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• W1981305427 abstract "Synapses throughout the brain are modified through associative mechanisms in which one input provides an instructive signal for changes in the strength of a second coactivated input. In cerebellar Purkinje cells, climbing fiber synapses provide an instructive signal for plasticity at parallel fiber synapses. Here, we show that noradrenaline activates α2-adrenergic receptors to control short-term and long-term associative plasticity of parallel fiber synapses. This regulation of plasticity does not reflect a conventional direct modulation of the postsynaptic Purkinje cell or presynaptic parallel fibers. Instead, noradrenaline reduces associative plasticity by selectively decreasing the probability of release at the climbing fiber synapse, which in turn decreases climbing fiber-evoked dendritic calcium signals. These findings raise the possibility that targeted presynaptic modulation of instructive synapses could provide a general mechanism for dynamic context-dependent modulation of associative plasticity. Synapses throughout the brain are modified through associative mechanisms in which one input provides an instructive signal for changes in the strength of a second coactivated input. In cerebellar Purkinje cells, climbing fiber synapses provide an instructive signal for plasticity at parallel fiber synapses. Here, we show that noradrenaline activates α2-adrenergic receptors to control short-term and long-term associative plasticity of parallel fiber synapses. This regulation of plasticity does not reflect a conventional direct modulation of the postsynaptic Purkinje cell or presynaptic parallel fibers. Instead, noradrenaline reduces associative plasticity by selectively decreasing the probability of release at the climbing fiber synapse, which in turn decreases climbing fiber-evoked dendritic calcium signals. These findings raise the possibility that targeted presynaptic modulation of instructive synapses could provide a general mechanism for dynamic context-dependent modulation of associative plasticity. Associative synaptic plasticity is a candidate substrate for the formation of real-world associations (Hebb, 1949Hebb D.O. The Organization of Behavior. John Wiley & Sons, New York1949Google Scholar). Synaptic plasticity typically requires precisely timed coactivation of a presynaptic input with postsynaptic events including depolarization and elevation of dendritic calcium (Abbott and Nelson, 2000Abbott L.F. Nelson S.B. Synaptic plasticity: taming the beast.Nat. Neurosci. 2000; 3: 1178-1183Crossref PubMed Scopus (1315) Google Scholar, Bi and Poo, 2001Bi G. Poo M. Synaptic modification by correlated activity: Hebb's postulate revisited.Annu. Rev. Neurosci. 2001; 24: 139-166Crossref PubMed Scopus (1019) Google Scholar, Bliss and Collingridge, 1993Bliss T.V. Collingridge G.L. A synaptic model of memory: long-term potentiation in the hippocampus.Nature. 1993; 361: 31-39Crossref PubMed Scopus (9151) Google Scholar). Induction of associative plasticity is often triggered by instructive synaptic inputs that influence the state of the postsynaptic cell (Blair et al., 2001Blair H.T. Schafe G.E. Bauer E.P. Rodrigues S.M. LeDoux J.E. Synaptic plasticity in the lateral amygdala: a cellular hypothesis of fear conditioning.Learn. Mem. 2001; 8: 229-242Crossref PubMed Scopus (476) Google Scholar, Dudman et al., 2007Dudman J.T. Tsay D. Siegelbaum S.A. A role for synaptic inputs at distal dendrites: instructive signals for hippocampal long-term plasticity.Neuron. 2007; 56: 866-879Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, Ito, 2001Ito M. Cerebellar long-term depression: characterization, signal transduction, and functional roles.Physiol. Rev. 2001; 81: 1143-1195Crossref PubMed Scopus (639) Google Scholar). A great deal is known about how postsynaptic spiking, and the presynaptic and postsynaptic properties of the synapses being modified, control the induction of associative plasticity (Duguid and Sjostrom, 2006Duguid I. Sjostrom P.J. Novel presynaptic mechanisms for coincidence detection in synaptic plasticity.Curr. Opin. Neurobiol. 