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• W3014509063 abstract "•Exogenous serotonin and dopamine potentiate hippocampal mossy fiber synapse•An endogenous monoamine causing synaptic potentiation is serotonin, but not dopamine•ECT enhances serotonergic synaptic modulation mediated by 5-HT4 receptor•ECT causes anxiolytic-like behavioral effects in a 5-HT4 receptor-dependent manner The hippocampal mossy fiber (MF) synapse has been implicated in the pathophysiology and treatment of psychiatric disorders. Alterations of dopaminergic and serotonergic modulations at this synapse are candidate mechanisms underlying antidepressant and other related treatments. However, these monoaminergic modulations share the intracellular signaling pathway at the MF synapse, which implies redundancy in their functions. We here show that endogenous monoamines can potentiate MF synaptic transmission in mouse hippocampal slices by activating the serotonin 5-HT4 receptor. Dopamine receptors were not effectively activated by endogenous agonists, suggesting that the dopaminergic modulation is latent. Electroconvulsive treatment enhanced the 5-HT4 receptor-mediated serotonergic synaptic potentiation specifically at the MF synapse, increased the hippocampal serotonin content, and produced an anxiolytic-like behavioral effect in a 5-HT4 receptor-dependent manner. These results suggest that serotonin plays a predominant role in monoaminergic modulations at the MF synapse. Augmentation of this serotonergic modulation may mediate anxiolytic effects of electroconvulsive treatment. The hippocampal mossy fiber (MF) synapse has been implicated in the pathophysiology and treatment of psychiatric disorders. Alterations of dopaminergic and serotonergic modulations at this synapse are candidate mechanisms underlying antidepressant and other related treatments. However, these monoaminergic modulations share the intracellular signaling pathway at the MF synapse, which implies redundancy in their functions. We here show that endogenous monoamines can potentiate MF synaptic transmission in mouse hippocampal slices by activating the serotonin 5-HT4 receptor. Dopamine receptors were not effectively activated by endogenous agonists, suggesting that the dopaminergic modulation is latent. Electroconvulsive treatment enhanced the 5-HT4 receptor-mediated serotonergic synaptic potentiation specifically at the MF synapse, increased the hippocampal serotonin content, and produced an anxiolytic-like behavioral effect in a 5-HT4 receptor-dependent manner. These results suggest that serotonin plays a predominant role in monoaminergic modulations at the MF synapse. Augmentation of this serotonergic modulation may mediate anxiolytic effects of electroconvulsive treatment. The hippocampal dentate gyrus and its mossy fiber (MF) output have been implicated in the pathophysiology of neuropsychiatric disorders and in their therapeutic treatments (Kobayashi, 2009Kobayashi K. Targeting the hippocampal mossy fiber synapse for the treatment of psychiatric disorders.Mol. Neurobiol. 2009; 39: 24-36Crossref PubMed Scopus (58) Google Scholar, DeCarolis and Eisch, 2010DeCarolis N.A. Eisch A.J. Hippocampal neurogenesis as a target for the treatment of mental illness: a critical evaluation.Neuropharmacology. 2010; 58: 884-893Crossref PubMed Scopus (213) Google Scholar, Tavitian et al., 2019Tavitian A. Song W. Schipper H.M. Dentate gyrus immaturity in schizophrenia.Neuroscientist. 