Long-term depression of climbing fiber-evoked calcium transients in Purkinje cell dendrites

Abstract

In recent years much has been learned about the molecular requirements for inducing long-term synaptic depression (LTD) in various brain regions. However, very little is known about the consequences of LTD induction for subsequent signaling events in postsynaptic neurons. We have addressed this issue by examining homosynaptic LTD at the cerebellar climbing fiber (CF)-Purkinje cell (PC) synapse. This synapse is built for reliable and massive excitation: Activation of a single axon produces an unusually large ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-mediated synaptic current, the depolarization of which drives a regenerative complex spike producing a large, widespread Ca 2؉ transient in PC dendrites. Here we test whether CF LTD has an impact on dendritic, complex spikeevoked Ca 2؉ signals by simultaneously performing long-term recordings of complex spikes and microfluorimetric Ca 2؉ measurements in PC dendrites in rat cerebellar slices. Our data show that LTD of the CF excitatory postsynaptic current produces a reduction in both slow components of the complex spike waveform and complex spikeevoked dendritic Ca 2؉ transients. This LTD of dendritic Ca 2؉ signals may provide a neuroprotective mechanism and͞or constitute ''heterosynaptic metaplasticity'' by reducing the probability for subsequent induction of those forms of use-dependent plasticity, which require CF-evoked Ca 2؉ signals such as parallel fiber-PC LTD and interneuron-PC LTP.I n the adult mammalian brain, Purkinje cells (PCs) receive two types of excitatory synaptic input: (i) from numerous parallel fibers (PFs), which are the axons of granule cells, and (ii) from a single climbing fiber (CF), which originates from the inferior olive. The PFs primarily form synaptic contacts at the distal compartments of the PC dendrite as well as at spiny branchlets of more proximal compartments, whereas the CF predominately contacts the proximal compartment at the primary dendrite via spines found in this region at low density (1-3). The CF input is extremely powerful, consisting of Ϸ1,400 release sites (4) that are characterized by a high release probability (5, 6). Accordingly, CF activation produces a strong postsynaptic depolarization that is mediated by ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and evokes an all-or-none spike with multiple peaks. These ''complex spikes'' are accompanied by a large Ca 2ϩ transient covering broad regions of the PC dendritic tree (7-10). Complex spikes, as recorded at the soma, are characterized by an initial, fast spike component followed by a series of smaller spikelets riding on top of a plateau. It has been suggested that the fast component is a somatically generated Na ϩ spike, whereas the following slower components are produced mainly by dendritic Ca 2ϩ conductances (11, 12). More recently it has been shown that isolated PC somata can fire repetitive spike patterns on their own that are mediated by a ''resurgent'' Na ϩ current (13). Thus, it is likely that both Ca 2ϩ and Na ϩ ...

Alcohol Potently Modulates Climbing Fiber→Purkinje Neuron Synapses: Role of Metabotropic Glutamate Receptors

“…LTD was induced by stimulating the CF at 5 Hz for 30 s, as described previously (Weber et al, 2003).…”

“…CF-dependent Ca 2ϩ elevations induce parallel fiber LTD, which has a higher Ca 2ϩ threshold than parallel fiber long-term potentiation (LTP) (Coesmans et al, 2004). CF LTD is associated with decreased dendritic Ca 2ϩ transients in PNs, and this increases the probability of parallel fiber LTP induction (Weber et al, 2003;Coesmans et al, 2004). By inhibiting CF LTD, EtOH could increase the probability of parallel fiber LTD induction.…”

Dendritic Calcium Signaling Triggered by Spontaneous and Sensory-Evoked Climbing Fiber Input to Cerebellar Purkinje Cells In Vivo

“…Accordingly, the CF signal has been proposed to act as a global signal integrating and controlling parallel fiber signals and their plasticity (Ito, 1984). The Ca 2ϩ signal triggered by CF input has also been shown to be crucial for long-term synaptic plasticity at CF synapses (Hansel and Linden, 2000;Weber et al, 2003).…”

Kv3.3 Channels at the Purkinje Cell Soma Are Necessary for Generation of the Classical Complex Spike Waveform

“…PCs possess multiple intrinsic somatic and dendritic conductances that may interact with synaptic inputs to sculpt membrane voltage signals (Llinas and Sugimori, 1980a,b;Raman and Bean, 1997;Womack and Khodakhah, 2002;Swensen and Bean, 2003;McKay and Turner, 2004;Khavandgar et al, 2005). However, discrepancies remain regarding the ionic mechanisms responsible for the generation of the complex spike, including whether spikelets are generated at somatic or dendritic membranes and, more generally, the importance of somatic versus dendritic excitability to the somatic complex spike waveform (Callaway et al, 1995;Callaway and Ross, 1997;Hansel and Linden, 2000;Schmolesky et al, 2002;Weber et al, 2003;Davie and Hausser, 2004).…”