2006; 16: 312-322Crossref PubMed Scopus (94) Google Scholar, Malenka and Bear, 2004Malenka R.C. Bear M.F. LTP and LTD: an embarrassment of riches.Neuron. 2004; 44: 5-21Abstract Full Text Full Text PDF PubMed Scopus (2736) Google Scholar, Nicoll, 2003Nicoll R.A. Expression mechanisms underlying long-term potentiation: a postsynaptic view.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2003; 358: 721-726Crossref PubMed Scopus (153) Google Scholar, Seol et al., 2007Seol G.H. Ziburkus J. Huang S. Song L. Kim I.T. Takamiya K. Huganir R.L. Lee H.K. Kirkwood A. Neuromodulators control the polarity of spike-timing-dependent synaptic plasticity.Neuron. 2007; 55: 919-929Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar). Much less is known about whether associative plasticity can be controlled by modulating instructive synaptic inputs. Cerebellar Purkinje cells (PCs) are well suited to studying the role of instructive synapses in the regulation of associative plasticity. PCs receive two very different classes of excitatory inputs: weak synaptic inputs from roughly 100,000 granule cell parallel fibers (PFs) (Eccles et al., 1966bEccles J.C. Llinas R. Sasaki K. Parallel fibre stimulation and the responses induced thereby in the Purkinje cells of the cerebellum.Exp. Brain Res. 1966; 1: 17-39PubMed Google Scholar) and a strong synaptic input from a single climbing fiber (CF) (Eccles et al., 1966aEccles J.C. Llinas R. Sasaki K. The excitatory synaptic action of climbing fibres on the purinje cells of the cerebellum.J. Physiol. 1966; 182: 268-296PubMed Google Scholar). The CF provides an important instructive signal that controls the induction of associative plasticity at the PF synapse and which is thought to be important for motor learning (Gilbert and Thach, 1977Gilbert P.F. Thach W.T. Purkinje cell activity during motor learning.Brain Res. 1977; 128: 309-328Crossref PubMed Scopus (400) Google Scholar, Kitazawa et al., 1998Kitazawa S. Kimura T. Yin P.B. Cerebellar complex spikes encode both destinations and errors in arm movements.Nature. 1998; 392: 494-497Crossref PubMed Scopus (268) Google Scholar, Raymond and Lisberger, 1998Raymond J.L. Lisberger S.G. Neural learning rules for the vestibulo-ocular reflex.J. Neurosci. 1998; 18: 9112-9129PubMed Google Scholar). Activation of the CF synapse elicits a characteristic postsynaptic complex spike that elevates calcium throughout PC dendrites (Schmolesky et al., 2002Schmolesky M.T. Weber J.T. De Zeeuw C.I. Hansel C. The making of a complex spike: ionic composition and plasticity.Ann. N Y Acad. Sci. 2002; 978: 359-390Crossref PubMed Scopus (117) Google Scholar). Activation of PFs followed by complex spikes within several hundred milliseconds leads to rapid synaptic suppression resulting from endocannabinoid release from PCs and retrograde activation of type 1 cannabinoid (CB1) receptors (Brenowitz and Regehr, 2005Brenowitz S.D. Regehr W.G. Associative short-term synaptic plasticity mediated by endocannabinoids.Neuron. 2005; 45: 419-431Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). Repetition of this stimulus for minutes induces cerebellar long-term depression (LTD) of PF synapses onto PCs (Ito, 2001Ito M. Cerebellar long-term depression: characterization, signal transduction, and functional roles.Physiol. Rev. 2001; 81: 1143-1195Crossref PubMed Scopus (639) Google Scholar, Safo and Regehr, 2005Safo P.K. Regehr W.G. Endocannabinoids control the induction of cerebellar LTD.Neuron. 2005; 48: 647-659Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar). Previous studies have suggested that altering the strength of CF inputs to PCs can provide a way to control the induction of associative plasticity (Coesmans et al., 2004Coesmans M. Weber J.T. De Zeeuw C.I. Hansel C. Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control.Neuron. 