2019; 25: 528-547Crossref PubMed Scopus (12) Google Scholar). Particular attention has been paid to their possible involvement in the mechanism of action of electroconvulsive treatment (ECT). ECT has a broad therapeutic potential for psychiatric disorders and is well known to have a fast-acting antidepressant effect (Husain et al., 2004Husain M.M. Rush A.J. Fink M. Knapp R. Petrides G. Rummans T. Biggs M.M. O'Connor K. Rasmussen K. Litle M. et al.Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report.J. Clin. Psychiatr. 2004; 65: 485-491Crossref PubMed Scopus (305) Google Scholar). ECT rapidly causes molecular and/or functional changes in the dentate gyrus and at the synapse made by MF onto CA3 pyramidal cells (Newton et al., 2003Newton S.S. Collier E.F. Hunsberger J. Adams D. Terwilliger R. Selvanayagam E. Duman R.S. Gene profile of electroconvulsive seizures: induction of neurotrophic and angiogenic factors.J. Neurosci. 2003; 23: 10841-10851Crossref PubMed Google Scholar, Segi-Nishida et al., 2008Segi-Nishida E. Warner-Schmidt J.L. Duman R.S. Electroconvulsive seizure and VEGF increase the proliferation of neural stem-like cells in rat hippocampus.Proc. Natl. Acad. Sci. U S A. 2008; 105: 11352-11357Crossref PubMed Scopus (184) Google Scholar, Imoto et al., 2017Imoto Y. Segi-Nishida E. Suzuki H. Kobayashi K. Rapid and stable changes in maturation-related phenotypes of the adult hippocampal neurons by electroconvulsive treatment.Mol. Brain. 2017; 10: 8Crossref PubMed Scopus (26) Google Scholar, Kobayashi et al., 2017Kobayashi K. Imoto Y. Yamamoto F. Kawasaki M. Ueno M. Segi-Nishida E. Suzuki H. Rapid and lasting enhancement of dopaminergic modulation at the hippocampal mossy fiber synapse by electroconvulsive treatment.J. Neurophysiol. 2017; 117: 284-289Crossref PubMed Scopus (18) Google Scholar). One characteristic functional feature of the MF-CA3 synapse is its dynamic regulation by various kinds of neuromodulators including monoamines (Jaffe and Gutiérrez, 2007Jaffe D.B. Gutiérrez R. Mossy fiber synaptic transmission: communication from the dentate gyrus to area CA3.Prog. Brain Res. 2007; 163: 109-132Crossref PubMed Scopus (43) Google Scholar, Kobayashi, 2010Kobayashi K. Hippocampal mossy fiber synaptic transmission and its modulation.Vitam. Horm. 2010; 82: 65-85Crossref PubMed Scopus (10) Google Scholar). Among monoamines, serotonin and dopamine induce robust potentiation of the MF synaptic transmission (Kobayashi and Suzuki, 2007Kobayashi K. Suzuki H. Dopamine selectively potentiates hippocampal mossy fiber to CA3 synaptic transmission.Neuropharmacology. 2007; 52: 552-561Crossref PubMed Scopus (33) Google Scholar, Kobayashi et al., 2008Kobayashi K. Ikeda Y. Haneda E. Suzuki H. Chronic fluoxetine bidirectionally modulates potentiating effects of serotonin on the hippocampal mossy fiber synaptic transmission.J. Neurosci. 2008; 28: 6272-6280Crossref PubMed Scopus (56) Google Scholar). These monoaminergic modulations show marked alterations after antidepressant drug administration or ECT in mice (Kobayashi et al., 2008Kobayashi K. Ikeda Y. Haneda E. Suzuki H. Chronic fluoxetine bidirectionally modulates potentiating effects of serotonin on the hippocampal mossy fiber synaptic transmission.J. Neurosci. 2008; 28: 6272-6280Crossref PubMed Scopus (56) Google Scholar, Kobayashi et al., 2010Kobayashi K. Ikeda Y. Sakai A. Yamasaki N. Haneda E. Miyakawa T. Suzuki H. Reversal of hippocampal neuronal maturation by serotonergic antidepressants.Proc. Natl. Acad. Sci. U S A. 2010; 107: 8434-8439Crossref PubMed Scopus (171) Google Scholar, Kobayashi et al., 2012Kobayashi K. Haneda E. Higuchi M. Suhara T. Suzuki H. Chronic fluoxetine selectively upregulates dopamine D1-like receptors in the hippocampus.Neuropsychopharmacology. 