5-HT7 receptor activation reverses mGluR-LTD in the hippocampus of wild-type and Fmr1 knockout mice.

Serotonin (5-HT) affects the excitability of hippocampal neurons and hippocampal-dependent cognitive functions. We have recently shown that 5-HT modulates AMPA receptor-mediated basal transmission in the CA3-CA1 synapse (Costa et al., Hippocampus, in press). Here, we tested the effects of 5-HT on metabotropic glutamate receptors (mGluRs)-induced synaptic plasticity, namely long-term depression (LTD), and related changes in the surface expression of AMPA receptors by patch clamp and immunocytochemistry, respectively. Application of either 5-HT or 8-OH DPAT (a 5-HT1A/5-HT7 agonist) reversed LTD of synaptic currents induced by the group-I mGluR agonist DHPG (mGluR-LTD) in CA1 pyramidal neurons of mouse hippocampus; this effect was abolished by SB-269970, a selective antagonist of 5-HT7 receptors. Consistently, 8-OH DPAT prevented DHPG-induced reduction in surface expression of AMPA receptors in cultured hippocampal neurons and this effect was blocked by SB-269970. Paired-pulse facilitation (PPF) recordings suggest that 5-HT-mediated reversal of LTD did not involve pre-synaptic changes. 5-HT and 8-OH DPAT failed to reverse mGluR-LTD when applied later than 10 min after LTD onset, thus probably disrupted the induction and not the expression of mGluR-LTD. We are currently investigating the intracellular pathways involved in 5-HT effect. We also studied 5-HT effect on mGluR-LTD in the Fmr1 knockout (KO) mouse model of Fragile X syndrome (FXS), the most common form of hereditary intellectual disability. In Fmr1 KO mice, DHPG-induced mGluR-LTD was increased compared to wild-type (WT), as previously reported; similarly to WT, 8-OH DPAT reversed mGluR-LTD and prevented DHPG-induced removal of surface AMPA receptors, an effect antagonized by SB-269970. Our results show that 5-HT7 receptor activation reverses mGluR-induced AMPAR endocytosis and LTD both in WT and Fmr1 KO mice, thus correcting abnormally enhanced mGluR-LTD. We suggest that a pharmacological treatment selectively targeting 5-HT7 receptors may be considered in the therapy of FXS. Supported by MIUR, PRIN 2007L92XSP; Telethon GGP07264; Fondation Léjeune.