2004; 44: 691-700Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar), but the circumstances under which such regulation might occur remain unclear. The cerebellum receives monoaminergic inputs from neuromodulatory centers throughout the brain. They, together with mossy fibers and CFs, comprise the three classes of cerebellar afferent input, and are a relatively poorly understood element of the cerebellar circuitry (Schweighofer et al., 2004Schweighofer N. Doya K. Kuroda S. Cerebellar aminergic neuromodulation: towards a functional understanding.Brain Res. Brain Res. Rev. 2004; 44: 103-116Crossref PubMed Scopus (118) Google Scholar). Anatomical studies indicate that noradrenergic fibers originate in the locus coeruleus and course through all layers of the cerebellar cortex (Bloom et al., 1971Bloom F.E. Hoffer B.J. Siggins G.R. Studies on norepinephrine-containing afferents to Purkinje cells of art cerebellum. I. Localization of the fibers and their synapses.Brain Res. 1971; 25: 501-521Crossref PubMed Scopus (242) Google Scholar, Hokfelt and Fuxe, 1969Hokfelt T. Fuxe K. Cerebellar monoamine nerve terminals, a new type of afferent fibers to the cortex cerebelli.Exp. Brain Res. 1969; 9: 63-72Crossref PubMed Scopus (222) Google Scholar, Kimoto et al., 1978Kimoto Y. Satoh K. Sakumoto T. Tohyama M. Shimizu N. Afferent fiber connections from the lower brain stem to the rat cerebellum by the horseradish peroxidase method combined with MAO staining, with special reference to noradrenergic neurons.J. Hirnforsch. 1978; 19: 85-100PubMed Google Scholar, Olson and Fuxe, 1971Olson L. Fuxe K. On the projections from the locus coeruleus noradrealine neurons: the cerebellar innervation.Brain Res. 1971; 28: 165-171Crossref PubMed Scopus (385) Google Scholar, Schroeter et al., 2000Schroeter S. Apparsundaram S. Wiley R.G. Miner L.H. Sesack S.R. Blakely R.D. Immunolocalization of the cocaine- and antidepressant-sensitive l-norepinephrine transporter.J. Comp. Neurol. 2000; 420: 211-232Crossref PubMed Scopus (202) Google Scholar), forming varicosities closely apposed to PC dendrites (Landis and Bloom, 1975Landis S.C. Bloom F.E. Ultrastructural identification of noradrenergic boutons in mutant and normal mouse cerebellar cortex.Brain Res. 1975; 96: 299-305Crossref PubMed Scopus (51) Google Scholar). Noradrenergic inhibition of PCs can be elicited through electrical stimulation of the locus coeruleus in vivo (Siggins et al., 1971bSiggins G.R. Hoffer B.J. Oliver A.P. Bloom F.E. Activation of a central noradrenergic projection to cerebellum.Nature. 1971; 233: 481-483Crossref PubMed Scopus (65) Google Scholar). Perturbation of noradrenergic inputs to the cerebellum interferes with cerebellum-dependent forms of motor learning (Galeotti et al., 2004Galeotti N. Bartolini A. Ghelardini C. Alpha-2 agonist-induced memory impairment is mediated by the alpha-2A-adrenoceptor subtype.Behav. Brain Res. 2004; 153: 409-417Crossref PubMed Scopus (37) Google Scholar, Keller and Smith, 1983Keller E.L. Smith M.J. Suppressed visual adaptation of the vestibuloocular reflex in catecholamine-depleted cats.Brain Res. 1983; 258: 323-327Crossref PubMed Scopus (27) Google Scholar, McCormick and Thompson, 1982McCormick D.A. Thompson R.F. Locus coeruleus lesions and resistance to extinction of a classically conditioned response: involvement of the neocortex and hippocampus.Brain Res. 1982; 245: 239-249Crossref PubMed Scopus (49) Google Scholar, Watson and McElligott, 1984Watson M. McElligott J.G. Cerebellar norepinephrine depletion and impaired acquisition of specific locomotor tasks in rats.Brain Res. 1984; 296: 129-138Crossref PubMed Scopus (83) Google Scholar, Pompeiano, 1998Pompeiano O. Noradrenergic influences on the cerebellar cortex: effects on vestibular reflexes under basic and adaptive conditions.Otolaryngol. Head Neck Surg. 1998; 119: 93-105Crossref PubMed Scopus (16) Google Scholar). Here we ask whether neuromodulation can control the induction of associative plasticity through selective regulation of instructive signals conveyed to Purkinje cells by climbing fibers. We find that noradrenaline acts through α2-adrenergic receptors to decrease the probability of release at the CF synapse. This in turn decreases CF-evoked dendritic calcium transients and interferes with the induction of short-term and long-term associative plasticity of PF synapses. We conclude that noradrenaline controls synaptic plasticity of PF synapses through selective regulation of instructive signals, thereby providing a mechanism that could allow for dynamic, context-dependent regulation of learning. We examined synaptic responses in Purkinje cells by making whole-cell voltage-clamp recordings with a Cs-based internal solution to minimize the contributions of active postsynaptic conductances. Climbing fibers were stimulated with pairs of stimuli separated by 30 ms. In control conditions, CF-EPSCs exhibited marked paired-pulse depression as previously described (Eccles et al., 1966aEccles J.C. Llinas R. Sasaki K. The excitatory synaptic action of climbing fibres on the purinje cells of the cerebellum.J. Physiol. 