2012; 37: 1500-1508Crossref PubMed Scopus (41) Google Scholar, Kobayashi et al., 2013Kobayashi K. Ikeda Y. Asada M. Inagaki H. Kawada T. Suzuki H. Corticosterone facilitates fluoxetine-induced neuronal plasticity in the hippocampus.PLoS One. 2013; 8: e63662Crossref PubMed Scopus (13) Google Scholar, Kobayashi et al., 2017Kobayashi K. Imoto Y. Yamamoto F. Kawasaki M. Ueno M. Segi-Nishida E. Suzuki H. Rapid and lasting enhancement of dopaminergic modulation at the hippocampal mossy fiber synapse by electroconvulsive treatment.J. Neurophysiol. 2017; 117: 284-289Crossref PubMed Scopus (18) Google Scholar) and also in mouse models of neuropsychiatric disorders including schizophrenia and epilepsy (Kobayashi et al., 2011bKobayashi K. Umeda-Yano S. Yamamori H. Takeda M. Suzuki H. Hashimoto R. Correlated alterations in serotonergic and dopaminergic modulations at the hippocampal mossy fiber synapse in mice lacking dysbindin.PLoS One. 2011; 6: e18113Crossref PubMed Scopus (12) Google Scholar, Ohira et al., 2013Ohira K. Kobayashi K. Toyama K. Nakamura H.K. Shoji H. Takao K. Takeuchi R. Yamaguchi S. Kataoka M. Otsuka S. et al.Synaptosomal-associated protein 25 mutation induces immaturity of the dentate granule cells of adult mice.Mol. Brain. 2013; 6: 12Crossref PubMed Scopus (48) Google Scholar, Shin et al., 2013Shin R. Kobayashi K. Hagihara H. Kogan J.H. Miyake S. Tajinda K. Walton N.M. Gross A.K. Heusner C.L. Chen Q. et al.The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease.Bipolar Disord. 2013; 15: 405-421Crossref PubMed Scopus (50) Google Scholar), suggesting possible roles in both therapeutic treatments and pathophysiology of neuropsychiatric disorders. The potentiating effects of serotonin and dopamine are mediated by 5-HT4 and D1-like receptors, respectively (Kobayashi and Suzuki, 2007Kobayashi K. Suzuki H. Dopamine selectively potentiates hippocampal mossy fiber to CA3 synaptic transmission.Neuropharmacology. 2007; 52: 552-561Crossref PubMed Scopus (33) Google Scholar, Kobayashi et al., 2008Kobayashi K. Ikeda Y. Haneda E. Suzuki H. Chronic fluoxetine bidirectionally modulates potentiating effects of serotonin on the hippocampal mossy fiber synaptic transmission.J. Neurosci. 2008; 28: 6272-6280Crossref PubMed Scopus (56) Google Scholar). Both of these receptors are coupled to the Gs-cAMP-dependent intracellular signaling pathway and therefore can occlude each other's signaling. Indeed, in the presence of dopamine, the serotonin-induced synaptic potentiation was greatly reduced (Kobayashi et al., 2008Kobayashi K. Ikeda Y. Haneda E. Suzuki H. Chronic fluoxetine bidirectionally modulates potentiating effects of serotonin on the hippocampal mossy fiber synaptic transmission.J. Neurosci. 2008; 28: 6272-6280Crossref PubMed Scopus (56) Google Scholar), suggesting redundancy in their modulatory effects. The functional meaning or the mode of operation of this redundant neuromodulatory system in physiological and pathological conditions remains to be elucidated. The 5-HT4 and D1-like receptor signaling at the MF synapse has been extensively investigated by applying exogenous serotonin and dopamine. However, how these receptors are activated by endogenous monoamines remains poorly characterized. Although ECT rapidly and strongly enhances the D1-like receptor-dependent synaptic potentiation induced by exogenous dopamine (Kobayashi et al., 2017Kobayashi K. Imoto Y. Yamamoto F. Kawasaki M. Ueno M. Segi-Nishida E. Suzuki H. Rapid and lasting enhancement of dopaminergic modulation at the hippocampal mossy fiber synapse by electroconvulsive treatment.J. Neurophysiol. 