Abstract
The parallel fiber-Purkinje cell (PF-PC) synapse represents the point of maximal signal divergence in the cerebellar cortex with an estimated number of about 60 billion synaptic contacts in the rat and 100,000 billions in humans. At the same time, the Purkinje cell dendritic tree is a site of remarkable convergence of more than 100,000 parallel fiber synapses. Parallel fiber activity generates fast postsynaptic currents via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and slower signals, mediated by mGlu1 receptors, resulting in Purkinje cell depolarization accompanied by sharp calcium elevation within dendritic regions. Long-term depression (LTD) and long-term potentiation (LTP) have been widely described for the PF-PC synapse and have been proposed as mechanisms for motor learning. The mechanisms of induction for LTP and LTD involve different signaling mechanisms within the presynaptic terminal and/or at the postsynaptic site, promoting enduring modification in the neurotransmitter release and change in responsiveness to the neurotransmitter. The PF-PC synapse is finely modulated by several neurotransmitters, including serotonin, noradrenaline and acetylcholine. The ability of these neuromodulators to gate LTP and LTD at the PF-PC synapse could, at least in part, explain their effect on cerebellar-dependent learning and memory paradigms. Overall, these findings have important implications for understanding the cerebellar involvement in a series of pathological conditions, ranging from ataxia to autism. For example, PF-PC synapse dysfunctions have been identified in several murine models of spino-cerebellar ataxia (SCA) types 1, 3, 5 and 27. In some cases, the defect is specific for the AMPA receptor signaling (SCA27), while in others the mGlu1 pathway is affected (SCA1, 3, 5). Interestingly, the PF-PC synapse has been shown to be hyper-functional in a mutant mouse model of autism spectrum disorder, with a selective deletion of Pten in Purkinje cells. However, the full range of methodological approaches, that allowed the discovery of the physiological principles of PF-PC synapse function, has not yet been completely exploited to investigate the pathophysiological mechanisms of diseases involving the cerebellum. We, therefore, propose to extend the spectrum of experimental investigations to tackle this problem.
Highlights
While the physiological mechanisms of the parallel fiber-Purkinje cell (PF-PC) synapse are known in detail and its plasticity has been investigated in depth, the role, mechanisms and consequences of cerebellar neuromodulation are not completely known
Only Gq is required for the generation of PF-mGlu1-excitatory post-synaptic current (EPSC) (Hartmann et al, 2004); but its downstream pathway leading to the activation of phospholipase C (PLC), IP3 or protein kinase C (PKC) is not involved (Tempia et al, 1998; Canepari et al, 2001)
The optogenetic activation of climbing fiber (CF), mimicking the visual error signals provided by retinal slip, was able to induce vestibulo-ocular reflex (VOR)-increase but not VOR-decrease learning. These results indicate that the CF activity and the plasticity of the PC responses are not so correlated during VOR-decrease training, as they are during VOR-increase learning
Summary
While the physiological mechanisms of the parallel fiber-Purkinje cell (PF-PC) synapse are known in detail and its plasticity has been investigated in depth, the role, mechanisms and consequences of cerebellar neuromodulation are not completely known. PCs selectively express G proteins of the Gq subclass (Tanaka et al, 2000), and more precisely Gq and Galpha (Tanaka et al, 2000) Among these two proteins, only Gq is required for the generation of PF-mGlu1-EPSC (Hartmann et al, 2004); but its downstream pathway leading to the activation of PLC, IP3 or protein kinase C (PKC) is not involved (Tempia et al, 1998; Canepari et al, 2001). Studies of in vitro preparations (i.e., cerebellar slices and cultures) have provided further insight into the cellular and molecular mechanisms of LTD (Ito, 2002) These studies indicate that PF-LTD requires the Ca2+ influx through P/Q voltage-gated channels, triggered by the CF-evoked depolarization, together with the release of glutamate by PFs, which acts upon both mGlu metabotropic receptors and AMPA receptors (Figure 1A). The MAPK-PKC positive feedback loop is likely responsible for the sustained PKC activation and the maintenance of LTD (Yamamoto et al, 2012)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