1966; 182: 268-296PubMed Google Scholar). The effects of noradrenaline (NA; 5 μM) on the CF-EPSC are shown (Figure 1A). NA decreased the EPSC amplitude and increased the paired-pulse ratio by 29% ± 5% (n = 6, p < 0.01) and 32% ± 3% respectively (n = 6, p < 0.01; Figure 1B). This decrease in paired-pulse depression is consistent with NA acting presynaptically to decrease the probability of release at the CF synapse (Foster and Regehr, 2004Foster K.A. Regehr W.G. Variance-mean analysis in the presence of a rapid antagonist indicates vesicle depletion underlies depression at the climbing fiber synapse.Neuron. 2004; 43: 119-131Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, Kreitzer and Regehr, 2001Kreitzer A.C. Regehr W.G. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells.Neuron. 2001; 29: 717-727Abstract Full Text Full Text PDF PubMed Scopus (671) Google Scholar, Maejima et al., 2001Maejima T. Hashimoto K. Yoshida T. Aiba A. Kano M. Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors.Neuron. 2001; 31: 463-475Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar, Wadiche and Jahr, 2001Wadiche J.I. Jahr C.E. Multivesicular release at climbing fiber-Purkinje cell synapses.Neuron. 2001; 32: 301-313Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar). We used selective agonists and antagonists to pharmacologically characterize the involvement of various adrenergic receptors in modulating CF-EPSCs. α1, α2, and β adrenergic receptors are expressed in cerebellum (Nicholas et al., 1996Nicholas A.P. Hokfelt T. Pieribone V.A. The distribution and significance of CNS adrenoceptors examined with in situ hybridization.Trends Pharmacol. Sci. 1996; 17: 245-255Abstract Full Text PDF PubMed Scopus (234) Google Scholar). Previous studies have shown that β adrenergic receptors can modulate PC output through direct postsynaptic effects on PCs (Hoffer et al., 1971Hoffer B.J. Siggins G.R. Bloom F.E. Studies on norepinephrine-containing afferents to Purkinje cells of rat cerebellum. II. Sensitivity of Purkinje cells to norepinephrine and related substances administered by microiontophoresis.Brain Res. 1971; 25: 523-534Crossref PubMed Scopus (276) Google Scholar, Siggins et al., 1971aSiggins G.R. Hoffer B.J. Bloom F.E. Studies on norepinephrine-containing afferents to Purkinje cells of rat cerebellum. 3. Evidence for mediation of norepinephrine effects by cyclic 3′,5′-adenosine monophosphate.Brain Res. 1971; 25: 535-553Crossref PubMed Scopus (172) Google Scholar) as well as through the augmentation of GABAergic inhibition of PCs (Mitoma and Konishi, 1999Mitoma H. Konishi S. Monoaminergic long-term facilitation of GABA-mediated inhibitory transmission at cerebellar synapses.Neuroscience. 1999; 88: 871-883Crossref PubMed Scopus (77) Google Scholar, Yeh and Woodward, 1983Yeh H.H. Woodward D.J. Beta-1 adrenergic receptors mediate noradrenergic facilitation of Purkinje cell responses to gamma-aminobutyric acid in cerebellum of rat.Neuropharmacology. 1983; 22: 629-639Crossref PubMed Scopus (46) Google Scholar). We found that the α2-receptor agonist UK14304 mimicked the effects of noradrenaline and the α2-receptor antagonist yohimbine reversed the effects of noradrenaline on the amplitude and paired-pulse ratio of CF-EPSCs (Figures 1C and 1D). UK14304 reduced EPSC amplitude and paired-pulse depression to a similar extent as NA (26% ± 4% decrease in EPSC1 and a 36% ± 4% increase in PPR, n = 5, p = 0.87; Figure 1D). In contrast, application of the α1 and β-adrenergic receptor agonists phenylephrine and isoproterenol (10 μM each) did not affect EPSC amplitude or paired-pulse ratio (Figures 1G and 1H). Thus, the decrease in probability of release at CF synapses by noradrenaline is mediated by α2-adrenergic receptors. Previously described modulators of the CF synapse, including activation of mGluRs, CB1Rs, adenosine receptors, and GABABRs, lack specificity, modulating PF-PC inputs to an even larger degree (Glaum et al., 1992Glaum S.R. Slater N.T. Rossi D.J. Miller R.J. Role of metabotropic glutamate (ACPD) receptors at the parallel fiber-Purkinje cell synapse.J. Neurophysiol. 