2017; 117: 284-289Crossref PubMed Scopus (18) Google Scholar), whether endogenous dopamine contributes to the effects of ECT remains unknown. Serotonergic fibers abundantly project to the hippocampus (Jacobs and Azmitia, 1992Jacobs B.L. Azmitia E.C. Structure and function of the brain serotonin system.Physiol. Rev. 1992; 72: 165-229Crossref PubMed Scopus (2126) Google Scholar), whereas dopaminergic innervation of the hippocampal dentate gyrus and CA3 region is sparse (McNamara et al., 2014McNamara C.G. Tejero-Cantero Á. Trouche S. Campo-Urriza N. Dupret D. Dopaminergic neurons promote hippocampal reactivation and spatial memory persistence.Nat. Neurosci. 2014; 17: 1658-1660Crossref PubMed Scopus (267) Google Scholar, Rosen et al., 2015Rosen Z.B. Cheung S. Siegelbaum S.A. Midbrain dopamine neurons bidirectionally regulate CA3-CA1 synaptic drive.Nat. Neurosci. 2015; 18: 1763-1771Crossref PubMed Scopus (88) Google Scholar, Broussard et al., 2016Broussard J.I. Yang K. Levine A.T. Tsetsenis T. Jenson D. Cao F. Garcia I. Arenkiel B.R. Zhou F.M. De Biasi M. et al.Dopamine regulates aversive contextual learning and associated in vivo synaptic plasticity in the hippocampus.Cell Rep. 2016; 14: 1930-1939Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, Takeuchi et al., 2016Takeuchi T. Duszkiewicz A.J. Sonneborn A. Spooner P.A. Yamasaki M. Watanabe M. Smith C.C. Fernández G. Deisseroth K. Greene R.W. et al.Locus coeruleus and dopaminergic consolidation of everyday memory.Nature. 2016; 537: 357-362Crossref PubMed Scopus (367) Google Scholar). Therefore, endogenous dopamine may contribute little to the modulation of the MF synaptic transmission, which casts doubt on the involvement of the hippocampal dopaminergic system in the neuronal mechanisms underlying ECT and other treatments. However, recent studies have shown that noradrenergic fibers innervating the hippocampus release dopamine in addition to noradrenaline (Kempadoo et al., 2016Kempadoo K.A. Mosharov E.V. Choi S.J. Sulzer D. Kandel E.R. Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory.Proc. Natl. Acad. Sci. U S A. 2016; 113: 14835-14840Crossref PubMed Scopus (282) Google Scholar) and suggested that dopamine derived from the noradrenergic fibers could activate D1-like receptor in the hippocampus (Kempadoo et al., 2016Kempadoo K.A. Mosharov E.V. Choi S.J. Sulzer D. Kandel E.R. Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory.Proc. Natl. Acad. Sci. U S A. 2016; 113: 14835-14840Crossref PubMed Scopus (282) Google Scholar, Takeuchi et al., 2016Takeuchi T. Duszkiewicz A.J. Sonneborn A. Spooner P.A. Yamasaki M. Watanabe M. Smith C.C. Fernández G. Deisseroth K. Greene R.W. et al.Locus coeruleus and dopaminergic consolidation of everyday memory.Nature. 2016; 537: 357-362Crossref PubMed Scopus (367) Google Scholar, Wagatsuma et al., 2018Wagatsuma A. Okuyama T. Sun C. Smith L.M. Abe K. Tonegawa S. Locus coeruleus input to hippocampal CA3 drives single-trial learning of a novel context.Proc. Natl. Acad. Sci. U S A. 2018; 115: E310-E316Crossref PubMed Scopus (108) Google Scholar). Since noradrenergic fibers densely project to the hippocampus including the CA3 region (Loy et al., 1980Loy R. Koziell D.A. Lindsey J.D. Moore R.Y. Noradrenergic innervation of the adult rat hippocampal formation.J. Comp. Neurol. 1980; 189: 699-710Crossref PubMed Scopus (364) Google Scholar, Takeuchi et al., 2016Takeuchi T. Duszkiewicz A.J. Sonneborn A. Spooner P.A. Yamasaki M. Watanabe M. Smith C.C. Fernández G. Deisseroth K. Greene R.W. et al.Locus coeruleus and dopaminergic consolidation of everyday memory.Nature. 