In the Fmr1 knock out (KO) mouse model of Fragile X syndrome (FRAX), activation of group-I metabotropic glutamate receptors (mGluRs) leads to an exaggerated hippocampal long term depression (mGluR-LTD), which is sustained by an increased AMPA receptor endocytosis. We studied the role of serotonin (5-HT) in modulating mGluR-LTD and AMPA receptor endocytosis by using patch clamp on brain slices and immunocytochemistry on cultured hippocampal neurons from wild type (WT) and Fmr1 KO mice. The group-I mGluR agonist DHPG induced mGluR-LTD of AMPA receptor-mediated excitatory post-synaptic currents (EPSCs) recorded from CA1 pyramidal neurons. When DHPG application was followed by application of either 5-HT or 8-OH DPAT (a mixed 5-HT_1A/5-HT₇ agonist), EPSC amplitude returned to control values 20 min after the onset of DHPG-induced inhibition; this effect was blocked by SB269970, a selective 5-HT₇ receptor antagonist. In Fmr1 KO mice DHPG-induced mGluR-LTD was higher than in WT mice and was equally reversed by 8-OH DPAT. As expected, application of DHPG reduced the surface expression of GluR2 subunits in cultured neurons; 8-OH DPAT was able to prevent DHPG-induced internalization of GluR2 and this effect was blocked by SB269970.

Our data show that activation of 5-HT₇ receptors prevents mGluR-induced AMPAR endocytosis and LTD both in WT and in Fmr1 KO mice; we suggest that pharmacological agents targeting 5-HT₇ receptors may be considered in the therapy of FRAX.