Endogenous serotonin facilitates hippocampal long-term potentiation at CA3/CA1 synapses.

Encoding of episodic memory requires long-term potentiation (LTP) of neurotransmission at excitatory synapses of the hippocampal circuitry. Previous data obtained with the application of exogenous 5-hydroxytryptamine (5-HT) in hippocampal slices indicate that 5-HT blocks LTP, which contrasts with the facilitatory effect of selective serotonin reuptake inhibitors (SSRIs) on learning and memory observed in vivo. Here, we investigated the effects of endogenous 5-HT, released from terminals by the monoamine releaser 3,4-methylenedioxymethamphetamine (MDMA), on LTP of field EPSPs induced by theta-burst stimulation and recorded at CA3/CA1 synapses of rat hippocampal slices. LTP was greater in the presence of MDMA (10 µM; 45.76 ± 15.75%; n = 28) than in controls (31.26 ± 11.03; n = 21; p < 0.01). This facilitatory effect on LTP persisted when the entry of MDMA in noradrenergic terminals was prevented by the selective noradrenaline reuptake inhibitor nisoxetine (44.90 ± 14.07%; n = 27 vs. 34.49 ± 12.94%; n = 20 in controls; p < 0.05). In both conditions, the facilitation of LTP was abolished by the SSRI citalopram that prevented the entry of MDMA in 5-HT terminals and the subsequent 5-HT release. These data show that, unlike exogenous 5-HT application, release of endogenous 5-HT does not impair cellular mechanisms responsible for induction of LTP, indicating that 5-HT is not detrimental to learning and memory. Moreover, facilitation of LTP by endogenous 5-HT may underlie the in vivo positive effects of augmented 5-HT tone on cognitive performance.

Antidepressant-induced increase in GluA2 expression does not translate in changes of AMPA receptor-mediated synaptic transmission at CA3/CA1 synapses in rats.

Chronic treatment with serotonin selective reuptake inhibitors or tryciclic antidepressant drugs in rodents has been shown to increase the expression of GluA1 and/or GluA2 AMPA receptor (AMPAR) subunits in several brain areas, including the hippocampus. These changes in AMPAR composition have been suggested to result in increased glutamatergic neurotransmission and possibly underlie enhanced hippocampal synaptic plasticity through the increased availability of calcium-permeable AMPARs, specifically at CA3/CA1 synapses. However, the possibility that chronic treatment with antidepressants actually results in strengthened glutamatergic neurotransmission in CA1 has poorly been investigated. Here, we studied whether chronic treatment with the multimodal antidepressant drug trazodone mimicked the effect of paroxetine on the expression of AMPAR subunits in male wistar rat hippocampus and whether these drugs produced a parallel facilitation of field excitatory postsynaptic potentials (fEPSP) responses evoked by activation of CA3/CA1 synapses in dorsal hippocampal slices. In addition, we investigated whether the quality of glutamatergic AMPARs involved in basal neurotransmission was changed by altered subunit expression, e.g. leading to appearance of calcium-permeable AMPARs. We found a significant increase in GluA2 subunit expression following treatment with trazodone or paroxetine for twenty-one days, but not after seven-days treatment. In contrast, we did not find any significant changes in fEPSP responses supporting either a facilitation of glutamatergic neurotransmission in basal conditions or the appearance of functional calcium-permeable AMPARs at CA3/CA1 pyramidal neuron synapses. Thus, neurochemically-detected increases in the expression of AMPAR subunits cannot directly be extrapolated in increased number of functioning receptors and/or facilitated basal neurotransmission.

Differential dendritic Ca2+ signalling in young and mature hippocampal granule cells.

Neuronal activity is critically important for development and plasticity of dendrites, axons and synaptic connections. Although Ca(2+) is an important signal molecule for these processes, not much is known about the regulation of the dendritic Ca(2+) concentration in developing neurons. Here we used confocal Ca(2+) imaging to investigate dendritic Ca(2+) signalling in young and mature hippocampal granule cells, identified by the expression of the immature neuronal marker polysialated neural cell adhesion molecule (PSA-NCAM). Using the Ca(2+)-sensitive fluorescent dye OGB-5N, we found that both young and mature granule cells showed large action-potential evoked dendritic Ca(2+) transients with similar amplitude of approximately 200 nm, indicating active backpropagation of action potentials. However, the decay of the dendritic Ca(2+) concentration back to baseline values was substantially different with a decay time constant of 550 ms in young versus 130 ms in mature cells, leading to a more efficient temporal summation of Ca(2+) signals during theta-frequency stimulation in the young neurons. Comparison of the peak Ca(2+) concentration and the decay measured with different Ca(2+) indicators (OGB-5N, OGB-1) in the two populations of neurons revealed that the young cells had an approximately 3 times smaller endogenous Ca(2+)-binding ratio ( approximately 75 versus approximately 220) and an approximately 10 times slower Ca(2+) extrusion rate ( approximately 170 s(-1) versus approximately 1800 s(-1)). These data suggest that the large dendritic Ca(2+) signals due to low buffer capacity and slow extrusion rates in young granule cells may contribute to the activity-dependent growth and plasticity of dendrites and new synaptic connections. This will finally support differentiation and integration of young neurons into the hippocampal network.

5-Arylbenzothiadiazine Type Compounds as Positive Allosteric Modulators of AMPA/Kainate Receptors.

The potential therapeutic benefit of compounds able to activate AMPA receptors (AMPAr) has led to the search for new AMPAr positive modulators. On the basis of crystallographic data of the benzothiadiazines binding mode in the S1S2 GluA2 dimer interface, a set of 5-aryl-2,3-dihydrobenzothiadiazine type compounds has been synthesized and tested. Electrophysiological results suggested that 5-heteroaryl substituents on the benzothiadiazine core like 3-furanyl and 3-thiophenyl dramatically enhance the activity as positive modulators of AMPAr with respect to IDRA21 and cyclothiazide. Mouse brain microdialysis studies have suggested that 7-chloro-5-(3-furyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide crosses the blood-brain barrier after intraperitoneal injection. Biological results have been rationalized by a computational docking simulation that it has currently employed to design new AMPAr-positive modulator candidates.

Phorbol ester uncouples adenosine inhibition of presynaptic Ca2+ transients at hippocampal synapses.

Synaptic transmission involves Ca2+ influx at presynaptic terminals. Adenosine receptors inhibit transmission, and this effect can be abolished by activation of PKC with phorbol esters. Whether protein kinase C (PKC) acts via alterations in Ca2+ entry at the presynaptic terminal is unknown. In the present study, we recorded the presynaptic Ca2+ transients (preCa(delta)) in hippocampal stratum radiatum, using fluorescence photometry. The calcium dye Fura-2 AM was used to load the Schaffer collateral/commissural tract and its terminals. Tetrodotoxin (TTX)-sensitive Na+ channels and Cd2+-sensitive, high-voltage activated Ca2+ channels (HVACCs) were required to elicit the preCa(delta). Application of the phorbol ester phorbol-12,13-dibutyrate (PDBu) abolished the adenosine inhibition of both preCa(delta) and the field excitatory postsynaptic potentials (fEPSPs). PDBu consistently potentiated fEPSPs, and also increased preCa(delta) in a large majority of the slices examined. Regardless of whether potentiation was observed, PDBu always prevented adenosine inhibition of preCa(delta). In contrast, the inactive phorbol ester, 4alpha-phorbol, did not alter adenosine inhibition of preCa(delta), indicating that PKC activation is necessary for the occurrence of the observed effects. Our findings suggest that PKC activation abolishes adenosine's inhibitory effect on synaptic activity involving presynaptic Ca2+ entry.