2016; 537: 357-362Crossref PubMed Scopus (367) Google Scholar), they could be a major source of dopamine for the activation of D1-like receptors at the MF synapse. The present study aimed at revealing how endogenous monoamines modulate the MF synaptic transmission and relevant hippocampal functions, especially focusing on their potential contribution to the mechanism of action of ECT. Our present results suggest a predominant role of serotonin in the modulation of the MF synaptic transmission that may be involved in an anxiolytic action of ECT. Chronic antidepressant treatments enhance serotonin- and dopamine-induced synaptic potentiation at the MF synapse (Kobayashi et al., 2010Kobayashi K. Ikeda Y. Sakai A. Yamasaki N. Haneda E. Miyakawa T. Suzuki H. Reversal of hippocampal neuronal maturation by serotonergic antidepressants.Proc. Natl. Acad. Sci. U S A. 2010; 107: 8434-8439Crossref PubMed Scopus (171) Google Scholar, Kobayashi et al., 2012Kobayashi K. Haneda E. Higuchi M. Suhara T. Suzuki H. Chronic fluoxetine selectively upregulates dopamine D1-like receptors in the hippocampus.Neuropsychopharmacology. 2012; 37: 1500-1508Crossref PubMed Scopus (41) Google Scholar). Although ECT strongly enhances the dopamine-induced synaptic potentiation (Kobayashi et al., 2017Kobayashi K. Imoto Y. Yamamoto F. Kawasaki M. Ueno M. Segi-Nishida E. Suzuki H. Rapid and lasting enhancement of dopaminergic modulation at the hippocampal mossy fiber synapse by electroconvulsive treatment.J. Neurophysiol. 2017; 117: 284-289Crossref PubMed Scopus (18) Google Scholar) (see Figure S1A), its effect on the serotonin-induced synaptic potentiation remains unknown. Therefore, we first examined the effect of ECT on the serotonin-induced synaptic modulation at the MF synapse. In acute hippocampal slices, bath-applied exogenous serotonin (5-hydroxytryptamine, 5-HT) potentiated synaptic transmission at the MF synapse, as shown previously (Kobayashi et al., 2008Kobayashi K. Ikeda Y. Haneda E. Suzuki H. Chronic fluoxetine bidirectionally modulates potentiating effects of serotonin on the hippocampal mossy fiber synaptic transmission.J. Neurosci. 2008; 28: 6272-6280Crossref PubMed Scopus (56) Google Scholar, Kobayashi et al., 2010Kobayashi K. Ikeda Y. Sakai A. Yamasaki N. Haneda E. Miyakawa T. Suzuki H. Reversal of hippocampal neuronal maturation by serotonergic antidepressants.Proc. Natl. Acad. Sci. U S A. 2010; 107: 8434-8439Crossref PubMed Scopus (171) Google Scholar). We found that three times of ECT (ECTx3) significantly enhanced this 5-HT-induced synaptic potentiation (Figures 1A and 1C ). The magnitude of synaptic potentiation monotonously increased by repeating ECT up to 11 times (Figures 1B and 1C). The 5-HT-induced synaptic potentiation at the MF synapse is mediated by the 5-HT4 receptor (Kobayashi et al., 2008Kobayashi K. Ikeda Y. Haneda E. Suzuki H. Chronic fluoxetine bidirectionally modulates potentiating effects of serotonin on the hippocampal mossy fiber synaptic transmission.J. Neurosci. 2008; 28: 6272-6280Crossref PubMed Scopus (56) Google Scholar, Kobayashi et al., 2010Kobayashi K. Ikeda Y. Sakai A. Yamasaki N. Haneda E. Miyakawa T. Suzuki H. Reversal of hippocampal neuronal maturation by serotonergic antidepressants.Proc. Natl. Acad. Sci. U S A. 2010; 107: 8434-8439Crossref PubMed Scopus (171) Google Scholar), a subtype of 5-HT receptor abundantly expressed in the dentate gyrus and along the MF pathway (Vilaró et al., 2005Vilaró M.T. Cortés R. Mengod G. Serotonin 5-HT4 receptors and their mRNAs in rat and Guinea pig brain: distribution and effects of neurotoxic lesions.J. Comp. Neurol. 