1992; 68: 1453-1462PubMed Google Scholar, Hashimoto and Kano, 1998Hashimoto K. Kano M. Presynaptic origin of paired-pulse depression at climbing fibre-Purkinje cell synapses in the rat cerebellum.J. Physiol. 1998; 506: 391-405Crossref PubMed Scopus (99) Google Scholar, Kreitzer and Regehr, 2001Kreitzer A.C. Regehr W.G. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells.Neuron. 2001; 29: 717-727Abstract Full Text Full Text PDF PubMed Scopus (671) Google Scholar, Maejima et al., 2001Maejima T. Hashimoto K. Yoshida T. Aiba A. Kano M. Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors.Neuron. 2001; 31: 463-475Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar, Takahashi and Linden, 2000Takahashi K.A. Linden D.J. Cannabinoid receptor modulation of synapses received by cerebellar Purkinje cells.J. Neurophysiol. 2000; 83: 1167-1180PubMed Google Scholar, Takahashi et al., 1995Takahashi M. Kovalchuk Y. Attwell D. Pre- and postsynaptic determinants of EPSC waveform at cerebellar climbing fiber and parallel fiber to Purkinje cell synapses.J. Neurosci. 1995; 15: 5693-5702Crossref PubMed Google Scholar). A previous study using field recordings in mice has suggested that α2-receptor activation can cause a small (up to 18% with 100 μM NA) reduction of PF synapses (Zhou et al., 2003Zhou Y.D. Turner T.J. Dunlap K. Enhanced G protein-dependent modulation of excitatory synaptic transmission in the cerebellum of the Ca2+ channel-mutant mouse, tottering.J. Physiol. 2003; 547: 497-507Crossref PubMed Scopus (49) Google Scholar). We therefore asked whether the adrenergic modulation of CF-EPSCs we observe was specific to climbing fibers, or whether parallel fiber-to-Purkinje cell synapses were also subject to this modulation. We assessed the effects of α2-receptor activation on PF synapses in voltage-clamp with a Cs-based internal solution, and found that neither NA nor yohimbine significantly altered the amplitude or paired-pulse ratio of PF-EPSCs (Figures 1E–1H). Neuromodulators can either act directly or indirectly to modulate transmission (Maejima et al., 2001Maejima T. Hashimoto K. Yoshida T. Aiba A. Kano M. Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors.Neuron. 2001; 31: 463-475Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar, Varma et al., 2001Varma N. Carlson G.C. Ledent C. Alger B.E. Metabotropic glutamate receptors drive the endocannabinoid system in hippocampus.J. Neurosci. 2001; 21: RC188PubMed Google Scholar, Vogt and Regehr, 2001Vogt K.E. Regehr W.G. Cholinergic modulation of excitatory synaptic transmission in the CA3 area of the hippocampus.J. Neurosci. 2001; 21: 75-83PubMed Google Scholar). We therefore determined whether activation of α2-adrenergic receptors indirectly modulated release at CF synapses through other signaling systems and receptors (Hashimoto and Kano, 1998Hashimoto K. Kano M. Presynaptic origin of paired-pulse depression at climbing fibre-Purkinje cell synapses in the rat cerebellum.J. Physiol. 1998; 506: 391-405Crossref PubMed Scopus (99) Google Scholar, Kreitzer and Regehr, 2001Kreitzer A.C. Regehr W.G. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells.Neuron. 2001; 29: 717-727Abstract Full Text Full Text PDF PubMed Scopus (671) Google Scholar, Kulik et al., 1999Kulik A. Haentzsch A. Luckermann M. Reichelt W. Ballanyi K. Neuron-glia signaling via alpha(1) adrenoceptor-mediated Ca(2+) release in Bergmann glial cells in situ.J. Neurosci. 1999; 19: 8401-8408Crossref PubMed Google Scholar, Takahashi et al., 1995Takahashi M. Kovalchuk Y. Attwell D. Pre- and postsynaptic determinants of EPSC waveform at cerebellar climbing fiber and parallel fiber to Purkinje cell synapses.J. Neurosci. 