Synaptic Plasticity and Calcium Signaling in Purkinje Cells of the Central Cerebellar Lobes of Mormyrid Fish

Han, Victor Z.; Zhang, Yueping; Bell, Charles E.; Hansel, Christian

doi:10.1523/jneurosci.2613-07.2007

Cited by 30 publications

(34 citation statements)

References 38 publications

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“…A critical prediction of this conclusion is that strong PF activation can induce LTD in the absence of CF coactivation. This replacement effect has indeed been demonstrated (37,38, also ref. 39), suggesting that strong calcium influx, regardless of synaptic origin, promotes LTD but that CF activity facilitates the induction process by amplifying calcium transients.…”

Section: Discussionsupporting

confidence: 70%

Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal

Piochon

Titley

Simmons

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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At glutamatergic synapses, both long-term potentiation (LTP) and long-term depression (LTD) can be induced at the same synaptic activation frequency. Instructive signals determine whether LTP or LTD is induced, by modulating local calcium transients. Synapses maintain the ability to potentiate or depress over a wide frequency range, but it remains unknown how calcium-controlled plasticity operates when frequency variations alone cause differences in calcium amplitudes. We addressed this problem at cerebellar parallel fiber-Purkinje cell synapses, which can undergo LTD or LTP in response to 1-Hz and 100-Hz stimulation. We observed that high-frequency activation elicits larger spine calcium transients than low-frequency stimulation under all stimulus conditions, but, regardless of activation frequency, climbing fiber (CF) coactivation provides an instructive signal that further enhances calcium transients and promotes LTD. At both frequencies, buffering calcium prevents LTD induction and LTP results instead, identifying the enhanced calcium signal amplitude as the critical parameter contributed by the instructive CF signal. These observations show that it is not absolute calcium amplitudes that determine whether LTD or LTP is evoked but, instead, the LTD threshold slides, thus preserving the requirement for relatively larger calcium transients for LTD than for LTP induction at any given stimulus frequency. Cerebellar LTD depends on the activation of calcium/ calmodulin-dependent kinase II (CaMKII). Using genetically modified (TT305/6VA and T305D) mice, we identified α-CaMKII inhibition upon autophosphorylation at Thr305/306 as a molecular event underlying the threshold shift. This mechanism enables frequencyindependent plasticity control by the instructive CF signal based on relative, not absolute, calcium thresholds.S ynaptic activation frequency is an important factor in the induction of long-term potentiation (LTP) and long-term depression (LTD). For example, it has been shown at Schaffer collateral-CA1 pyramidal cell synapses that application of 900 pulses at 1-3 Hz causes LTD, whereas the same number of pulses applied at 50 Hz causes LTP (1). However, LTP and LTD can also be induced at the same stimulus frequency. This phenomenon has been demonstrated at hippocampal, neocortical, and cerebellar synapses, where potentiation and depression mechanisms operate over a wide range of activation frequencies (2-7). In the neocortex and hippocampus, the level of postsynaptic depolarization determines whether LTP or LTD results from stimulation at a given frequency (2, 5). These voltage-dependent thresholds for LTP and LTD induction reflect thresholds in calcium signal amplitudes (3,4,(8)(9)(10)(11)) that, when maintained for sufficiently long time periods (12), control synaptic plasticity in concert with distinct calcium sensors that are restricted to local microenvironments (13,14).At cerebellar parallel fiber (PF)-Purkinje cell synapses, both LTP and LTD can be induced using 1-Hz and 100-Hz PF stimulation protocols, ...

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Section: Discussionsupporting

confidence: 70%

Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal

Piochon

Titley

Simmons

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…At PF synapses, LTD induction is promoted by CF coactivity, but LTD can also be elicited in the absence of CF stimulation if calcium sources are recruited downstream from synaptic activation (Finch and Augustine 1998), or PF inputs are strongly stimulated (Hartell 1996;Han et al 2007). Our finding that enhancement of AMPA receptor function by CX546 has the same effect and allows for LTD induction without CF coactivation shows that the strength of synaptic activation and local calcium transients ultimately determines the polarity of synaptic gain change at these synapses.…”

