5‐HT_1A and 5‐HT₇ receptors differently modulate AMPA receptor‐mediated hippocampal synaptic transmission

Abstract

We have studied the effects of 5-HT(1A) and 5-HT(7) 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-HT(1A)/5-HT(7) receptor agonist, inhibited AMPA receptor-mediated excitatory post synaptic currents (EPSCs); this effect was mimicked by the 5-HT(1A) receptor agonist 8-OH PIPAT and blocked by the 5-HT(1A) antagonist NAN-190. 8-OH DPAT increased paired-pulse facilitation and reduced the frequency of mEPSCs, indicating a presynaptic 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 postsynaptic action; this effect persisted in the presence of NAN-190 and was blocked by the 5-HT(7) receptor antagonist SB-269970. To confirm that EPSC enhancement was mediated by 5-HT(7) receptors, we used the compound LP-44, which is considered a selective 5-HT(7) 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-HT(1A) and 5-HT(7) receptor antagonists, indicating that both receptors exert a postsynaptic action. Our results show that 5-HT(1A) receptors inhibit CA3-CA1 synaptic transmission acting both pre- and postsynaptically, whereas 5-HT(7) receptors enhance CA3-CA1 synaptic transmission acting exclusively at a postsynaptic 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-HT(7) receptors.

5-HT1A and 5-HT7 receptor crosstalk in the regulation of emotional memory: Implications for effects of selective serotonin reuptake inhibitors

“…In fact, AS19 and LP-44 may function as partial 5-HT 7 agonists thereby lowering agonist function of endogenous 5-HT at 5-HT 7 Rs. Additionally, LP-44 has 5-HT 1A R agonist function (Costa et al, 2012). Further studies are required to fully characterize these compounds and determine their specificity, particularly in view of the failure of SB269970 to block LP-44-induced phosphorylation (Fig.…”

“…In accordance, prevention of 5-HT 1A R signaling was shown to unmask a stimulatory effect of 5-HT on hippocampal excitability and the 5-HT 7 R has been implicated in the shifted 5-HTR signaling. In the hippocampus 5-HT and 8-OH-DPAT inhibit excitatory pyramidal neurons via 5-HT 1A R activation, whereas stimulation of 5-HT 7 Rs activates pyramidal cell firing, via opposing effects on cAMP-dependent pathways (Bickmeyer et al, 2002;Costa et al, 2012). 5-HT 1A R stimulation increases hyperpolarizing currents and inhibits spontaneous hippocampal firing, while combination of 8-OH-DPAT or 5-CT with 5-HT 1A R blockade not only reverses hyperpolarization of CA1 and CA3 pyramidal neurons but even stimulate burst activity (Bacon and Beck, 2000;Bickmeyer et al, 2002;Costa et al, 2012;Tada et al, 1999).…”

“…However, 5-HT 7 Rs agonist studies are needed to better determine the potential involvement of the 5-HT 7 R on memory processing. Recent electrophysiological studies have shown that 5-HT 1A R and 5-HT 7 Rs oppositely modulate hippocampal glutamatergic neurotransmission (Costa et al, 2012). Evidence for such opposing roles was also found in PA where the memory impairment by the 5-HT 1A R/5-HT 7 R agonist 8-OH-DPAT (0.3 mg/kg) was worsened by the selective 5-HT 7 R antagonist SB269970 in mice .…”

The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK

“…In particular, it has been shown that the stimulation of 5-HT7R results in a marked enhancement of spontaneous neuronal activity leading to saturation of LTP and thus preventing further potentiation. On the other hand, 5-HT7R activation reverses the mGluR-LTD in CA3-CA1 synapse in mouse hippocampal slices by preventing the mGluR-induced endocytosis of AMPA receptors (Costa et al, 2012). Having shown that 5-HT7R activation results in long-lasting depression of PF-PC synapses, we next assessed whether such depression affects the expression and/or maintenance of postsynaptic forms of PF-PC synaptic plasticity, i.e.…”

Drug design of 5-substituted-2-aminotetralins targeting the serotonin 5-HT7 receptor

“…For example, 5-HT 7 activation has been shown to increase AMPA excitatory post-synaptic currents (EPSCs) 37 , and reverse mGluR induced endocytosis of AMPA receptors 38,39 , promoting long-term potentiation (LTP) and pro-cognitive effects. 5-HT 7 knockout mice on the other hand showed deficits in LTP.…”