2005; 484: 418-439Crossref PubMed Scopus (111) Google Scholar, Imoto et al., 2015Imoto Y. Kira T. Sukeno M. Nishitani N. Nagayasu K. Nakagawa T. Kaneko S. Kobayashi K. Segi-Nishida E. Role of the 5-HT4 receptor in chronic fluoxetine treatment-induced neurogenic activity and granule cell dematuration in the dentate gyrus.Mol. Brain. 2015; 8: 29Crossref PubMed Scopus (43) Google Scholar). In mice lacking the 5-HT4 receptor, 5-HT had no significant effect on the synaptic transmission even after 11 times of ECT (ECTx11) (Figure 1B), indicating that the 5-HT4 receptor solely mediates the prominent 5-HT-induced synaptic potentiation in ECT-treated mice. We also examined the effect of ECT on serotonergic synaptic modulation in the CA1 region of the hippocampus. At the Schaffer collateral/commissural fiber-CA1 synapse, 5-HT caused small synaptic potentiation that was dependent on the 5-HT4 receptor at least in part (Figures 1D and 1E). ECTx3 had no significant effect on this synaptic potentiation (Figures 1D and 1E). These results indicate that ECT enhances the 5-HT4 receptor-dependent synaptic modulation in a synapse-specific manner. We then examined the mechanism underlying the enhancement of the 5-HT4 receptor-dependent synaptic potentiation by ECT. The rapid change in the phenotype of the dentate gyrus neurons requires glutamate NMDA receptors (Imoto et al., 2017Imoto Y. Segi-Nishida E. Suzuki H. Kobayashi K. Rapid and stable changes in maturation-related phenotypes of the adult hippocampal neurons by electroconvulsive treatment.Mol. Brain. 2017; 10: 8Crossref PubMed Scopus (26) Google Scholar). To address the involvement of NMDA receptors, their antagonist CPP was injected before each ECT. Although CPP slightly increased the 5-HT-induced synaptic potentiation, ECTx3 significantly enhanced the 5-HT-induced potentiation in both saline- and CPP-treated mice (Figure 2A). Although ECTx3 appeared even more effective in the CPP-treated mice, there was no statistically significant interaction between ECT and CPP treatments. These results suggest that NMDA receptor activation is not required for the enhanced 5-HT4 receptor-dependent synaptic modulation by ECT. Next, we examined the possibility that increased 5-HT4 receptor expression underlies the enhanced synaptic modulation. Since the 5-HT4 receptor-dependent synaptic potentiation at the MF synapse is independent of GABA-mediated synaptic inhibition and is mediated by presynaptic mechanisms (Kobayashi et al., 2008Kobayashi K. Ikeda Y. Haneda E. Suzuki H. Chronic fluoxetine bidirectionally modulates potentiating effects of serotonin on the hippocampal mossy fiber synaptic transmission.J. Neurosci. 2008; 28: 6272-6280Crossref PubMed Scopus (56) Google Scholar), we analyzed the 5-HT4 receptor gene expression in the dentate gyrus. In contrast to the prominent enhancement of the synaptic modulation, there was no significant change in the expression level of the 5-HT4 receptor gene after single or repeated ECT (Figure 2B). We also examined a possible change in cAMP-dependent signaling, a downstream cascade of 5-HT4 receptor activation (Kobayashi et al., 2008Kobayashi K. Ikeda Y. Haneda E. Suzuki H. Chronic fluoxetine bidirectionally modulates potentiating effects of serotonin on the hippocampal mossy fiber synaptic transmission.J. Neurosci. 