Abstract
Protein phosphatase 2B (PP2B) is critical for synaptic plasticity and learning, but the molecular mechanisms involved remain unclear. Here we identified different types of proteins that interact with PP2B, including various structural proteins of the postsynaptic densities (PSDs) of Purkinje cells (PCs) in mice. Deleting PP2B reduced expression of PSD proteins and the relative thickness of PSD at the parallel fiber to PC synapses, whereas reexpression of inactive PP2B partly restored the impaired distribution of nanoclusters of PSD proteins, together indicating a structural role of PP2B. In contrast, lateral mobility of surface glutamate receptors solely depended on PP2B phosphatase activity. Finally, the level of motor learning covaried with both the enzymatic and nonenzymatic functions of PP2B. Thus, PP2B controls synaptic function and learning both through its action as a phosphatase and as a structural protein that facilitates synapse integrity.SIGNIFICANCE STATEMENT Phosphatases are generally considered to serve their critical role in learning and memory through their enzymatic operations. Here, we show that protein phosphatase 2B (PP2B) interacts with structural proteins at the synapses of cerebellar Purkinje cells. Differentially manipulating the enzymatic and structural domains of PP2B leads to different phenotypes in cerebellar learning. We propose that PP2B is crucial for cerebellar learning via two complementary actions, an enzymatic and a structural operation.
Highlights
The maintenance and modulation of synaptic transmission are critical for virtually all brain functions, varying from online control of perception and action up to long-term processes, such as memory formation and retrieval
To assess the potential influence of a lack of PP2B on the postsynaptic density at the parallel fiber (PF) inputs to Purkinje cells (PCs) beyond the age of 5 months (Schonewille et al, 2010), we investigated these synapses of lobules 3 and 9 in 6- to 8-month-old L7-PP2B KO mice and WT littermates at the EM level
AMPAR mobility depends on PP2B phosphatase activity Given that the function of synapses is affected by the lateral mobility of their glutamate receptors (Heine et al, 2008; Penn et al, 2017), we examined to what extent the mobility of GluR2 was affected by pharmacological inhibition or genetic ablation of PP2B in cultured PCs
Summary
The maintenance and modulation of synaptic transmission are critical for virtually all brain functions, varying from online control of perception and action up to long-term processes, such as memory formation and retrieval. Depending on synaptic Ca21 influx and the resulting Ca21 levels, PP2B is activated and thought to functionally counteract protein kinases PKA and CaMKII, which together provide a complex phosphorylation/dephosphorylation signature of proteins (Stemmer and Klee, 1991). The precise phosphorylation state of AMPARs determines to what extent they will be subject to exocytosis or endocytosis (Jörntell and Hansel, 2006) Such a Ca21-dependent dynamic switch of the phosphorylation state of AMPARs has been postulated to determine the threshold and direction for the induction of long-term plasticity, that is, controlling the level of LTP or LTD ( referred to as the Bienenstock-Cooper-Munro plasticity rule) (Bienenstock et al, 1982), which has been validated in various brain regions. For cerebellar Purkinje cells (PCs), synaptic plasticity has been shown to depend on proper functioning of PP2B (Malleret et al, 2001; Zeng et al, 2001; Mansuy, 2003)
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
