Pairing of pre‐ and postsynaptic activities in cerebellar Purkinje cells induces long‐term changes in synaptic efficacy in vitro.

Abstract

SUMMARY1. An in vitro slice preparation of rat cerebellar cortex was used to analyse longlasting modifications of synaptic transmission at parallel fibre (PF)-Purkinje cell (PC) synapses. These use-dependent changes were induced by pairing PF-mediated EPSPs evoked at low frequency (1 Hz) with different levels of membrane polarization (or bioelectrical activities) of PCs for 15 min.2. Experiments were performed on forty-eight PCs recorded intracellularly in a conventional perfused chamber, and in fifty other cells maintained in a static chamber either in the presence (n = 21) or in the absence (n = 29) of 400 nM-phorbol 12,13-dibutyrate (PDBu).3. In these three experimental conditions, PF-mediated EPSPs were always measured on PCs maintained at a holding potential of -75 mV, and further hyperpolarized by constant hyperpolarizing pulses. This allowed us both to test the input resistance of PCs and to avoid their firing during PF-mediated EPSPs.4. In all cells retained for the present study, latencies of PF-mediated EPSPs evoked at 0-2 Hz were stable during the pre-pairing period, and the same was true for their amplitude and time course.5. In the perfused chamber, pairing of PF-mediated EPSPs with the same hyperpolarization of PCs as that used for measurements of synaptic responses had no effect on these EPSPs in 30% of PCs. It induced long-term depression (LTD) and long-term potentiation (LTP) in 23 and 47 % of the tested cells respectively (n = 17).6. In the perfused chamber, pairing of PF-mediated EPSPs with moderate depolarization of PCs (n = 19) giving rise to a sustained firing of sodium spikes significantly favoured the appearance of LTP as compared to the previous pairing protocol. However, there were still 27 and 15 % of cells which showed no modification and LTD respectively.7. In contrast, pairing of PF-mediated EPSPs with calcium (Ca2") spikes evoked by strong depolarization of PCs (n = 12) led to LTD of synaptic transmission in nearly half of the tested cells, whereas LTP was now observed in less than 20 % of them. MS 8485F. CREPEL AND D. JAILLARD 8. In the static chamber and in the absence of PDBu, LTD of PF-mediated EPSPs was observed in most cells, whatever the pairing protocol with sodium or Ca2+ spikes.9. This shift towards LTD was significantly reversed by PDBu in the pairing protocol using firing of sodium spikes, but not in the case of pairings with Ca2+ spikes.10. Whatever the protocol used, long-term synaptic changes were not accompanied by any significant variation of cell input resistance or latency of EPSPs. In all cases, LTP and LTD were accompanied by increase and decrease of the initial slope of PF-mediated EPSPs.11. These results, together with those from previous studies, suggest that induction of LTP at PF-PC synapses is at least partly presynaptic and can be increased by direct activation of protein kinase C. They also suggest that PCs can reinforce this LTP or alternatively can convert it into LTD depending on their firing on sodium or Ca2+ spikes.

Is the Cerebellum a Smith Predictor?

“…Armstrong, Edgley, and Lidierth (1988) and Gellman, Gibson, and Houk ( 1985) have shown that the most potent stimulus for climbing fibers is an unexpected sensory event and that similar "reafferent" sensory stimuli resulting from the ani-mal's own actions do not excite the climbing fibers. There is now strong evidence that coincidence of climbing fiber and parallel fiber inputs to Purkinje cells results in longterm depression of the parallel fiber:Purkinje cell synapse (Crepel & Jaillard, 1991 ;Ito, 1989). This may allow the cerebellar cortex to learn or modify a neural representation of the limb dynamics.…”

Local dendritic Ca2+ signaling induces cerebellar long-term depression.

“…Second, a CF-induced rise in Ca 2+ concentration is necessary for LTD because induction of LTD is prevented by injection of Ca 2+ chelators into Purkinje cells (Sakurai 1990;Konnerth et al 1992). Finally, an increase in postsynaptic Ca 2+ concentration is sufficient to produce LTD because direct elevation of Ca 2+ concentration--either by depolarization-induced activation of voltage-gated Ca 2+ channels (Crepel and Jaillard 1991;Linden et al 1991;Kon-nerth et al 1992) or by photolysis of "caged Ca 2+'' compounds (Kasono and Hirano 1994;Lev-Ram et al 1995)--can substitute for activation of the CF synapse. Thus, it is clear that CF activity initiates LTD by elevating postsynaptic Ca 2+ concentration.…”

A new form of cerebellar long-term potentiation is postsynaptic and depends on nitric oxide but not cAMP

“…However, the PF-PC synapse also needs long-term potentiation (LTP), driven by presynaptic activity without postsynaptic depolarization, to prevent saturation of LTD, allow extinction of learned associations, and refine the temporal precision of learned responses (10)(11)(12). Although a few examples of LTP at the PF-PC synapse had been anecdotally reported in articles focusing on LTD (8,(13)(14)(15)(16), the first systematic characterization of LTP was by Salin et al (17), who stimulated the PFs 120 times at 4-8 Hz and observed a subsequent 40-50% long-term enhancement of excitatory postsynaptic potentials. This work and several subsequent studies have shown that such LTP is induced and expressed presynaptically by means of cAMP signaling (18)(19)(20)(21).…”