2008; 28: 6272-6280Crossref PubMed Scopus (56) Google Scholar), by using the adenylate cyclase activator forskolin. Bath-applied forskolin (10 μM) greatly potentiated the MF synaptic transmission, and ECTx11 had no significant effect on this forskolin-induced synaptic potentiation (Figure 2C). We next examined endogenous monoamines involved in the regulation of the MF synaptic transmission using methamphetamine, which can induce the release of monoamines including serotonin and dopamine (Rothman and Baumann, 2003Rothman R.B. Baumann M.H. Monoamine transporters and psychostimulant drugs.Eur. J. Pharmacol. 2003; 479: 23-40Crossref PubMed Scopus (384) Google Scholar). Bath-applied methamphetamine caused slowly developing synaptic potentiation in naive mice. The 5-HT4 receptor antagonist GR125487 suppressed this methamphetamine-induced synaptic potentiation by about 85% (Figures 3A and 3D ). On the other hand, the D1-like receptor antagonist SCH23390, applied at a concentration sufficient for suppressing the exogenous dopamine-induced potentiation (see Figure S1A) (Kobayashi et al., 2017Kobayashi K. Imoto Y. Yamamoto F. Kawasaki M. Ueno M. Segi-Nishida E. Suzuki H. Rapid and lasting enhancement of dopaminergic modulation at the hippocampal mossy fiber synapse by electroconvulsive treatment.J. Neurophysiol. 2017; 117: 284-289Crossref PubMed Scopus (18) Google Scholar), had no significant effect (Figures 3B and 3D). The dopamine content in the hippocampal slice may be insufficient for activation of D1-like receptors at the MF synapse. It is also possible that methamphetamine is not effective in releasing dopamine in the slice preparation. To distinguish between these possibilities, we added the dopamine precursor L-dopa to increase the dopamine content in the slice. In the presence of L-dopa and GR125487, methamphetamine induced robust synaptic potentiation (Figures 3C and 3D). SCH23390 completely suppressed the methamphetamine-induced synaptic potentiation in the L-dopa-loaded slice (Figure 3E), suggesting that the extracellular dopamine level was sufficient for activation of D1-like receptors in this condition. These results support the former possibility that the hippocampal dopamine content is insufficient for activation of D1-like receptors at the MF synapse in the control condition. We further examined the synaptic modulation by endogenous monoamines in ECT-treated mice. Repeated ECT strongly enhanced the methamphetamine-induced synaptic potentiation (Figures 4A and 4B ). As in the naive mice, GR125487 largely inhibited the methamphetamine-induced potentiation in ECT-treated mice (Figure 4B), suggesting that ECT enhanced synaptic potentiation caused by endogenous 5-HT acting on the 5-HT4 receptor. The effects of endogenous 5-HT depletion were also examined by inhibiting tryptophan hydroxylase (TPH), a rate-limiting enzyme in the 5-HT biosynthesis. The TPH inhibitor 4-chloro-DL-phenylalanine methyl ester (p-chlorophenylalanine, pCPA) significantly reduced the methamphetamine-induced synaptic potentiation in ECT-treated mice (Figures 4C and 4D), which agrees with the effect of the 5-HT4 receptor antagonist GR125487. Furthermore, in 5-HT4 receptor knockout mice, the methamphetamine-induced synaptic potentiation was strongly reduced in both control and ECT-treated mice (Figure S3). In the L-dopa-loaded slice, methamphetamine caused robust D1-like receptor-dependent synaptic potentiation in the presence of GR125487, as shown above, which was strongly increased by ECTx3 (Figure 4E). Therefore, although ECTx3 enhanced the D1-like receptor-dependent synaptic modulation as well, the dopamine content in the hippocampal slices was insufficient for robust activation of D1-like receptors without