1995; 15: 5693-5702Crossref PubMed Google Scholar). Coapplication of antagonists of group l and II mGluRs, GABABRs, adenosine A1Rs, and cannabinoid CB1Rs (MCPG, 500 μM; CGP 55845A, 2 μM; DPCPX, 5 μM; AM251, 5 μM) did not affect the ability of NA to decrease the EPSC and alter paired-pulse plasticity (Figures 1G and 1H; 36% ± 4% suppression in blockers versus 29% ± 5% in control, n = 7, p = 0.31). This indicates that noradrenaline does not act indirectly in a manner that requires the activation of any of these signaling systems and is consistent with noradrenaline decreasing the probability of release by acting directly on CF terminals. Together, these findings (Figure 1) indicate that NA selectively decreases the amplitude and increases the PPR of CF-EPSCs by activating α2-receptors. The decrease in paired-pulse depression of CF-EPSCs is consistent with α2-adrenergic receptors acting presynaptically to decrease transmitter release (Foster and Regehr, 2004Foster K.A. Regehr W.G. Variance-mean analysis in the presence of a rapid antagonist indicates vesicle depletion underlies depression at the climbing fiber synapse.Neuron. 2004; 43: 119-131Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, Kreitzer and Regehr, 2001Kreitzer A.C. Regehr W.G. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells.Neuron. 2001; 29: 717-727Abstract Full Text Full Text PDF PubMed Scopus (671) Google Scholar, Maejima et al., 2001Maejima T. Hashimoto K. Yoshida T. Aiba A. Kano M. Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors.Neuron. 2001; 31: 463-475Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar, Takahashi and Linden, 2000Takahashi K.A. Linden D.J. Cannabinoid receptor modulation of synapses received by cerebellar Purkinje cells.J. Neurophysiol. 2000; 83: 1167-1180PubMed Google Scholar, Wadiche and Jahr, 2001Wadiche J.I. Jahr C.E. Multivesicular release at climbing fiber-Purkinje cell synapses.Neuron. 2001; 32: 301-313Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar), as at other synapses (Bertolino et al., 1997Bertolino M. Vicini S. Gillis R. Travagli A. Presynaptic alpha2-adrenoceptors inhibit excitatory synaptic transmission in rat brain stem.Am. J. Physiol. 1997; 272: G654-G661PubMed Google Scholar, Delaney et al., 2007Delaney A.J. Crane J.W. Sah P. Noradrenaline modulates transmission at a central synapse by a presynaptic mechanism.Neuron. 2007; 56: 880-892Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, Hein, 2006Hein L. Adrenoceptors and signal transduction in neurons.Cell Tissue Res. 2006; 326: 541-551Crossref PubMed Scopus (134) Google Scholar, Langer, 1977Langer S.Z. Sixth gaddum memorial lecture, National Institute for Medical Research, Mill Hill, January 1977. Presynaptic receptors and their role in the regulation of transmitter release.Br. J. Pharmacol. 1977; 60: 481-497Crossref PubMed Scopus (820) Google Scholar, Leao and Von Gersdorff, 2002Leao R.M. Von Gersdorff H. Noradrenaline increases high-frequency firing at the calyx of held synapse during development by inhibiting glutamate release.J. Neurophysiol. 2002; 87: 2297-2306Crossref PubMed Scopus (50) Google Scholar). However, transmission at the powerful CF synapse is influenced by postsynaptic saturation of AMPA receptors, which could potentially make it difficult to distinguish between postsynaptic and presynaptic sites of modulation (Wadiche and Jahr, 2001Wadiche J.I. Jahr C.E. Multivesicular release at climbing fiber-Purkinje cell synapses.Neuron. 2001; 32: 301-313Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar). We therefore used two additional approaches to further investigate the mechanism of noradrenergic suppression of the CF synapse. First, we used the rapid, low affinity AMPA receptor antagonist DGG to relieve postsynaptic receptor saturation and provide a more accurate readout of presynaptic glutamate release (Wadiche and Jahr, 2001Wadiche J.I. Jahr C.E. Multivesicular release at climbing fiber-Purkinje cell synapses.Neuron. 2001; 32: 301-313Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar; Foster et al., 2002Foster K.A. Kreitzer A.C. Regehr W.G. Interaction of postsynaptic receptor saturation with presynaptic mechanisms produces a reliable synapse.Neuron. 