receptors exert a post-synaptic action. Our results show that 5-HT1A receptors inhibit CA3-CA1 synaptic transmission acting both pre- and post-synaptically, whereas 5-HT7 receptors enhance CA3-CA1 synaptic transmission acting exclusively at a post-synaptic site. We suggest that a selective pharmacological targeting of either subtype may be envisaged in pathological loss of hippocampal-dependent cognitive functions. In this respect, we underline the need for new selective agonists of 5-HT7 receptors.