L-dopa. These results suggest that 5-HT serves as the predominant endogenous monoamine in modulation of the MF synaptic transmission in normal and ECT-treated mice. We noted that the effect of ECTx3 on the methamphetamine-induced potentiation was 2- to 3-fold larger than that on 5-HT-induced potentiation (Figure S4A). This result is somewhat contradictory to the above observation that the methamphetamine-induced potentiation is mostly mediated by 5-HT. ECT might have increased the amount of endogenous releasable 5-HT in the hippocampus. To test this possibility, we performed an immunohistochemical analysis of 5-HT levels along the MF tract in the hippocampal CA3 region. Fluorescent immunostaining using an antibody against 5-HT revealed puncta-like structures in the MF projection area (i.e., the stratum lucidum) of the CA3 region (Figure 5A). These puncta most likely represented the serotonergic nerve terminals. We found that the number of the detectable immunoreactive puncta increased after ECTx3 (Figure 5B), whereas there was no significant change in the relative fluorescence intensity distribution between control and ECTx3-treated mice (Figure 5C). These results suggest that ECTx3 increased the amount of endogenous 5-HT in the stratum lucidum. On the other hand, there was no significant change in the number of 5-HT puncta after ECTx11 (Figure S4C). The relative fluorescence intensity distribution shifted downward after ECTx11, likely owing to a trend increase in the number of low-intensity puncta (Figures S4D and S4E). This lack of an obvious effect of ECTx11 on the 5-HT immunoreactivity is consistent with the comparable effects of ECTx11 on 5-HT- and methamphetamine-induced synaptic potentiation shown by electrophysiological methods (Figure S4B). We further examined a possible increase in the amount of endogenous 5-HT after ECTx3. Since TPH is not saturated by the substrate tryptophan in physiological conditions (Richard et al., 2009Richard D.M. Dawes M.A. Mathias C.W. Acheson A. Hill-Kapturczak N. Dougherty D.M. L-Tryptophan: basic metabolic functions, behavioral research and therapeutic indications.Int. J. Tryptophan Res. 2009; 2: 45-60Crossref PubMed Google Scholar), an increase in tryptophan availability can increase 5-HT biosynthesis. To test whether a change in tryptophan availability occurred after ECT, TPH saturation was assessed by electrophysiology. In control mice, acute supplementation of tryptophan in the slice preparation significantly increased the methamphetamine-induced potentiation (Figure 5D), suggesting that TPH is not saturated by endogenous tryptophan in the control condition. In contrast, tryptophan supplementation had no significant effect in ECTx3-treated mice (Figure 5E). Therefore, TPH appeared to be more saturated by endogenous tryptophan in ECT-treated mice than in control mice. These results support the idea that the tryptophan availability increased after ECT and may explain the increased 5-HT immunoreactive puncta after ECTx3 (see Discussion). The 5-HT4 receptor has been implicated in both antidepressant- and anxiolytic-like behavioral effects in rodents (Lucas et al., 2007Lucas G. Rymar V.V. Du J. Mnie-Filali O. Bisgaard C. Manta S. Lambas-Senas L. Wiborg O. Haddjeri N. 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• W3014509063 date "2020-04-01" @default.
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• W3014509063 title "Predominant Role of Serotonin at the Hippocampal Mossy Fiber Synapse with Redundant Monoaminergic Modulation" @default.
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