On the induction of postsynaptic granule cell-Purkinje neuron LTP and LTD

Abstract

In the last decade, several experimental studies have demonstrated that particular patterns of synaptic activity can induce postsynaptic parallel fiber (PF) long-term potentiation (LTP). This form of plasticity can reverse postsynaptic PF long-term depression (LTD), which has been traditionally considered as the principal form of plasticity underlying cerebellar learning. Postsynaptic PF-LTP requires a transient increase in intracellular Ca(2+) concentration and, in contrast to PF-LTD, is induced without concomitant climbing fiber (CF) activation. Thus, it has been postulated that the polarity of long-term synaptic plasticity is determined by the amplitude of the Ca(2+) transient during the induction protocol, with PF-LTP induced by smaller Ca(2+) signals without concomitant CF activation. However, this hypothesis is contradicted by recent studies. A quantitative analysis of Ca(2+) signals associated with induction of PF-LTP indicates that the bidirectional induction of long-term plasticity is regulated by more complex mechanisms. Here we review the state-of-the-art of research on postsynaptic PF-LTP and PF-LTD and discuss the principal open questions on this topic.

Fig.1

Protocols that induce postsynaptic PF-LTP. (a) One-pulse induced parallel PF-LTP: one PF stimulus repeated every second for five minutes. Characterised in brain slices of the rat at postnatal days 17–21 [11] and 18–27 [12]. (b) Burst induced parallel PF-LTP: A train of 7 PF stimuli at 100 Hz repeated every second for one minutes. Characterised in brain slices of the mouse at postnatal days 25-25, resistant to block of GABAA receptors, NMDA receptors and mGluR1 [14]. (c) Single-train induced parallel PF-LTP: One train of 15 PF stimuli at 100 Hz. Characterised in the mouse in vivo at postnatal months 5–8, abolished by blocking mGluR1 [19].

Fig.2

Schematic of four [Ca²⁺]_i signals associated with excitatory synaptic transmission. (a) Associated with glutamate release from presynaptic terminals and depolarisation due to AMPA receptor (AMPAR) activation, [Ca²⁺]_i can elevate via Ca²⁺ entry through VGCCs (signals b and c), via Ca²⁺ release from stores triggered by mGluR1 activation and InsP3 (signal d) and via Ca²⁺ entry through TRPC3 triggered by mGluR1 activation (signal e). (b) [Ca²⁺]_i signal associated with one calcium spike: peak ~100–200 nM, duration ~10 ms; estimate from [14]. (c) [Ca²⁺]_i signal associated with a burst of 6 calcium spikes at 100 Hz (calcium bursts): peak 0.5-2 μM, duration ~80 ms; estimate from [14]. (d) [Ca²⁺]_i signal mediated by mGluR1 and Ca²⁺ release from stores (fast mGluR1): peak: ~1 μM, delay from mGluR1 activation ~50 ms, duration ~100 ms; estimate from [26]. (e) [Ca²⁺]_i signal mediated by mGluR1 and slow Ca²⁺ influx (slow mGluR1): peak: ~100–200 nM, time-to-peak from mGluR1 activation ~0.5-1s, duration ~1s; estimate from [26, 30]. (f) The four [Ca²⁺]_i signals normalised in amplitude and superimposed.

Fig.3

Possible spatial arrangement of two simultaneously active CGC-PN synapses. (a) Schematic of a sagittal/coronal section of the cerebellum with Molecular Layer (ML), PN Layer (PNL) and Granule Cell layer (GCL); PF stimulation: stimulation in the ML; AF stimulation: stimulation in the GCL behind the PN. (b) Adjacent: afferents contacting two adjacent spines in the same dendritic branch allowing for chemical crosstalk between the two synapses. (c) Same branch: afferents contacting non-adjacent spines but in the same dendritic branch allowing for local depolarisation of the dendrite. (d) Different branches: afferents contacting two different dendritic branches.