Section: Discussionmentioning

confidence: 99%

“…It rather seems that at both hippocampal and cerebellar synapses ampakines-and high-calcium conditions in general-trigger kinase-dominated pathways that involve the activation of CaMKII (see Jörntell and Hansel 2006). It is the AMPA receptor subunit composition (dominance of GluA2 subunits in Purkinje cell synaptic transmission and plasticity; Baude et al 1994;Chung et al 2003) that determines which receptor trafficking rules apply.At PF synapses, LTD induction is promoted by CF coactivity, but LTD can also be elicited in the absence of CF stimulation if calcium sources are recruited downstream from synaptic activation (Finch and Augustine 1998), or PF inputs are strongly stimulated (Hartell 1996;Han et al 2007). Our finding that enhancement of AMPA receptor function by CX546 has the same effect and allows for LTD induction without CF coactivation shows that the strength of synaptic activation and local calcium transients ultimately determines the polarity of synaptic gain change at these synapses.…”

mentioning

confidence: 99%

Enhanced AMPA receptor function promotes cerebellar long-term depression rather than potentiation

et al. 2014

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Ampakines are allosteric modulators of AMPA receptors that facilitate hippocampal long-term potentiation (LTP) and learning, and have been considered for the treatment of cognition and memory deficits. Here, we show that the ampakine CX546 raises the amplitude and slows the decay time of excitatory postsynaptic currents (EPSCs) at cerebellar parallel fiber (PF) to Purkinje cell synapses, thus resembling CX546 effects described at hippocampal synapses. Using the fluorescent calcium indicator dye Oregon Green BAPTA-2 and an ultra-high-speed CCD camera, we also monitored calcium transients in Purkinje cell dendrites. In the presence of CX546 in the bath, PF-evoked calcium transients were enhanced and prolonged, suggesting that CX546 not only enhances synaptic transmission, but also boosts dendritic calcium signaling at cerebellar synapses. In contrast to previous observations in the hippocampus, however, CX546 applied during cerebellar recordings facilitates long-term depression (LTD) rather than LTP at PF synapses. These findings show that ampakines selectively modify the LTP -LTD balance depending on the brain area and type of synapse, and may provide tools for the targeted regulation of synaptic memories.[Supplemental material is available for this article.]At glutamatergic synapses onto hippocampal and neocortical pyramidal cells, respectively, coincident pre-and postsynaptic activity elicits long-term potentiation (LTP), which typically requires the activation of N-methyl-D-aspartate (NMDA) receptors (Bliss and Collingridge 1993). Long-term depression (LTD), in contrast, may or may not require NMDA receptor activation, but results from activity patterns that activate the postsynaptic neuron in a less efficient or less well-timed manner (Artola and Singer 1993;Kirkwood et al. 1993). It has been suggested that LTP requires a larger calcium signal amplitude for its induction than LTD (Bienenstock et al. 1982;Bear et al. 1987;Hansel et al. 1997). It seems likely that other calcium signaling parameters are crucial as well (Neveu and Zucker 1996;Nevian and Sakmann 2006), but the amplitude of calcium signaling might be the one parameter that most faithfully reflects synaptic input strength during the induction phase. Efforts to develop memory-enhancing drugs have thus focused on the strategy that the magnitude and induction probability of LTP might be enhanced by drugs that boost synaptic transmission and calcium signaling. Ampakines, which are allosteric modulators of AMPA receptors that enhance transmission by slowing both desensitization and deactivation of AMPA receptors (Lynch 2002), have indeed been shown to facilitate LTP induction (Stäubli et al. 1994;Arai et al. 2004). These observations demonstrate that a selective manipulation of synaptic activation strength can affect the LTP induction probability. Moreover, ampakines positively affect memory encoding and recall in humans (Ingvar et al. 1997;Lynch et al. 1997;Lynch and Gall 2006) and reduce effects of sleep deprivation on cognitive performance (Porrino et...

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“…The basic connectional organisation pattern in the cerebellum of teleosts is similar to that reported for mammals (Wullimann & Northcutt 1988;Meek & Nieuwenhuys 1998;Ikenaga et al 2006;Meek et al 2008;Xue et al 2008), suggesting that it could also support the convergence of CS and US required for classical conditioning to occur. In fact, the paired stimulation of climbing and parallel fibres in the mormyrid fish cerebellum produces plastic changes in the synapses of the parallel fibres onto Purkinje cells (Han et al 2007).…”

Section: Delay Motor Classical Conditioning and Teleost Fish Cerebellummentioning

confidence: 99%

Brain and Cognition in Teleost Fish

Broglio

Gómez

Durán

et al. 2011

Fish Cognition and Behavior

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Synaptic Plasticity and Calcium Signaling in Purkinje Cells of the Central Cerebellar Lobes of Mormyrid Fish

Cited by 30 publications

References 38 publications

Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal

Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal

Enhanced AMPA receptor function promotes cerebellar long-term depression rather than potentiation

Brain and Cognition in Teleost Fish

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