2002; 36: 1115-1126Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). When NA was applied in the presence of DGG, we found that CF-EPSCs were more strongly suppressed by NA than in control conditions (Figures 2A and 2B versus Figures 1A and 1B; 42% ± 5% suppression in DGG versus 29% ± 5%, suppression in control, n = 7). Similarly, NA increased the paired-pulse ratio to a larger extent in DGG compared to control (60% ± 6% increase in DGG versus 32% ± 3% increase in control). The greater effect of NA in the presence of DGG suggests that NA causes a presynaptic decrease in glutamate release. Interestingly, in the presence of DGG, the α2-adrenergic receptor antagonist yohimbine not only blocked the effect of NA but caused an enhancement of synaptic transmission relative to control conditions (Figure 2B). This finding is consistent with the observation that by relieving saturation, DGG unmasks the effects of modulators that increase release at the high-p CF synapse (Foster et al., 2002Foster K.A. Kreitzer A.C. Regehr W.G. Interaction of postsynaptic receptor saturation with presynaptic mechanisms produces a reliable synapse.Neuron. 2002; 36: 1115-1126Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). The enhancement of CF synaptic strength in yohimbine could be due to inverse agonist properties of the drug (Murrin et al., 2000Murrin L.C. Gerety M.E. Happe H.K. Bylund D.B. Inverse agonism at alpha(2)-adrenoceptors in native tissue.Eur. J. Pharmacol. 2000; 398: 185-191Crossref PubMed Scopus (26) Google Scholar) or tonic α2-receptor activation in control conditions. Second, to further distinguish between presynaptic and postsynaptic effects of NA at the CF synapse, we measured the effect of NA on miniature CF-EPSC amplitude and frequency. To do this, we replaced the calcium in our extracellular recording solution with strontium (Figures 2C–2G). In the presence of strontium, vesicles are released asynchronously (Miledi, 1966Miledi R. Strontium as a substitute for calcium in the process of transmitter release at the neuromuscular junction.Nature. 1966; 212: 1233-1234Crossref PubMed Scopus (131) Google Scholar, Augustine and Eckert, 1984Augustine G.J. Eckert R. Divalent cations differentially support transmitter release at the squid giant synapse.J. Physiol. 1984; 346: 257-271Crossref PubMed Scopus (76) Google Scholar, Goda and Stevens, 1994Goda Y. Stevens C.F. Two components of transmitter release at a central synapse.Proc. Natl. Acad. Sci. USA. 1994; 91: 12942-12946Crossref PubMed Scopus (423) Google Scholar, Xu-Friedman and Regehr, 1999Xu-Friedman M.A. Regehr W.G. Presynaptic strontium dynamics and synaptic transmission.Biophys. J. 1999; 76: 2029-2042Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). The prolongation of release in response to a CF stimulus allows us to isolate CF-mEPSCs from PF-mEPSCs and measure amplitude and frequency of miniature CF synaptic events (Otis et al., 1997Otis T.S. Kavanaugh M.P. Jahr C.E. Postsynaptic glutamate transport at the climbing fiber-Purkinje cell synapse.Science. 1997; 277: 1515-1518Crossref PubMed Scopus (150) Google Scholar). In the presence of Sr, NA greatly reduced the evoked EPSC amplitude (Figure 2C) and the frequency of CF-mEPSCs (Figure 2D, red versus black; Figure 2G; 64% ± 10% reduction in mini frequency), but did not affect the amplitude of CF-mEPSCs (Figures 2E–2G; 0% ± 1% change, p = 0.72, paired t test). This suggests that NA acts presynaptically to reduce mEPSC frequency and does not affect the postsynaptic sensitivity of AMPA receptors. Further, because of the reduction in synchronous release together with the fact that strontium is less effective than calcium at driving transmitter release overall (Xu-Friedman and Regehr, 2000Xu-Friedman M.A. Regehr W.G. Probing fundamental aspects of synaptic transmission with strontium.J. Neurosci. 2000; 20: 4414-4422PubMed Google Scholar), strontium relieves both presynaptic and postsynaptic saturation at the CF synapse (Foster et al., 2002Foster K.A. Kreitzer A.C. Regehr W.G. Interaction of postsynaptic receptor saturation with" @default.
• W1981305427 created "2016-06-24" @default.
• W1981305427 creator A5045839083 @default.
• W1981305427 creator A5053791142 @default.
• W1981305427 date "2009-04-01" @default.
• W1981305427 modified "2023-10-16" @default.
• W1981305427 title "Noradrenergic Control of Associative Synaptic Plasticity by Selective Modulation of Instructive Signals" @default.
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