A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression

Abstract

The expression of long-term depression (LTD) in cerebellar Purkinje cells results from the internalisation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) from the postsynaptic membrane. This process is regulated by a complex signalling pathway involving sustained protein kinase C (PKC) activation, inhibition of serine/threonine phosphatase, and an active protein tyrosine phosphatase, PTPMEG. In addition, two AMPAR-interacting proteins–glutamate receptor-interacting protein (GRIP) and protein interacting with C kinase 1 (PICK1)–regulate the availability of AMPARs for trafficking between the postsynaptic membrane and the endosome. Here we present a new computational model of these overlapping signalling pathways. The model reveals how PTPMEG cooperates with PKC to drive LTD expression by facilitating the effect of PKC on the dissociation of AMPARs from GRIP and thus their availability for trafficking. Model simulations show that LTD expression is increased by serine/threonine phosphatase inhibition, and negatively regulated by Src-family tyrosine kinase activity, which restricts the dissociation of AMPARs from GRIP under basal conditions. We use the model to expose the dynamic balance between AMPAR internalisation and reinsertion, and the phosphorylation switch responsible for the perturbation of this balance and for the rapid plasticity initiation and regulation. Our model advances the understanding of PF-PC LTD regulation and induction, and provides a validated extensible platform for more detailed studies of this fundamental synaptic process.

Dendritic spine geometry and spine apparatus organization govern the spatiotemporal dynamics of calcium

“…We model a single dendritic spine of a rat hippocampal area CA1 pyramidal neuron as an isolated system, because we focus on the 10- to 100-ms timescale and the ability of the spine neck to act as a diffusion barrier for calcium ( Yuste and Denk, 1995 ; Bloodgood and Sabatini, 2005 ; Byrne et al, 2011 ; Gallimore et al, 2016 ). As a result, we do not consider calcium dynamics due to the mitochondria.…”

Switching On Depression and Potentiation in the Cerebellum

“…Under basal conditions, these phosphatases actively suppress the key components of the feedback loop and prevent its spontaneous activation. Indeed, PP2A inhibition alone will elicit robust PF-PC LTD (Launey et al, 2004), presumably resulting from spontaneous loop activation, in addition to unopposed AMPAR-GluA2-S880 phosphorylation (Kohda et al, 2013;Gallimore et al, 2016). Inhibition of PP1, in contrast, has no effect (Launey et al, 2004).…”

Flexible and adaptive processes in speech perception

“…For example, in other domains, supervised learning is thought to result from long-term depression of parallel fiber-purkinje cell synapses (and long-term potentiation of parallel fiber and interneuron synapses) in the cerebellum (De Zeeuw et al, 1998;Ito, 2002;Jorntell, 2016;Hirano, Yamazaki & Nakamura, 2016), implicating γ-aminobutyric acid (GABA-ergic) dependent plasticity (e. g., Lee et al, 2015). Phosphorylation mechanisms that are dependent on sustained protein kinase activation may regulate AMPA receptor internalization and long-term depression in the cerebellum, as suggested recent neurobiological computational (Gallimore et al, 2016). If these mechanisms apply to other domains, including speech perception, adapting perception to distorted sensory input, may involve neurobiological changes that occur over time and thus do not contribute to immediate effects of context on flexibility in perception.…”